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Human Caliciviruses: a study of viral evolution, host genetics and disease susceptibility
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The viruses described in this thesis are the norovirus and sapoviruses, which belong to the family of human caliciviruses and are known to cause gastroenteritis in humans. Gastroenteritis has emerged as a global health problem and is based on the large number of infected considered as one of the most common diseases today. According to estimates of the World Health Organization (WHO), gastroenteritis causes over five times more pediatric deaths compared to pediatric deaths caused by HIV/AIDS worldwide. Norovirus, the cause of the famous “winter vomiting disease”, is alone responsible for more than 200 000 deaths each year in children less than 5 years of age.

The mechanism for emergence and evolution of new human calicivirus strains, as well as protective immunity in the human population is poorly understood. The main focus for this thesis was to elucidate the possible correlation between human calicivirus evolution, host genetics and disease susceptibility. One of the main findings presented in this thesis is the documentation of in vivo capsid gene evolution and quasispecies dynamics during chronic NoV GI.3 infection (Paper 1). In paper II, we reported that the G428A nonsense mutation in the FUT2 gene provides strong but not absolute protection against symptomatic GII.4 NoV infection. In my last two papers (Paper III and IV), we were the first to investigate host genetic susceptibility factors during authentic SaV infection.

To summarize, the results presented in this thesis show that the success of human calicivirus infection probably is determined by a delicate interplay between virus evolution and susceptibility of the host, both genetically and immunologically.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2012. , 77 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1303
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-76036ISBN: 978-91-7519-922-1 (print)OAI: oai:DiVA.org:liu-76036DiVA: diva2:511714
Public defence
2012-04-12, Eken, Hälsouniversitetet, Campus US, Linköpings univeristet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2012-03-23 Created: 2012-03-23 Last updated: 2012-05-07Bibliographically approved
List of papers
1. Quasispecies dynamics and molecular evolution of human norovirus capsid P region during chronic infection
Open this publication in new window or tab >>Quasispecies dynamics and molecular evolution of human norovirus capsid P region during chronic infection
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2009 (English)In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 90, 432-441 p.Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-16852 (URN)10.1099/vir.0.005082-0 (DOI)
Available from: 2009-02-21 Created: 2009-02-20 Last updated: 2017-12-13
2. The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection.
Open this publication in new window or tab >>The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection.
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2009 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 4, no 5, e5593- p.Article in journal (Refereed) Published
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.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18974 (URN)10.1371/journal.pone.0005593 (DOI)19440360 (PubMedID)
Note
Original Publication: Beatrice Carlsson, Elin Kindberg, Javier Buesa, Gustaf E Rydell, Marta Fos Lidón, Rebeca Montava, Reem Abu Mallouh, Ammi Grahn, Jesús Rodríguez-Díaz, Juan Bellido, Alberto Arnedo, Göran Larson and Lennart Svensson, The G428A nonsense mutation in FUT2 provides strong but not absolute protection against symptomatic GII.4 Norovirus infection., 2009, PLoS ONE, (4), 5, e5593. http://dx.doi.org/10.1371/journal.pone.0005593 Licensed under Creative CommonsAvailable from: 2009-06-10 Created: 2009-06-07 Last updated: 2017-12-13Bibliographically approved
3. Susceptibility of Children to Sapovirus Infections, Nicaragua, 2005–2006
Open this publication in new window or tab >>Susceptibility of Children to Sapovirus Infections, Nicaragua, 2005–2006
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2012 (English)In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 18, no 11, 1875-1878 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Atlanta, GA, USA: U.S. Department of Health and Human Services * Centers for Disease Control and Prevention, 2012
National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-76034 (URN)10.3201/eid1811.111581 (DOI)000328172600023 ()23092588 (PubMedID)
Note

On the day of the defence day the status of this article was

Manuscript

Available from: 2012-03-23 Created: 2012-03-23 Last updated: 2017-12-07Bibliographically approved
4. Susceptibility to symptomatic sapovirus infection in Denmark is not associated with secretor or Lewis status
Open this publication in new window or tab >>Susceptibility to symptomatic sapovirus infection in Denmark is not associated with secretor or Lewis status
(English)Manuscript (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.

Keyword
Sapovirus, disease susceptibility, fucosyltransferase II, histo-blood group
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76035 (URN)
Available from: 2012-03-23 Created: 2012-03-23 Last updated: 2012-03-23Bibliographically approved

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