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  • 1.
    Bally, M
    et al.
    Chalmers.
    Gunnarsson, A
    Chalmers.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Larson, G
    University of Gothenburg.
    Zhdanov, V P
    Chalmers.
    Hook, F
    Chalmers.
    Interaction of Single Viruslike Particles with Vesicles Containing Glycosphingolipids2011In: Physical Review Letters, ISSN 0031-9007, E-ISSN 1079-7114, Vol. 107, no 18, p. 188103-Article in journal (Refereed)
    Abstract [en]

    Glycosphingolipids are involved in the first steps of virus-cell interaction, where they mediate specific recognition of the host cell membrane. We have employed total-internal-reflection fluorescence microscopy to explore the interaction kinetics between individual unlabeled noroviruslike particles, which are attached to a glycosphingolipid-containing lipid bilayer, and fluorescent vesicles containing different types and concentrations of glycosphingolipids. Under association equilibrium, the vesicle-binding rate is found to be kinetically limited, yielding information on the corresponding activation energy. The dissociation kinetics are logarithmic over a wide range of time. The latter is explained by the vesicle-size-related distribution of the dissociation activation energy. The biological, pharmaceutical, and diagnostic relevance of the study is briefly discussed.

  • 2.
    Bally, Marta
    et al.
    Chalmers, Sweden .
    Rydell, Gustaf E.
    Institute Curie, France .
    Zahn, Raphael
    University of Zurich, Switzerland Swiss Federal Institute Technology, Switzerland .
    Nasir, Waqas
    University of Gothenburg, Sweden .
    Eggeling, Christian
    Max Planck Institute Biophys Chemistry, Germany .
    Breimer, Michael E.
    University of Gothenburg, Sweden .
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Hook, Fredrik
    Chalmers, Sweden .
    Larson, Gran
    University of Gothenburg, Sweden .
    Norovirus GII.4 Virus-like Particles Recognize Galactosylceramides in Domains of Planar Supported Lipid Bilayers2012In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 51, no 48, p. 12020-12024Article in journal (Refereed)
    Abstract [en]

    n/a

  • 3.
    Becker-Dreps, Sylvia
    et al.
    University of N Carolina, NC 27599 USA.
    Bucardo, Filemon
    National Autonomous University of Nicaragua, Nicaragua.
    Vilchez, Samuel
    National Autonomous University of Nicaragua, Nicaragua.
    Enrique Zambrana, Luis
    Centre Epidemiol and Health CIDS, Nicaragua.
    Liu, Lan
    University of N Carolina, NC USA.
    Weber, David J.
    University of N Carolina, NC 27599 USA.
    Pena, Rodolfo
    Centre Health Research CIS, Nicaragua.
    Barclay, Leslie
    Centre Disease Control and Prevent, GA USA.
    Vinje, Jan
    Centre Disease Control and Prevent, GA USA.
    Hudgens, Michael G.
    University of N Carolina, NC USA.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Morgan, Douglas R.
    University of N Carolina, NC 27599 USA; Vanderbilt University, TN 37235 USA.
    Espinoza, Felix
    National Autonomous University of Nicaragua, Nicaragua.
    Paniagua, Margarita
    National Autonomous University of Nicaragua, Nicaragua.
    Etiology of Childhood Diarrhea After Rotavirus Vaccine Introduction A Prospective, Population-based Study in Nicaragua2014In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 33, no 11, p. 1156-1163Article in journal (Refereed)
    Abstract [en]

    Background: Nicaragua was the first developing nation to implement routine immunization with the pentavalent rotavirus vaccine (RV5). In this RV5-immunized population, understanding infectious etiologies of childhood diarrhea is necessary to direct diarrhea treatment and prevention efforts. Methods: We followed a population-based sample of children less than5 years in Leon, Nicaragua for diarrhea episodes through household visits. Information was obtained on RV5 history and sociodemographics. Stool samples collected during diarrhea episodes and among healthy children underwent laboratory analysis for viral, bacterial and parasitic enteropathogens. Detection frequency and incidence of each enteropathogen was calculated. Results: The 826 children in the cohort experienced 677 diarrhea episodes during 607.5 child-years of exposure time (1.1 episodes per child-year). At least 1 enteropathogen was detected among 61.1% of the 337 diarrheal stools collected. The most common enteropathogens among diarrheal stools were: norovirus (20.4%), sapovirus (16.6%), enteropathogenic Escherichia coli (11.3%), Entamoeba histolytica/dispar (8.3%), Giardia lamblia (8.0%) and enterotoxigenic E. coli (7.7%), with rotavirus detected among 5.3% of diarrheal stools. Enteropathogenic Escherichia coli and enterotoxigenic E. coli were frequently detected among stools from healthy children. Among children with diarrhea, norovirus was more commonly detected among younger children (less than2 years) and G. lamblia was more commonly detected among older children (2-4 years). The mean age of rotavirus detection was 34.6 months. Conclusions: In this Central American community after RV5 introduction, rotavirus was not commonly detected among children with diarrhea. Prevention and appropriate management of norovirus and sapovirus should be considered to further reduce the burden of diarrheal disease.

  • 4.
    Bialowas, Sonja
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Hagbom, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Karlsson, Thommie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Sharma, Sumit
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-­Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Intracellularly expressed rotavirus NSP4 stimulates release of serotonin (5-HT) from human enterochromaffin cellsManuscript (preprint) (Other academic)
    Abstract [en]

    Rotavirus (RV) is associated with diarrhoea and vomiting, but the mechanisms behind these symptoms remain unresolved. While RV have been shown to infect and stimulate secretion of serotonin (5-hydroxytryptamine; 5-HT) from human enterochromaffin (EC) cells and to infect EC cells in the small intestine of mice, it remains to identify which intracellularly expressed viral protein (VP) being responsible for this novel property.

    To address this issue, human EC cells were transfected with small interfering RNA (siRNA) targeting the structural (VP4, VP6 and VP7) and the non-structural protein 4 (NSP4) followed by infection with Rhesus rotavirus (RRV). siRNA specific to NSP4 (siRNANSP4) significantly attenuated secretion of 5-HT compared to siRNAVP4, siRNAVP6 , siRNAVP7 and non-targeting (Nt) siRNAnt. Intracellular calcium clamping with BABTA/AM showed that intracellularly expressed NSP4-stimulated secretion of 5-HT from EC cells was calcium-dependent. Furthermore RV down-regulated the 5-HT transporter (SERT) mRNA in ileum but not tryptophan hydroxylase 1 (TPH1) mRNA the rate-limiting enzyme for 5-HT synthesis. The unaffected expression of TPH1 mRNA in the intestinal segments suggests that release of 5- HT primarily originates from pre-made 5-HT rather than from newly synthesised 5-HT mRNA. Moreover, down-regulation of SERT mRNA in ileum presumably resulted in reduced re- uptake of 5-HT by SERT to EC cells and thus increased extracellular 5-HT in the small intestine. Moreover, 7/7 infant mice responded following intraperitoneal administration of 5-HT with rapid (<30 min) diarrhoea in dose-dependent manner. In the light of these results and the fact that both 5-HT and NSP4 can induce diarrhoea in mice, a disease mechanism to RV diarrhoea is proposed.

  • 5. Bucardo, F
    et al.
    Karlsson, B
    Nordgren, J
    Paniagua, M
    Gonzalez, A
    Amador, JJ
    Espinoza, F
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Mutated G4P[8] rotavirus associated with a nationwide outbreak of gastroenteritis in Nicaragua in 20052007In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 45, no 3, p. 990-997Article in journal (Refereed)
    Abstract [en]

    During February and March 2005, one of the largest national recorded outbreaks of severe acute gastroenteritis occurred in Nicaragua, affecting ≥64,000 individuals and causing ≥56 deaths, predominantly in children under 5 years of age. Through a nationwide laboratory-based study, stool samples were collected and investigated for rotavirus. Of 108 stool samples examined, 72 (67%) were positive for rotavirus. While 69% (50/72) of the positive samples were found in children less than 2 years of age, 50% (6/12) of the adult samples were positive. A mutated G4P[8] strain was the most commonly recognized strain (85%), followed by mixed G strains (8%) and G9P[8] (7%) strains. Phylogenetic analysis of the VP7 gene revealed that the G4 strains belonged to the emerging lineage Ic and was distantly related to the ST3 and VA70 G4 strains. Secondary structure predictions of the VP7 G4 protein revealed an insert of an asparagine residue in position 76, which, combined with additional mutations, surprisingly modified two downstream β-sheets at amino acid positions 80 to 85 and 115 to 119. The 2005 G4P[8] strain compared to a G4P[8] strain from 2002 had a substitution of an asparagine residue for threonine (Asn→Thr) at position 96 within antigenic region A, thus eliminating a potential glycosylation site. The mutated G4 virus was introduced in Nicaragua after 2002 and probably emerged from Brazil, Argentina, or Uruguay. Copyright © 2007, American Society for Microbiology. All Rights Reserved.

  • 6.
    Bucardo, Filemon
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Department of Microbiology, University of León, UNAN-León, Nicaragua.
    Carlsson, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Larson, Göran
    University of Gothenburg, Göteborg, Sweden.
    Blandon, Patricia
    Department of Microbiology University of León, Nicaragua (UNAN-León).
    Vilchez, Samuel
    Department of Microbiology University of León, Nicaragua (UNAN-León).
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Susceptibility of Children to Sapovirus Infections, Nicaragua, 2005–20062012In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 18, no 11, p. 1875-1878Article in journal (Refereed)
    Abstract [en]

    We describe the genetic diversity of sapovirus (SaV) in children in Nicaragua and investigate the role of host genetic factors and susceptibility to SaV infections. Our results indicate that neither ABO blood group, Lewis phenotype, nor secretor status affects susceptibility to SaV infection in Nicaragua.

  • 7.
    Bucardo, Filemon
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Kindberg, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Paniagua, Margarita
    Department of Microbiology, University of León, Nicaragua.
    Vildevall, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Genetic susceptibility to symptomatic norovirus infection in Nicaragua2009In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 81, no 4, p. 728-735Article in journal (Refereed)
    Abstract [en]

    Host genetic resistance to Norovirus (NoV) has been observed in challenge and outbreak studies in populations from Europe, Asia, and USA. In this study, we have investigated if histo-blood group antigens can predict susceptibility to diarrhea caused by NoV in Nicaragua, Central America, and if this can be reflected in antibody-prevalence and titer to NoV among individuals with different histo-blood group antigen phenotypes. Investigation of 28 individuals infected with NoV and 131 population controls revealed 6% of non-secretors in the population and nil non-secretors among patients infected with NoV, suggesting that non-secretors may be protected against NoV disease in Nicaragua. Surprisingly, 25% of the population was Lewis negative (Le(a-b-)). NoV infections with genogroup I (GI) and GII occurred irrespective of Lewis genotype, but none of the Lewis a positive (Le(a + b-)) were infected. The globally dominating GII.4 virus infected individuals of all blood groups except AB (n = 5), while the GI viruses (n = 4) infected only blood type O individuals. Furthermore, O blood types were susceptible to infections with GI.4, GII.4, GII.7, GII.17, and GII.18-Nica viruses, suggesting that secretors with blood type O are susceptible (OR = 1.52) and non-secretors resistant. The overall antibody-prevalence to NoV GII.3 VLP was 62% with the highest prevalence among blood type B carriers (70%) followed by A (68%) and O (62%). All four investigated individuals carrying blood type AB were antibody-negative. Among secretors, 63% were antibody-positive compared to 33% among non-secretors (P = 0.151). This study extends previous knowledge about the histo-blood group antigens role in NoV disease in a population with different genetic background than North American and European.

  • 8.
    Bucardo, Filemon
    et al.
    University of Leon.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Low Prevalence of Rotavirus and High Prevalence of Norovirus in Hospital and Community Wastewater after Introduction of Rotavirus Vaccine in Nicaragua2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 10Article in journal (Refereed)
    Abstract [en]

    Rotavirus (RV) and norovirus (NoV) are major causes of pediatric diarrhea and are altogether associated with approximately 800,000 deaths in young children every year. In Nicaragua, national RV vaccination program using the pentavalent RV5 vaccine from Merck was implemented in October 2006. To determine whether RV vaccination decreased the overall number of RV infections, we investigated the occurrence of RV and NoV in wastewater in the city of Leon from July 2007 to July 2008 and compared these data with pre-vaccination data. The major finding was the low prevalence of RV compared to NoV in all sampling points (11% vs 44%, pandlt;0.05), and that RV concentration was lower as compared to NoV. RV was observed mainly during the rainy season (July-September), and the majority of all RV detected (6/9) belonged to subgroup (SG) I. The partial VP7-gene obtained from one RV positive sample was similar (99% nt identity) to a G6 VP7-gene of bovine origin and similar to the corresponding gene of the vaccine strain (98%). Furthermore RV G-types 2 and 4 were found in the incoming wastewater. NoV strains were detected throughout the year, of which a majority (20/21) were of genotype GII.4. We conclude that the introduction of RV vaccination reduced the transmission of RV in the community in Nicaragua. However, the burden of diarrhea in the country remains high, and the high prevalence of NoVs in hospital and municipal wastewater is noteworthy. This study highlights the need for further assessment of NoV following RV vaccine introduction.

  • 9.
    Bucardo, Filemon
    et al.
    Department of Microbiology, University of León, UNAN-León, Nicaragua.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Carlsson, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Paniagua, Margarita
    Microbiology, Tumor and Cell Biology Centre, Karolinska Institutet, S-171 77 Stockholm, Sweden.
    Lindgren, Per-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Espinoza, Felix
    Department of Microbiology, University of León, UNAN-León, Nicaragua.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Pediatric norovirus diarrhea in Nicaragua2008In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 46, no 8, p. 2573-2580Article in journal (Refereed)
    Abstract [en]

    Information about norovirus (NoV) infections in Central America is limited. Through a passive community and hospital pediatric diarrhea surveillance program, a total of 542 stool samples were collected between March 2005 and February 2006 in León, Nicaragua. NoV was detected in 12% (65/542) of the children; of these, 11% (45/409) were in the community and 15% (20/133) were in the hospital, with most strains (88%) belonging to genogroup II. NoV infections were age and gender associated, with children of <2 years of age (P < 0.05) and girls (P < 0.05) being most affected. Breast-feeding did not reduce the number of NoV infections. An important proportion (57%) of NoV-infected children were coinfected with diarrheagenic Escherichia coli. A significant proportion (18/31) of NoV-positive children with dehydration required intravenous rehydration. Nucleotide sequence analysis (38/65) of the N-terminal and shell region in the capsid gene revealed that at least six genotypes (GI.4, GII.2, GII.4, GII.7, GII.17, and a potentially novel cluster termed "GII.18-Nica") circulated during the study period, with GII.4 virus being predominant (26/38). The majority (20/26) of those GII.4 strains shared high nucleotide homology (99%) with the globally emerging Hunter strain. The mean viral load was approximately 15-fold higher in children infected with GII.4 virus than in those infected with other G.II viruses, with the highest viral load observed for the group of children infected with GII.4 and requiring intravenous rehydration. This study, the first of its type from a Central American country, suggests that NoV is an important etiological agent of acute diarrhea among children of <2 years of age in Nicaragua.

  • 10.
    Bucardo, Filemon
    et al.
    University of Leon.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology . Linköping University, Faculty of Health Sciences.
    Paniagua, Margarita
    University of Leon.
    Mollby, Roland
    Karolinska Institute.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Asymptomatic Norovirus Infections in Nicaraguan Children and its Association With Viral Properties and Histo-blood Group Antigens2010In: PEDIATRIC INFECTIOUS DISEASE JOURNAL, ISSN 0891-3668, Vol. 29, no 10, p. 934-939Article in journal (Refereed)
    Abstract [en]

    Background: It has been previously reported that histo-blood group antigens (HBGAs) and particularly secretor status provides protection against symptomatic norovirus infection, but it remains unclear to what extent this includes asymptomatic infections in children. Methods: To explore whether HBGAs or certain viral genotypes are associated with asymptomatic norovirus infections in a pediatric population in Nicaragua, we investigated 163 children andlt;= 5 years of age, without a recent history of diarrhea (andlt;= 10 days). Results: Asymptomatic norovirus infections were observed in 11.7% (19/163), with children andlt;= 6 months of age being most frequently infected (16%). Of the 19 norovirus-positive children, 4 (21%) and 10 (53%) were infected with genogroups GI and GII, respectively, and 4 children (21%) were infected with viruses of both genogroups. Most children had andgt;= 10(6) viral genomes per gram of feces. Nucleotide sequence analysis (15/19) revealed uncommon genotypes, such as, GII. 7 (n = 5) and GII. 2 (n = 3). An interesting observation was the low frequency of norovirus GII. 4 strains among the asymptomatic children. AB blood type, Lewis a (Lea(a+b-)) phenotype and nonsecretor genotype (se(428)se(428)) were not found among the asymptomatic children, but they occurred in population controls. Conclusions: Frequency of asymptomatic norovirus infections was similar to that observed in symptomatic children from Nicaragua. Norovirus GII. 2 and GII. 7 were frequently detected but the globally dominating GII. 4 was infrequent. Host genetic factors previously observed to be associated with protection against symptomatic norovirus infection were not found in this study.

  • 11.
    Bucardo, Filemon
    et al.
    University of Leon UNAN Leon, Nicaragua .
    Reyes, Yaoska
    University of Leon UNAN Leon, Nicaragua .
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Predominance of Norovirus and Sapovirus in Nicaragua after Implementation of Universal Rotavirus Vaccination2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 5, p. e0098201-Article in journal (Refereed)
    Abstract [en]

    Background: Despite significant reduction of rotavirus (RV) infections following implementation of RotaTeq vaccination in Nicaragua, a large burden of patients with diarrhea persists. Methods: We conducted a community-and hospital-based study of the burden of RV, norovirus (NV) and sapovirus (SV) infections as cause of sporadic acute gastroenteritis (GE) among 330 children less than= 5 years of age between September 2009 and October 2010 in two major cities of Nicaragua with a RotaTeq coverage rate of 95%. Results: We found that NV, SV and RV infections altogether accounted for 45% of cases of GE. Notably, NV was found in 24% (79/330) of the children, followed by SV (17%, 57/330) and RV (8%, 25/330). The detection rate in the hospital setting was 27%, 15% and 14% for NV, SV and RV respectively, whereas in the community setting the detection rate of RV was less than 1%. Among each of the investigated viruses one particular genogroup or genotype was dominant; GII.4 (82%) for NV, GI (46%) for SV and G1P[8] (64%) in RV. These variants were also found in higher proportions in the hospital setting compared to the community setting. The GII.4.2006 Minerva strain circulating globally since 2006 was the most common among genotyped NV in this study, with the GII.4-2010 New Orleans emerging in 2010. Conclusions: This study shows that NV has become the leading viral cause of gastroenteritis at hospital and community settings in Nicaragua after implementation of RV vaccination.

  • 12.
    Bucardo, Filemon
    et al.
    University of Leon, Nicaragua .
    Rippinger, Christine M.
    NIAID, USA .
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Patton, John T.
    NIAID, USA .
    Vaccine-derived NSP2 segment in rotaviruses from vaccinated children with gastroenteritis in Nicaragua2012In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 12, no 6, p. 1282-1294Article in journal (Refereed)
    Abstract [en]

    Rotavirus (RV) vaccination programs have been established in several countries using the human-attenuated G1P[8] monovalent vaccine Rotarix (TM) (GlaxoSmithKline) and/or the human-bovine reassortant G1, G2, G3, G4, P[8] pentavalent vaccine Rotaleq (TM) (Merck). The efficacy of both vaccines is high (similar to 90%) in developed countries, but can be remarkably lower in developing countries. For example, a vaccine efficacy against severe diarrhea of only 58% was observed in a 2007-2009 Nicaraguan study using RotaTeq. To gain insight into the significant level of vaccine failure in this country, we sequenced the genomes of RVs recovered from vaccinated Nicaraguan children with gastroenteritis. The results revealed that all had genotype specificities typical for human RVs (11G1P[8], 1G3P[8]) and that the sequences and antigenic epitopes of the outer capsid proteins (VP4 and VP7) of these viruses were similar to those reported for RVs isolated elsewhere in the world. As expected, nine of the G1 P[8] viruses and the single G3P[8] virus had genome constellations typical of human G1 P[8] and G3P[8] RVs: G1/3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. However, two of the G1P[8] viruses had atypical constellations, G1-P[8]-I1-R1-C1-M1-A1-N2-T1-E1-H1, due to the presence of a genotype-2 NSP2 (N2) gene. The sequence of the N2 NSP2 gene was identical to the bovine N2 NSP2 gene of RotaTeq, indicating that the two atypical viruses originated via reassortment of human G1P[8] RVs with RotaTeq viruses. Together, our data suggest that the high level of vaccine failure in Nicaraguan is probably not due to antigenic drift of commonly circulating virus strains nor the emergence of new antigenetically distinct virus strains. Furthermore, our data suggest that the widespread use of the RotaTeq vaccine has led to the introduction of vaccine genes into circulating human RVs.

  • 13.
    Carlsson, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Kindberg, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Buesa, Javier
    University of Valencia.
    Rydell, Gustaf E
    Sahlgrenska University Hospital.
    Lidón, Marta Fos
    University of Valencia.
    Montava, Rebeca
    University of Valencia.
    Abu Mallouh, Reem
    University of Valencia.
    Grahn, Ammi
    Sahlgrenska University Hospital.
    Rodríguez-Díaz, Jesús
    University of Valencia.
    Bellido, Juan
    Centro de Salud Pública.
    Arnedo, Alberto
    Centro de Salud Pública.
    Larson, Göran
    Sahlgrenska University Hospital.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection.2009In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 5, p. e5593-Article in journal (Refereed)
    Abstract [en]

    In November 2004, 116 individuals in an elderly nursing home in El Grao de Castellón, Spain were symptomatically infected with genogroup II.4 (GII.4) norovirus. The global attack rate was 54.2%. Genotyping of 34 symptomatic individuals regarding the FUT2 gene revealed that one patient was, surprisingly, a non-secretor, hence indicating secretor-independent infection. Lewis genotyping revealed that Lewis-positive and negative individuals were susceptible to symptomatic norovirus infection indicating that Lewis status did not predict susceptibility. Saliva based ELISA assays were used to determine binding of the outbreak virus to saliva samples. Saliva from a secretor-negative individual bound the authentic outbreak GII.4 Valencia/2004/Es virus, but did not in contrast to secretor-positive saliva bind VLP of other strains including the GII.4 Dijon strain. Amino acid comparison of antigenic A and B sites located on the external loops of the P2 domain revealed distinct differences between the Valencia/2004/Es and Dijon strains. All three aa in each antigenic site as well as 10/11 recently identified evolutionary hot spots, were unique in the Valencia/2004/Es strain compared to the Dijon strain. To the best of our knowledge, this is the first example of symptomatic GII.4 norovirus infection of a Le(a+b-) individual homozygous for the G428A nonsense mutation in FUT2. Taken together, our study provides new insights into the host genetic susceptibility to norovirus infections and evolution of the globally dominating GII.4 viruses.

  • 14.
    Carlsson, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Larson, Göran
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Böttiger, Blenda
    Department of Virology, Statens Serum Institut, Copenhagen, Denmark.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Susceptibility to symptomatic sapovirus infection in Denmark is not associated with secretor or Lewis statusManuscript (preprint) (Other academic)
    Abstract [en]

    Background. Sapovirus (SaV) infections are increasing globally but there is no information available regarding factors determining susceptibility to SaV infections in the Caucasian population.

    Methods. Saliva samples were collected from 64 individuals with sapovirus gastroenteritis in Denmark between October 2008 and November 2010. These were genotyped for the FUT2 G428A nonsense mutation (secretor status) and phenotyped for ABO and Lewis histo-blood groups.

    Results. We found that neither secretor status nor Lewis phenotype, were associated with susceptibility to symptomatic infection with SaV. However, individuals of histo-blood groups B and AB had significantly lower risk to be infected (OR 0.18, p≤0.01 and OR 0.10, p<0.05, respectively). For 39 of the 64 SaV positive samples viral strains were genotyped and 41%, (16/39) belonged to genotype GI.2, 10% was GI.1 (4/39), 2.5% was GI.5 (1/39), 8% was GII.1 (3/39), 5% was GII.4 (2/39), 18% was GIV (7/39) and 15.5% was GV (6/39).

    Conclusion. This is the first report investigating the role of host genetic factors in SaV susceptibility in the Caucasian population. We found a reduced risk of infection in individuals with blood group B (and AB), but no association to the FUT2 G428A nonsense mutation determining secretor status nor to the Lewis status.

  • 15.
    Douagi, I.
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
    McInerney, G.M.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
    Hidmark, A.S.
    Miriallis, V.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
    Johansen, K.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Hedestam, G.B.K.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 77 Stockholm, Sweden, Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden.
    Role of interferon regulatory factor 3 in type I interferon responses in rotavirus-infected dendritic cells and fibroblasts2007In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 81, no 6, p. 2758-2768Article in journal (Refereed)
    Abstract [en]

    The main pathway for the induction of type I interferons (IFN) by viruses is through the recognition of viral RNA by cytosolic receptors and the subsequent activation of interferon regulatory factor 3 (IRF-3), which drives IFN-a/ß transcription. In addition to their role in inducing an antiviral state, type I IFN also play a role in modulating adaptive immune responses, in part via their effects on dendritic cells (DCs). Many viruses have evolved mechanisms to interfere with type I IFN induction, and one recently reported strategy for achieving this is by targeting IRF-3 for degradation, as shown for rotavirus nonstructural protein 1 (NSP1). It was therefore of interest to investigate whether rotavirus-exposed DCs would produce type I IFN and/or mature in response to the virus. Our results demonstrate that IRF-3 was rapidly degraded in rotavirus-infected mouse embryonic fibroblasts (MEFs) and type I IFN was not detected in these cultures. In contrast, rotavirus induced type I IFN production in myeloid DCs (mDCs), resulting in their activation. Type I IFN induction in response to rotavirus was reduced in mDCs from IRF-3-/- mice, indicating that IRF-3 was important for mediating the response. Exposure of mDCs to UV-treated rotavirus induced significantly higher type I IFN levels, suggesting that rotavirus-encoded functions also antagonized the response in DCs. However, in contrast to MEFs, this action was not sufficient to completely abrogate type I IFN induction, consistent with a role for DCs as sentinels for virus infection. Copyright © 2007, American Society for Microbiology. All Rights Reserved.

  • 16.
    Espinoza, F.
    et al.
    Department of Microbiology, University of León, León, Nicaragua.
    Bucardo, F.
    Department of Microbiology, University of León, León, Nicaragua.
    Paniagua, M.
    Department of Microbiology, University of León, León, Nicaragua.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Hallander, H.O.
    Swedish Institute for Infectious Disease Control, Solna, Sweden.
    Bondeson, K.
    Department of Medical Sciences, Section of Virology, Uppsala University, Uppsala, Sweden, Department of Clinical Virology, Karolinska University Hospital, SE 141 86 Stockholm, Sweden.
    Shifts of rotavirus G and P types in Nicaragua - 2001-20032006In: The Pediatric Infectious Disease Journal, ISSN 0891-3668, E-ISSN 1532-0987, Vol. 25, no 11, p. 1078-1080Article in journal (Refereed)
    Abstract [en]

    The present study reports the diversity of rotavirus strains circulating in León, Nicaragua during three years. There was a shift of G and P genotypes with increment of one specific genotype during the second most important peak of diarrhea occurring in the beginning of every year. © 2006 Lippincott Williams & Wilkins, Inc.

  • 17.
    Gunaydin, Gokce
    et al.
    Karolinska University Hospital, Sweden .
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Hammarstrom, Lennart
    Karolinska University Hospital, Sweden .
    Mutations in Toll-Like Receptor 3 Are Associated with Elevated Levels of Rotavirus-Specific IgG Antibodies in IgA-Deficient but Not IgA-Sufficient Individuals2014In: Clinical and Vaccine Immunology, ISSN 1556-6811, E-ISSN 1556-679X, Vol. 21, no 3, p. 298-301Article in journal (Refereed)
    Abstract [en]

    Double-stranded RNA (dsRNA) triggers immune-mediated responses through toll-like receptor 3 (TLR3), which is involved in innate antiviral defense. Low expression of TLR3 was recently suggested to contribute to susceptibility to rotavirus infection. Thus, we investigated the role of two TLR3 polymorphisms (rs3775291 and rs5743305), both of which resulted in reduced protein function or expression, in healthy blood donors and IgA-deficient (IgAD) individuals. These polymorphisms were associated with elevated rotavirus-specific IgG titers in IgAD individuals but not in healthy individuals. Thus, we propose that TLR3 signaling does not contribute to the rotavirus-specific antibody response in IgA-sufficient individuals, whereas it is associated with elevated antibody titers in IgAD individuals.

  • 18.
    Günaydın, Gökçe
    et al.
    Division of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Nordgren, Johan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine.
    Hammarström, Lennart
    Division of Clinical Immunology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
    TLR3-dependent antibody response against rotavirus in individuals with immunoglobulin A deficiency2013In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613Article in journal (Refereed)
  • 19.
    Hagbom, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Istrate, Claudia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology.
    Engblom, David
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Karlsson, Thommie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology.
    Rodriguez-Diaz, Jesus
    University of Valencia.
    Buesa, Javier
    University of Valencia.
    Taylor, John A
    University of Auckland.
    Loitto, Vesa
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Ahlman, Hakan
    University of Gothenburg.
    Lundgren, Ove
    University of Gothenburg.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Rotavirus Stimulates Release of Serotonin (5-HT) from Human Enterochromaffin Cells and Activates Brain Structures Involved in Nausea and Vomiting2011In: PLOS PATHOGENS, ISSN 1553-7366, Vol. 7, no 7Article in journal (Refereed)
    Abstract [en]

    otavirus (RV) is the major cause of severe gastroenteritis in young children. A virus-encoded enterotoxin, NSP4 is proposed to play a major role in causing RV diarrhoea but how RV can induce emesis, a hallmark of the illness, remains unresolved. In this study we have addressed the hypothesis that RV-induced secretion of serotonin (5-hydroxytryptamine, 5-HT) by enterochromaffin (EC) cells plays a key role in the emetic reflex during RV infection resulting in activation of vagal afferent nerves connected to nucleus of the solitary tract (NTS) and area postrema in the brain stem, structures associated with nausea and vomiting. Our experiments revealed that RV can infect and replicate in human EC tumor cells ex vivo and in vitro and are localized to both EC cells and infected enterocytes in the close vicinity of EC cells in the jejunum of infected mice. Purified NSP4, but not purified virus particles, evoked release of 5-HT within 60 minutes and increased the intracellular Ca(2+) concentration in a human midgut carcinoid EC cell line (GOT1) and ex vivo in human primary carcinoid EC cells concomitant with the release of 5-HT. Furthermore, NSP4 stimulated a modest production of inositol 1,4,5-triphosphate (IP(3)), but not of cAMP. RV infection in mice induced Fos expression in the NTS, as seen in animals which vomit after administration of chemotherapeutic drugs. The demonstration that RV can stimulate EC cells leads us to propose that RV disease includes participation of 5-HT, EC cells, the enteric nervous system and activation of vagal afferent nerves to brain structures associated with nausea and vomiting. This hypothesis is supported by treating vomiting in children with acute gastroenteritis with 5-HT(3) receptor antagonists.

  • 20.
    Hagbom, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ge, Ray
    School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
    Lundin, Samuel
    Department of Microbiology and Immunology, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
    Wigzell, Hans
    Microbiology & Tumor biology Center, Karolinska Institute, Stockholm, Sweden.
    Taylor, John A
    School of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand.
    Andersson, Ulf
    Department of Women's and Children's Health, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    The Cholinergic Anti-Inflammatory Pathway Contributes to the Limited Inflammatory Response following Rotavirus InfectionManuscript (preprint) (Other academic)
    Abstract [en]

    Rotavirus causes acute gastroenteritis in young children and is characterized by severe diarrhoea and vomiting. Surprisingly, although rotavirus infection results in significant intestinal pathology, the inflammatory response is limited. We tested the novel hypothesis that rotavirus infection stimulates the cholinergic anti-inflammatory pathway to suppress gut inflammation. The role of the vagus nerve and the α7 nicotinic acetylcholine receptor (α7 nAChR) in rotavirus infection were explored in α7 nAChR gene-deficient mice, vagotomized mice and wild-type mice treated with the α7 nAChR antagonist mecamylamine. TNF-α, IL-1β and IL-6 were measured in serum, spleen, duodenum, jejunum and ileum at 48 hours post infection. To determine if modulation of the inflammatory response affects virus shedding, α7 nAChRs was blocked and virus quantified in faeces. To investigate if stimulation of α7 nAChRs could attenuate rotavirus toxin NSP4-induced cytokine release, mouse peritoneal- and human blood-macrophages were treated with nicotine before NSP4 stimulation.

    Our results shows that stimulation of the vagus nerve and α7 nAChRs attenuated the pro- inflammatory response during rotavirus infection and blockade of the α7 nAChR reduced virus shedding from infected mice. IL-6 was increased in duodenum (p<0.05) and serum (p<0.05) of vagotomized mice and in jejunum (p<0.05) and spleen (p<0.05) of α7 nAChR gene-deficient mice. Furthermore, IL-6 mRNA (p<0.01) and TNF-α mRNA (p<0.05) were increased in duodenum of vagotomized animals. Similarly, nicotine attenuated the release of TNF-α (p<0.05) and IL-6 (p<0.05) from macrophages stimulated by NSP4 in vitro, all suggesting that the cholinergic anti- inflammatory pathway contributes to attenuate inflammation during rotavirus infection.

  • 21.
    Hagbom, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nybom, Rolf
    Karolinska Institute, Sweden.
    Hedlund, Kjell-Olof
    Swedish Institute Communicable Disease Control, Sweden.
    Wigzell, Hans
    Karolinska Institute, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ionizing air affects influenza virus infectivity and prevents airborne-transmission2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, no 11431Article in journal (Refereed)
    Abstract [en]

    By the use of a modified ionizer device we describe effective prevention of airborne transmitted influenza A (strain Panama 99) virus infection between animals and inactivation of virus (greater than 97%). Active ionizer prevented 100% (4/4) of guinea pigs from infection. Moreover, the device effectively captured airborne transmitted calicivirus, rotavirus and influenza virus, with recovery rates up to 21% after 40 min in a 19 m(3) room. The ionizer generates negative ions, rendering airborne particles/aerosol droplets negatively charged and electrostatically attracts them to a positively charged collector plate. Trapped viruses are then identified by reverse transcription quantitative real-time PCR. The device enables unique possibilities for rapid and simple removal of virus from air and offers possibilities to simultaneously identify and prevent airborne transmission of viruses.

  • 22.
    Hagbom, Marie
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Sharma, Sumit
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Lundgren, Ove
    Gothenburg University, Sweden .
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Towards a human rotavirus disease model2012In: CURRENT OPINION IN VIROLOGY, ISSN 1879-6257, Vol. 2, no 4, p. 408-418Article in journal (Refereed)
    Abstract [en]

    While the clinical importance of human rotavirus (RV) disease is well recognized and potent vaccines have been developed, our understanding of how human RV causes diarrhoea, vomiting and death remains unresolved. The fact that oral rehydration corrects electrolyte and water loss, indicates that enterocytes in the small intestine have a functional sodium-glucose co-transporter. Moreover, RV infection delays gastric emptying and loperamide appears to attenuate RV diarrhoea, thereby suggesting activation of the enteric nervous system. Serotonin (5-HT) receptor antagonists attenuate vomiting in young children with gastroenteritis while zinc and enkephalinase inhibitors attenuate RV-induced diarrhoea. In this review we discuss clinical symptoms, pathology, histology and treatment practices for human RV infections and compile the data into a simplified disease model.

  • 23. Istrate, C
    et al.
    Douagi, I
    Charpilienne, A
    McInnerney, GM
    Hidmark, Å
    Johansen, K
    Larsson, Marie
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Magnusson, Karl-Eric
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology.
    Poncet, D
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Bone marrow dendritic cells internalize live RF-81 bovine rotavirus and rotavirus-like particles (RF 2/6-GFP-VLP and RF 8*2/6/7-VLP) but are only activated by live bovine rotavirus2007In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 65, no 6, p. 494-502Article in journal (Refereed)
    Abstract [en]

    Dendritic cells (DC) represent the link between innate and adaptive immunity. They are classified as antigen-presenting cells (APC) and can initiate and modulate the immune response. To investigate the interaction with DCs, live RF-81 bovine rotavirus strain (RFV) and rotavirus-like particles (rota-VLP), RF 2/6-GFP-VLP and rota RF 8*2/6/7-VLP, were added in vitro to murine bone marrow-derived DCs (bmDCs). Live RFV, RF 2/6-GFP-VLP and RF 8*2/6/7-VLP all bound to bmDC and were internalized but only live RFV stimulated phenotypic maturation of the bmDCs as shown by the upregulation of the co-stimulatory molecule CD86. Even though bmDCs internalized RF 2/6-GFP-VLP and RF 8*2/6/7-VLP as efficiently as live RFV, these rota-VLP were not able to activate the cells. Supernatants derived from bmDC cultures treated with live RFV, RF 2/6-GFP-VLP or RF 8*2/6/7-VLP were examined for TNF-α production. At 6, 18 and 24 h post-infection, TNF-α concentrations were significantly increased in cultures treated with live RFV and rota-VLP compared with untreated cultures. In conclusion, this study showed that live RF-81 bovine rotavirus strain was internalized and induced bmDCs activation, whereas both RF 2/6-GFP-VLP and RF 8*2/6/7-VLP were internalized by bmDCs without triggering their activation. © 2007 The Authors.

  • 24.
    Istrate, Claudia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Hinkula, Jorma
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Hammarström, Lennart
    Division of Clinical Immunology, Karolinska University Hospital, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Individuals with selective IgA deficiency resolve rotavirus disease and develop higher antibody titers ( IgG, IgG1) than IgA competent individuals2008In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 80, no 3, p. 531-535Article in journal (Refereed)
    Abstract [en]

    While IgA is proposed to be essential to control rotavirus disease, no information is available how IgA deficient individuals modulate rotavirus disease and immune responses. We report that individuals (n=62) with selective IgA deficiency ( IgA-D) (<0,05g/l) resolve rotavirus disease and show higher total IgG and IgG1 subclass antibody titers to rotavirus than IgA proficient individuals ( n=62) (GMT 18101 vs 4000 (p<0.005); 8463 vs 1691, (p<0.005). We conclude that IgA is not essential for resolving rotavirus infection in humans.

  • 25.
    Istrate, Claudia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Hagbom, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Vikström, Elena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Magnusson, Karl-Eric
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Rotavirus Infection Increases Intestinal Motility but Not Permeability at the Onset of Diarrhea2014In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 88, no 6, p. 3161-3169Article in journal (Refereed)
    Abstract [en]

    The disease mechanisms associated with onset and secondary effects of rotavirus (RV) diarrhea remain to be determined and may not be identical. In this study, we investigated whether onset of RV diarrhea is associated with increased intestinal permeability and/or motility. To study the transit time, fluorescent fluorescein isothiocyanate (FITC)-dextran was given to RV-infected adult and infant mice. Intestinal motility was also studied with an opioid receptor agonist (loperamide) and a muscarinic receptor antagonist (atropine). To investigate whether RV increases permeability at the onset of diarrhea, fluorescent 4- and 10-kDa dextran doses were given to infected and noninfected mice, and fluorescence intensity was measured subsequently in serum. RV increased transit time in infant mice. Increased motility was detected at 24 h postinfection (h p.i.) and persisted up to 72 h p.i in pups. Both loperamide and atropine decreased intestinal motility and attenuated diarrhea. Analysis of passage of fluorescent dextran from the intestine into serum indicated unaffected intestinal permeability at the onset of diarrhea (24 to 48 h p.i.). We show that RV-induced diarrhea is associated with increased intestinal motility via an activation of the myenteric nerve plexus, which in turn stimulates muscarinic receptors on intestinal smooth muscles.

  • 26.
    Istrate, Claudia
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Charpilienne, Annie
    Poncet, Didier
    Cohen, Jean
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Johansen, Kari
    Parenteral administration of RF 8-2/6/7 rotavirus-like particles in a one-dose regimen induce protective immunity in mice2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 35, p. 4594-4601Article in journal (Refereed)
    Abstract [en]

    Rotavirus virus-like particles (RV-VLPs) represent a novel strategy for development of a rotavirus subunit vaccine. In this study, RF 8-2/6/7-VLPs with rotavirus VP8 protein (amino acid 1-241 of VP4) fused to the amino terminal end of a truncated VP2, were evaluated for their immunogenic and protective properties. A single intramuscular dose of, either 2 or 20 μg, RF 8-2/6/7-VLPs alone or combined with a potent adjuvant poly[di(carboxylatophenoxy)]phosphazene] (PCPP) induced rotavirus-specific serum IgG and IgA, fecal IgG titers that were enhanced 5-90-fold by adjuvant. Passive protective immunity was achieved in offspring to dams vaccinated with 2 and 20 μg RV-VLPs in presence of adjuvant and 20 μg RV-VLP without adjuvant. © 2008 Elsevier Ltd. All rights reserved.

  • 27. Johansson, E.
    et al.
    Istrate, Claudia
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine.
    Charpilienne, A.
    Cohen, J.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Poncet, D.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Johansen, K.
    Amount of maternal rotavirus-specific antibodies influence the outcome of rotavirus vaccination of newborn mice with virus-like particles2008In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 26, no 6, p. 778-785Article in journal (Refereed)
    Abstract [en]

    In presence of low or high levels of rotavirus-specific maternal antibodies, the ability of newborn mice to respond to immunization with rotavirus RF 8*-2/6/7 VLPs, was evaluated. After parenteral vaccination, 100% of offspring born to low-antibody-titer dams developed rotavirus-specific IgG antibodies (n = 7). In contrast, only 25% of offsprings born to high-antibody-titer dams responded to parenteral immunization (n = 12). When comparing parenteral versus oral immunization in offspring to low-antibody-titer dams only 45% responded after oral immunization (n = 6). In conclusion, the response to parenteral immunization was not hampered by the presence of low levels of maternal antibodies induced by a natural infection while oral immunization was impaired. However, high levels of maternal antibodies impaired the response to parenteral immunization. © 2008 Elsevier Ltd. All rights reserved.

  • 28.
    Jonsson, Nina
    et al.
    Linnaeus University, Sweden .
    Wahlström, Kristin
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Serrander, Lena
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Lindberg, A. Michael
    Linnaeus University, Sweden .
    Aichi virus infection in elderly people in Sweden2012In: Archives of Virology, ISSN 0304-8608, E-ISSN 1432-8798, Vol. 157, no 7, p. 1365-1369Article in journal (Refereed)
    Abstract [en]

    Aichi virus (AiV), genus Kobuvirus, family Picornaviridae, is associated with gastroenteritis in humans. Previous studies have shown high seroprevalence but low incidence (0.9-4.1%) in clinical samples. We report here the first detection of AiV in Sweden. Two hundred twenty-one specimens from hospitalized patients with diarrhea, who were negative for other enteric viruses, were included in the study. AiV were detected in three specimens, all from elderly patients. Phylogenetic analysis revealed that the three Swedish isolates belonged to genotype A and were genetically closest to European and Asian strains of AiV.

  • 29.
    Karlsson, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Michael Lindberg, A
    University of Kalmar.
    Rodriguez-Diaz, Jesus
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Hedlund, Kjell-Olof
    Swedish Institute for Infectious Disease Control.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics . Linköping University, The Institute of Technology.
    Svensson , Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Quasispecies dynamics and molecular evolution of human norovirus capsid P region during chronic infection2009In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 90, p. 432-441Article in journal (Refereed)
    Abstract [en]

    In this novel study, we have for the first time identified evolutionarily conserved capsid residues in an individual chronically infected with norovirus (GGII.3). From 2000 to 2003, a total of 147 P1-1 and P2 capsid sequences were sequenced and investigated for evolutionarily conserved and functionally important residues by the evolutionary trace (ET) algorithm. The ET algorithm revealed more absolutely conserved residues (ACR) in the P1-1 domain (47/53, 88 %) as compared with the P2 domain (86/133, 64 %). The capsid P1-1 and P2 domains evolved in time-dependent manner, with a distinct break point observed between autumn/winter of year 2000 (isolates P1, P3 and P5) and spring to autumn of year 2001 (isolates P11, P13 and P15), which presumably coincided with a change of clinical symptoms. Furthermore, the ET analysis revealed a similar receptor-binding pattern as reported for Norwalk and VA387 strains, with the CS-4 and CS-5 patch (Norwalk strain) including residues 329 and 377 and residues 306 and 310, respectively, all being ACR in all partitions. Most interesting was that residues 343, 344, 345, 374, 390 and 391 of the proposed receptor A and B trisaccharide binding site (VA387 strain) within the P2 domain remained ACR in all partitions, presumably because there was no selective advantage to alter the histo blood group antigens (HBGA) receptor binding specificity. In conclusion, this study provides novel insights to the evolutionary process of norovirus during chronic infection.

  • 30.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Ax, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Fiore, Lucia
    Ist Super Sanita.
    Svensson , Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Ala67Thr Mutation in the Poliovirus Receptor CD155 is a Potential Risk Factor for Vaccine and Wild-Type Paralytic Poliomyelitis2009In: JOURNAL OF MEDICAL VIROLOGY, ISSN 0146-6615 , Vol. 81, no 5, p. 933-936Article in journal (Refereed)
    Abstract [en]

    Poliovirus infections can be asymptomatic or cause severe paralysis. Why some individuals develop paralytic poliomyelitis is unknown, but a role for host genetic factors has been suggested. To investigate if a polymorphism, Ala67Thr, in the poliovirus receptor, which has been found to facilitate increased resistance against poliovirus-induced cell lysis and apoptosis, is associated with increased risk of paralytic poliomyelitis, poliovirus receptor genotyping was undertaken among Italian subjects with vaccine-associated (n = 9), or with wild-type paralytic poliomyelitis (n = 6), and control subjects (n = 71), using RFLP-PCR and pyrosequencing. Heterozygous poliovirus receptor Ala67Thr genotype was found in 13.3% of the patients with paresis and in 8.5% of the controls (Odds Ratio = 1.667). The frequency of Ala67Thr among the controls is in agreement with earlier published data. It is concluded that the Ala67Thr mutation in the poliovirus receptor is a possible risk factor for the development of vaccine-associated or paralytic poliomyelitis associated with wild-type virus.

  • 31.
    Kindberg, Elin
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Hejdeman, Bo
    Bratt, Göran
    Wahren, Britta
    Lindblom, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Forensic Genetics.
    Hinkula, Jorma
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    A nonsense mutation (428G→A) in the fucosyltransferase FUT2 gene affects the progression of HIV-1 infection2006In: AIDS (London), ISSN 0269-9370, E-ISSN 1473-5571, Vol. 20, no 5, p. 685-689Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The human FUT2 gene encodes the α(1,2)fucosyltransferase that determines secretor status. Homozygous for the nonsense mutation are called non-secretors and are unable to express histo-blood group antigens in secretions and on mucosal surfaces. In this study we have investigated the importance of the FUT2 fucosyltransferase activity on the progress of HIV-1 infection. METHODS: Swedish blood donors (n = 276), 15 long-term non-progressors (LTNP) and 19 progressors were genotyped with respect to the nonsense mutation 428G→A in the FUT2 gene. In addition 265/276 blood donors and 19 progressors with rapid or expected progression rate were Δ32 CCR5 genotyped. RESULTS: Of 276 blood donors 218 (79%) were found to be secretor positive (se+), either homozygous (se+/+) wild type (30%) or heterozygous (se+/-) (49%) and 58 (21%) were homozygous non-secretors (se-/-). Five LTNP (33%) were found to be secretor-positive (se+/+, se+/-) and 10 (67%) se-/-. Of the 19 individuals with normal HIV-1 progression 15 (79 %) were found to be secretor positive and four (21%) were non-secretors. No frequency differences were found in the Δ32 CCR5 allele among the groups studied. CONCLUSION: Strong association (P < 0.001) was observed between the nonsense mutation 428G→A in the FUT2 gene and a slow disease progression of HIV-1 infection. © 2006 Lippincott Williams & Wilkins.

  • 32.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Mickiene, Aukse
    Department of Medicine Karolinska University Hospital Huddinge.
    Ax, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Åkerlind, Britt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology . Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Vene, Sirkka
    5Swedish Institute for Infectious Disease Control Karolinska Institutet, Stockholm.
    Lindquist, Lars
    Department of Medicine Karolinska University Hospital Huddinge.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control Karolinska Institutet, Stockholm.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    A deletion in the chemokine receptor 5 (CCR5) gene is associated with tickborne encephalitis2008In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 197, no 2, p. 266-269Article in journal (Refereed)
    Abstract [en]

    Tickborne encephalitis (TBE) virus infections can be asymptomatic or cause moderate to severe injuries of the central nervous system. Why some individuals develop severe disease is unknown, but a role for host genetic factors has been suggested. To investigate whether chemokine receptor CCR5 is associated with TBE, CCR5Δ32 genotyping was performed among Lithuanian patients with TBE (n = 129) or with aseptic meningoencephalitis (n = 76) as well as among control subjects (n = 134). We found individuals homozygous for CCR5Δ32 (P = .026) only among patients with TBE and a higher allele prevalence among patients with TBE compared with the other groups studied. CCR5Δ32 allele prevalence also increased with the clinical severity of disease. © 2007 by the Infectious Diseases Society of America. All rights reserved.

  • 33.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Genetic basis of host resistance to norovirus infection2009In: FUTURE VIROLOGY, ISSN 1746-0794, Vol. 4, no 4, p. 369-382Article, review/survey (Refereed)
    Abstract [en]

    Noroviruses have emerged as a major cause of acute gastroenteritis in humans of all ages and are responsible for 200,000 deaths every year, mainly in developing countries. Despite high infectivity and lack of long-term immunity, authentic and volunteer studies have shown existence of inherited protective factors. Recent studies have shown that secretor status controlled by the alpha(1,2)-fucosyltransferase gene located on chromosome 19 determines susceptibility to most, if not all, norovirus infections, with individuals homozygous for the G428A nonsense mutation (nonsecretors) representing 20% of the highly protected European population.

  • 34.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Vene, Sirkka
    Swedish Institute Infectious Disease Control.
    Mickiene, Aukse
    Kaunas University of Medicine.
    Lundkvist, Ake
    Swedish Institute Infectious Disease Control.
    Lindquist, Lars
    Karolinska University.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    A Functional Toll-Like Receptor 3 Gene (TLR3) May Be a Risk Factor for Tick-borne Encephalitis Virus (TBEV) Infection2011In: JOURNAL OF INFECTIOUS DISEASES, ISSN 0022-1899, Vol. 203, no 4, p. 523-528Article in journal (Refereed)
    Abstract [en]

    Background. Tick-borne encephalitis virus (TBEV) infections may be asymptomatic or cause severe symptoms in the central nervous system. A mutation in the chemokine receptor 5 gene has been associated with increased risk of TBE but explains only a limited number of cases. Investigations of further risk factors are needed. Method. To investigate the importance of the innate immune response, we analyzed 128 TBE patients, 77 patients with aseptic meningoencephalitis (AME) and 135 healthy controls, for 3mutations: 2 in the Toll-like receptor 3 (TLR3) gene and 1 in the 2-5-oligoadenylate synthetase (OAS1) gene. Results. Although no association was found between the mutation in the OAS1 gene and TBE, the genotype distribution ofrs3775291, a mutation in TLR3, differed significantly between TBE patients and controls; 61%, 32%, and 7% of the TBE patients were carriers of the wild-type, heterozygous, and mutant genotype of rs3775291, respectively. The corresponding percentages among healthy controls (n = 126) were 52%, 29%, and 19% (P = .02), and among AME patients (n = 75) were 47%, 32%, and 21% (P = .009). Additionally, the wild-type rs3775291 allele was more common among TBE patients than among healthy controls (allele frequency, .768 vs .663; P = .01). Conclusion. A functional TLR3 is a risk factor for TBEV infection.

  • 35.
    Kindberg, Elin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    Vene, Sirkka
    Swedish Institute for Infectious Disease Control and Karolinska Institutet, Stockholm, Sweden.
    Mickiene, Aukse
    Clinic of Infectious Diseases, Kaunas University of Medicine, Kaunas, Lithuania.
    Lundkvist, Åke
    Swedish Institute for Infectious Disease Control and Karolinska Institutet, Stockholm, Sweden.
    Lindquist, Lars
    Unit for Infectious Diseases, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology . Linköping University, Faculty of Health Sciences.
    A Missense Mutation in the Toll‐like Receptor 3 Gene (TLR3) is Associated with Decreased Risk of Tick‐borne EncephalitisManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    Infections with tick‐borne encephalitis virus (TBEV) may be asymptomatic or cause severe symptoms from the central nervous system, such as meningitis or encephalitis. A mutation in the chemokine receptor 5 (CCR5) gene has been associated with increased risk of TBE but can only explain a limited number of cases and investigations of further risk factors are clearly needed. To investigate the importance of the innate immune response, 128 Lithuanian TBE patients with meningitis or encephalitis, 77 patients with aseptic meningoencephalitis (AME) and 135 healthy controls were analyzed for three mutations: two in the toll‐like receptor 3 (TLR3) gene and one in the 2´‐5´ oligoadenylate synthetase 1 (OAS1) gene. While no association was found between the mutation in OAS1 and TBE, the genotype distribution of one of the mutations in TLR3, rs3775291, differed significantly between the TBE patients and the controls. 61%, 32% and 7% of the TBE patients (n=127) were carriers of the wild‐type/wild‐type, heterozygous and mutant/mutant genotype of TLR3 rs3775291 genotype respectively. The corresponding percentages for healthy controls (n=126) were 52%, 29% and 19% (P=0.02) and for AME patients (n=75) 47%, 32% and 21% (P=0.009). The wild‐type rs3775291 allele was more common among TBE patients than healthy controls (allele frequency 0.768 vs. 0.663, P=0.01), suggesting that functional TLR3 is a risk factor for severe TBEV infection.

  • 36.
    Kindberg, Elin
    et al.
    Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Åkerlind, Britt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Clinical Microbiology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Microbiology.
    Johnsen, Christina
    Department of Virology, Statens Serum Institut, Copenhagen, Denmark4;.
    Knudsen, Jenny Dahl
    Department of Microbiology, Hvidovre Hospital, Hvidovre, Denmark.
    Heltberg, Ole
    Department of Microbiology, Næstved Hospital, Næstved, Denmark.
    Larson, Göran
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
    Böttiger, Blenda
    Department of Virology, Statens Serum Institut, Copenhagen, Denmark.
    Svensson, Lennart
    Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Host genetic resistance to symptomatic norovirus (GGII.4) infections in Denmark2007In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 45, no 8, p. 2720-2722Article in journal (Refereed)
    Abstract [en]

    A total of 61 individuals involved in five norovirus outbreaks in Denmark were genotyped at nucleotides 428 and 571 of the FUT2 gene, determining secretor status, i.e., the presence of ABH antigens in secretions and on mucosa. A strong correlation (P = 0.003) was found between the secretor phenotype and symptomatic disease, extending previous knowledge and confirming that nonsense mutations in the FUT2 gene provide protection against symptomatic norovirus (GGII.4) infections. Copyright © 2007, American Society for Microbiology. All Rights Reserved.

  • 37. Koopmans, Marion
    et al.
    Vennema, Harry
    Heersma, Herre
    van Strien, Elisabeth
    van Duynhoven, Yvonne
    Brown, David
    Reacher, Marc
    Lopman, Ben
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Early identification of common-source foodborne virus outbreaks in Europe.2003In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 9, no 9, p. 1136-1142Article in journal (Refereed)
  • 38. Kordasti, Shirin
    et al.
    Istrate, Claudia
    Banasaz, Mahanez
    Rottenberg, Martin
    Sjöwall, Henrik
    Lundgren, Ove
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Rotavirus infection is not associated with small intestinal fluid secretion in the adult mouse2006In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 80, no 22, p. 11355-11361Article in journal (Refereed)
    Abstract [en]

    In contrast to humans, adult but not infant small animals are resistant to rotavirus diarrhea. The pathophysiological mechanism behind this age-restricted diarrhea is currently unresolved, and this question was investigated by studying the secretory state of the small intestines of adult mice infected with rotavirus. Immunohistochemistry and histological examinations revealed that rotavirus (strain EDIM) infects all parts of the small intestines of adult mice, with significant numbers of infected cells in the ilea at 2 and 4 days postinfection. Furthermore, quantitative PCR revealed that 100-fold more viral RNA was produced in the ilea than in the jejuna or duodena of adult mice. In vitro perfusion experiments of the small intestine did not reveal any significant changes in net fluid secretion among mice infected for 3 days or 4 days or in those that were noninfected (37 ± 9 μl · h -1 · cm-1, 22 ± 13 μl · h -1 · cm-1, and 33 ± 6 μl · h -1 · cm-1, respectively) or in transmucosal potential difference (4.0 ± 0.3 mV versus 3.9 ± 0.4 mV), a marker for active chloride secretion, between control and rotavirus-infected mice. In vivo experiments also did not show any differences in potential difference between uninfected and infected small intestines. Furthermore, no significant differences in weight between infected and uninfected small intestines were found, nor were any differences in fecal output observed between infected and control mice. Altogether, these data suggest that rotavirus infection is not sufficient to stimulate chloride and water secretion from the small intestines of adult mice. Copyright © 2006, American Society for Microbiology. All Rights Reserved.

  • 39. Kordasti, Shirin
    et al.
    Sjövall, Henrik
    Lundgren, Ove
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Serotonin and vasoactive intestinal peptide antagonists attenuate rotavirus diarrhoea2004In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 53, no 7, p. 952-957Article in journal (Refereed)
    Abstract [en]

    Background and aims: The mechanisms underlying intestinal secretion in rotavirus diarrhoea remain to be established. We previously reported that rotavirus evokes intestinal fluid and electrolyte secretion by activation of the enteric nervous system. We now report that antagonists for the 5-hydroxytryptamine 3 receptor (5-HT3) and vasoactive intestinal peptide (VIP) receptor, but not antagonists for 5-hydroxytryptamine 4 receptor or the muscarinic receptor, attenuate rotavirus induced diarrhoea. Methods: Neurotransmitter antagonists were administered to wild-type or neurokinin 1 receptor knockout mice infected with homologous (EDIM) or heterologous (RRV) rotavirus. Results: While RRV infected mice had diarrhoea for 3.3 (0.2) days (95% confidence interval (CI) 3.04-3.56), the 5-HT3 receptor antagonist (granisetron) and the VIP receptor antagonist (4Cl-D-Phe 6,Leu17)-VIP both reduced the total number of days of RRV induced diarrhoea to 2.1 (0.3) (95% CI 1.31-2.9) (p<0.01). EDIM infected mice treated with granisetron had a significantly shorter duration of diarrhoea (5.6 (0.4) days) compared with untreated mice (8.0 (0.4) days, p<0.01). Experiments with neurokinin 1 receptor antagonists suggest that this receptor may possibly be involved in the secretory response to rotavirus. On the other hand, rotavirus diarrhoea was not attenuated in the neurokinin 1 receptor knockout mice. Conclusions: Our results suggest that the neurotransmitters serotonin and VIP are involved in rotavirus diarrhoea, observations that could imply new principles for treatment of this disease with significant global impact.

  • 40. Le Guyader, Francoise S
    et al.
    Mittelholzer, Christian
    Haugarreau, Larissa
    Hedlund, Kjell-Olof
    Alsterlund, Rolf
    Pommepuy, Monique
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Detection of noroviruses in raspberries associated with a gastroenteritis outbreak2004In: International Journal of Food Microbiology, ISSN 0168-1605, E-ISSN 1879-3460, Vol. 97, no 2, p. 179-186Article in journal (Refereed)
    Abstract [en]

    Following an acute foodborne gastroenteritis outbreak in southern Sweden, stool specimens from five of nine ill patients were found positive for norovirus using reverse transcriptase polymerase chain reaction. Epidemiological data pointed to raspberry cakes as the source of the outbreak. Using a combination of generic and patient-specific primers and novel food analysis methodology (with extraction efficiency control and inhibitor removal), norovirus strains from two different genogroups were directly identified in the contaminated raspberries.

  • 41. Le Pendu, Jacques
    et al.
    Ruvoën-Clouet, Nathalie
    Kindberg, Elin
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Mendelian resistance to human norovirus infections2006In: Seminars in Immunology, ISSN 1044-5323, E-ISSN 1096-3618, Vol. 18, no 6, p. 375-386Article in journal (Refereed)
    Abstract [en]

    Noroviruses have emerged as a major cause of acute gastroenteritis in humans of all ages. Despite high infectivity of the virus and lack of long-term immunity, volunteer and authentic studies has suggested the existence of inherited protective factors. Recent studies have shown that histo-blood group antigens (HBGAs) and in particular secretor status controlled by the α1,2fucosyltransferase FUT2 gene determine susceptibility to norovirus infections, with nonsecretors (FUT2-/-), representing 20% of Europeans, being highly resistant to symptomatic infections with major strains of norovirus. Moreover, the capsid protein from distinct strains shows different HBGA specificities, suggesting a host-pathogen co-evolution driven by carbohydrate-protein interactions. © 2006.

  • 42. Lopman, Ben
    et al.
    Vennema, Harry
    Kohli, Evelyne
    Pothier, Pierre
    Sanchez, Alicia
    Negredo, Anabel
    Buesa, Javier
    Schreir, Eckart
    Reacher, Mark
    Brown, David
    Gray, Jim
    Iturriza, Miren
    Gallimore, Chris
    Bottiger, Blenda
    Hedlund, Kjell-Olof
    Torvén, Maria
    von Bondsdorff, Carl-Henrik
    Maunula, Leena
    Poljsak-Prijatelj, Mateja
    Zimsek, Janet
    Reuter, Gábor
    Szücs, Gyorgy
    Melegh, Béla
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    van Duijnhoven, Yvonne
    Koopmans, Marion
    Increase in viral gastroenteritis outbreaks in Europe and epidemic spread of new norovirus variant2004In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 363, no 9410, p. 682-688Article in journal (Refereed)
    Abstract [en]

    Background Highly publicised outbreaks of norovirus gastroenteritis in hospitals in the UK and Ireland and cruise ships in the USA sparked speculation about whether this reported activity was unusual. Methods We analysed data collected through a collaborative research and surveillance network of viral gastroenteritis in ten European countries (England and Wales were analysed as one region). We compiled data on total number of outbreaks by month, and compared genetic sequences from the isolated viruses. Data were compared with historic data from a systematic retrospective review of surveillance systems and with a central database of viral sequences. Findings Three regions (England and Wales, Germany, and the Netherlands) had sustained epidemiological and viral characterisation data from 1995 to 2002. In all three, we noted a striking increase in norovirus outbreaks in 2002 that coincided with the detection and emergence of a new predominant norovirus variant of genogroup II4, which had a consistent mutation in the polymerase gene. Eight of nine regions had an annual peak in 2002 and the new genogroup II4 variant was detected in nine countries. Also, the detection of the new variant preceded an atypical spring and summer peak of outbreaks in three countries. Interpretation Our data from ten European countries show a striking increase and unusual seasonal pattern of norovirus gastroenteritis in 2002 that occurred concurrently with the emergence of a novel genetic variant. In addition to showing the added value of an international network for viral gastroenteritis outbreaks, these observations raise questions about the biological properties of the variant and the mechanisms for its rapid dissemination.

  • 43.
    Lundgren, Ove
    et al.
    University of Gothenburg.
    Jodal, Mats
    University of Gothenburg.
    Jansson, Madeleine
    University of Gothenburg.
    T Ryberg, Anders
    University of Gothenburg.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Intestinal Epithelial Stem/Progenitor Cells Are Controlled by Mucosal Afferent Nerves2011In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 2, p. 16295-Article in journal (Refereed)
    Abstract [en]

    Background: The maintenance of the intestinal epithelium is of great importance for the survival of the organism. A possible nervous control of epithelial cell renewal was studied in rats and mice. Methods: Mucosal afferent nerves were stimulated by exposing the intestinal mucosa to capsaicin (1.6 mM), which stimulates intestinal external axons. Epithelial cell renewal was investigated in the jejunum by measuring intestinal thymidine kinase (TK) activity, intestinal H-3-thymidine incorporation into DNA, and the number of crypt cells labeled with BrdU. The influence of the external gut innervation was minimized by severing the periarterial nerves. Principal Findings: Luminal capsaicin increased all the studied variables, an effect nervously mediated to judge from inhibitory effects on TK activity or H-3-thymidine incorporation into DNA by exposing the mucosa to lidocaine (a local anesthetic) or by giving four different neurotransmitter receptor antagonists i.v. (muscarinic, nicotinic, neurokinin1 (NK1) or calcitonin gene related peptide (CGRP) receptors). After degeneration of the intestinal external nerves capsaicin did not increase TK activity, suggesting the involvement of an axon reflex. Intra-arterial infusion of Substance P (SP) or CGRP increased intestinal TK activity, a response abolished by muscarinic receptor blockade. Immunohistochemistry suggested presence of M3 and M5 muscarinic receptors on the intestinal stem/progenitor cells. We propose that the stem/progenitor cells are controlled by cholinergic nerves, which, in turn, are influenced by mucosal afferent neuron(s) releasing acetylcholine and/or SP and/or CGRP. In mice lacking the capsaicin receptor, thymidine incorporation into DNA and number of crypt cells labeled with BrdU was lower than in wild type animals suggesting that nerves are important also in the absence of luminal capsaicin, a conclusion also supported by the observation that atropine lowered thymidine incorporation into DNA by 60% in control rat segments. Conclusion: Enteric nerves are of importance in maintaining the intestinal epithelial barrier.

  • 44.
    Lundgren, Ove
    et al.
    Sahlgrenska US .
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Pathophysiology of Rotavirus diarrhea2004In: Current topics in virology, ISSN 0972-4591, Vol. 4, p. 51-61Article in journal (Refereed)
  • 45. Lundgren, Ove
    et al.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    The enteric nervous system and infectious diarrhea.2003In: Viral gastroenteritis / [ed] Ulrich Desselberger and Jim Gray, Linköping: Linköpings universitet , 2003, p. 51-67Chapter in book (Other academic)
  • 46.
    Mickiene, Aukse
    et al.
    Lithuanian University of Health Science, Lithuania; Karolinska University Hospital Huddinge, Sweden.
    Pakalniene, Jolita
    Lithuanian University of Health Science, Lithuania.
    Nordgren, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Carlsson, Beatrice
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Hagbom, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Lindquist, Lars
    Karolinska University Hospital Huddinge, Sweden.
    Polymorphisms in Chemokine Receptor 5 and Toll-Like Receptor 3 Genes Are Risk Factors for Clinical Tick-Borne Encephalitis in the Lithuanian Population2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e106798-Article in journal (Refereed)
    Abstract [en]

    Background: Tick-borne encephalitis virus (TBEV) infections can be asymptomatic or cause moderate to severe injuries of the nervous system. We previously reported that a nonfunctional chemokine receptor 5 (CCR5) and a functional Toll-like receptor 3 (TLR3) predispose adults to clinical tick-borne encephalitis (TBE). This study expands our previous findings and further examines polymorphisms in CCR5 and TLR3 genes in different age and disease severity groups. Methods: 117 children and 129 adults, stratified into mild, moderate and severe forms of TBE, and 103 adults with severe TBE were analyzed. 135 healthy individuals and 79 patients with aseptic meningoencephalitis served as controls. CCR5 delta 32 and rs3775291 TLR3 genotypes were established by pyrosequencing, and their frequencies were analyzed using recessive genetic, genotype and allelic models. Findings: The prevalence of CCR5 Delta 32 homozygotes was higher in children (2.5%), in adults with severe TBE (1.9%), and in the combined cohort of TBE patients (2.3%) than in controls (0%) (pless than0.05). The nonfunctional homozygous TLR3 genotype was less prevalent among the combined TBE cohort (11.5%) than among controls (19.9%) (p = 0.025), but did not differ between children TBE and controls. The genotype and allele prevalence of CCR5 and TLR3 did not differ in children nor adult TBE cohorts stratified by disease severity. However, in the severe adult TBE cohort, homozygous functional TLR3 genotype and wt allele were less prevalent compared to the adult cohort with the whole disease severity spectrum (44.4% vs 59.8% p = 0.022 and 65.2% vs 76.4% p = 0.009; respectively). Conclusions: Independently of age, nonfunctional CCR5D32 mutation is a significant risk factor for development of clinical TBE, but not for disease severity. The polymorphism of TLR3 gene predisposes to clinical TBE in adults only and may be associated with disease severity. Further studies are needed to clarify the role of these polymorphisms in susceptibility to TBEV infection.

  • 47.
    Mirazimi, Ali
    et al.
    Department of Virology, Swedish Institute for Infectious Disease Control/Karolinska Institute, Solna, Sweden.
    Magnusson, Karl-Eric
    Linköping University, Department of Molecular and Clinical Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Svensson, Lennart
    Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    A cytoplasmic region of the NSP4 enterotoxin of rotavirus is involved in retention in the endoplasmic reticulum2003In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 84, no 4, p. 875-883Article in journal (Refereed)
    Abstract [en]

    The rotavirus genome encodes two glycoproteins, one structural (VP7) and one non-structural (NSP4), both of which mature and remain in the endoplasmic reticulum (ER). While three amino acids in the N terminus have been proposed to function as a retention signal for VP7, no information is yet available on how NSP4 remains associated with the ER. In this study, we have investigated the ER retention motif of NSP4 by producing various C-terminal truncations. Deleting the C terminus by 52 amino acids did not change the intracellular distribution of NSP4, but an additional deletion of 38 amino acids diminished the ER retention and resulted in the expression of NSP4 on the cell surface. Brefeldin A treatment prevented NSP4 from reaching the cell surface, suggesting that C-terminal truncated plasma membrane NSP4 is transported through the normal secretory pathway. On the basis of these results, we propose that the region between amino acids 85 and 123 in the cytoplasmic region of NSP4 are involved in ER retention.

  • 48.
    Mittelholzer, C.
    et al.
    Department of Virology, Swed. Inst. for Infect. Dis. Control, Solna, Sweden, Department of Aquaculture, Institute of Marine Research, Storebø, Norway.
    Englund, L.
    Department of Small Animals, National Veterinary Institute, Uppsala, Sweden.
    Hedlund, K.-O.
    Dept. of Molec. Epidemiol./Biotech., Swed. Inst. for Infect. Dis. Control, Solna, Sweden.
    Dietz, H.-H.
    Dept. of Poultry, Fish/Fur Animals, Danish Veterinary Institute, Arhus, Denmark.
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology .
    Detection and Sequence Analysis of Danish and Swedish Strains of Mink Astrovirus2003In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 41, no 11, p. 5192-5194Article in journal (Refereed)
    Abstract [en]

    The sequences of mink astroviruses collected from 11 farms in Denmark and Sweden were analyzed and found to be homologous with one another but different from those of other astroviruses. A species-specific reverse transcriptase-PCR for mink astrovirus was established and shown to be suitable for the analysis of clinical samples.

  • 49. Mittelholzer, Christian
    et al.
    Hedlund, Kjell-Olof
    Englund, Lena
    Dietz, Hans-Henrik
    Svensson, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Molecular and Clinical Medicine, Molecular Virology.
    Molecular characterization of a novel astrovirus associated with disease in mink2003In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 84, no 11, p. 3087-3094Article in journal (Refereed)
    Abstract [en]

    Pre-weaning diarrhoea is a well-known problem in mink farming in Europe, causing morbidity that varies between farms, regions and season. Different causalities for the disease have been proposed, but only most recently has a novel astrovirus been identified as an important risk factor. In this report, the molecular characterization, origin and evolution of this novel astrovirus of mink are discussed. The polyadenylated, positive-stranded RNA genome was sequenced and found to contain 6610 nt, organized into three ORFs and two short UTRs. A ribosomal frameshift sequence links the 5' two ORFs, containing sequence motifs for a serine protease (ORF1a) and an RNA-dependent RNA polymerase (ORF1b). The structural proteins are encoded by ORF2 and, presumably, are expressed as a polyprotein precursor to be cleaved into the mature capsid proteins. These results indicate that mink astrovirus (MiAstV) has all of the features typical of members of the Astroviridae. Phylogenetic analyses revealed that MiAstV is distantly related to established astroviruses, showing less than 67 % similarity at the nucleotide level with its closest relative, ovine astrovirus, and even lower identities at the predicted amino acid level. Nevertheless, sequence analysis of MiAstV isolates from geographically distinct Swedish and Danish farms showed much less diversity. This suggests either the spread in the mink population of a virus that has evolved a long time ago or the recent introduction of an ancient virus into a new host species.

  • 50.
    Modin Larsson, Malin
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Rydell, Gustaf
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg.
    Grahn, Ammi
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg.
    Rodríguez-Díaz, Jesús
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Åkerlind, Britt
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Microbiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Microbiology.
    Hutson, Anne
    Departments of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA .
    Estes, Mary
    Departments of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, USA.
    Larson, Göran
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg.
    Svensson, Lennart
    Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
    Antibody Prevalence and Titer to Norovirus (Genogroup II) Correlate with Secretor (FUT2) but Not with ABO Phenotype or Lewis (FUT3) Genotype2006In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 194, no 10, p. 1422-1427Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Histo-blood group antigens and secretor status have been associated with susceptibility to Norovirus infections, which suggests that antibody prevalence and titer might correlate with these phenotypes.

    METHODS:

    Plasma samples (n = 105) from Swedish blood donors that had been genotyped for secretor (FUT2) and Lewis (Le; FUT3) genotypes and phenotyped for ABO and Le blood groups were analyzed for immunoglobulin G antibody prevalence and titers to norovirus genogroup (GG) II.4.

    RESULTS:

    The results showed that nonsecretors (se4128se428) and Lea+b- individuals not only had significantly lower antibody titers than did secretors (P < .0001) and Lea-b+ individuals (P < .0002) but were also significantly more often antibody negative (P < .05). Antibody titers in secretors were not significantly different between individuals of different Le (FUT3) genotypes or different ABO phenotypes.

    CONCLUSIONS:

    Nonsecretors and Lea+b- individuals are significantly less prone to be infected with GGII noroviruses. This new information extends previous knowledge and supports the hypothesis that nonsecretors are relatively but not absolutely resistant to norovirus infections.

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