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The Norovirus Puzzle: Characterization of human and bovine norovirus susceptibility patterns
Linköping University, Department of Clinical and Experimental Medicine, Molecular Virology. Linköping University, Faculty of Health Sciences.
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Winter vomiting disease is caused by norovirus (NoV) and affects millions of people every year resulting in 200.000 deaths among children in developing countries. It was observed early that not all individuals exposed to the norovirus became ill. The reason for this is now recognized to be dependent upon the secretor status of an individual. The secretor status determines the ability of an individual to express histo-blood group antigens (HBGA) on mucosa and in saliva. A non-secretor is unable to express HBGAs due to a mutation in a gene called FUT2. In this thesis, I have investigated the antibody prevalence and titer in humans in Sweden and Nicaragua to the most common GII NoV and the correlation to secretor status, Lewis status and ABO. I found that secretors had significantly higher antibody prevalence and titer to GII NoV than non-secretors suggesting that non-secretors are less prone to be infected by the GII NoV. In Nicaragua, I also found several different NoV strains circulating at the same time. The NoVs have been circulating and evolving in the human population for some time and the same individuals seems to be infected over and over again with the same virus. This suggests that there is no long-term immunity present but possibly short-term immunity, which would make it very difficult to produce a vaccine against NoV. However, recent studies have shown the possibility of using virus like particles as a vaccine candidate and have demonstrated long-term immunity.

The bovine NoV (boNoV) cause gastroenteritis in cattle and are closely related to the human NoV. The possibility of zoonotic transfer to humans is currently being investigated. I found that 26% of Swedish blood donors have antibodies to the boNoV suggesting that they have been exposed to the virus. The human NoV has been observed to be able to infect and cause disease in cattle, could the boNoV do the same in humans? To date, no boNoV strain has been found in humans. The proposed receptor structure for boNoV is the αGal epitope, which is present in many mammals like cow, pig, horse, sheep and rabbit but not in humans. This indicates that humans are not at risk for boNoV infection because we lack the proper receptor structure. However, recombinations between different NoV strains have been demonstrated and the possibility of more than one receptor being present has been suggested. I found that aa position 365-379 on the boNoV capsid seems to be important for binding to erythrocytes. In this thesis, I hope to add some new pieces to the Norovirus Puzzle.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2011. , 72 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1244
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:liu:diva-68386ISBN: 978-91-7393-181-6OAI: oai:DiVA.org:liu-68386DiVA: diva2:418471
Public defence
2011-05-20, Berzelius salen, ing. 65, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2011-06-01 Created: 2011-05-23 Last updated: 2011-06-01Bibliographically approved
List of papers
1. Antibody Prevalence and Titer to Norovirus (Genogroup II) Correlate with Secretor (FUT2) but Not with ABO Phenotype or Lewis (FUT3) Genotype
Open this publication in new window or tab >>Antibody Prevalence and Titer to Norovirus (Genogroup II) Correlate with Secretor (FUT2) but Not with ABO Phenotype or Lewis (FUT3) Genotype
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2006 (English)In: Journal of Infectious Diseases, ISSN 0022-1899, Vol. 194, no 10, 1422-1427 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Oxford University Press, 2006
Keyword
norovirus
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-68382 (URN)10.1086/508430 (DOI)000241820500011 ()
Available from: 2011-05-23 Created: 2011-05-23 Last updated: 2012-11-02
2. Genetic susceptibility to symptomatic norovirus infection in Nicaragua
Open this publication in new window or tab >>Genetic susceptibility to symptomatic norovirus infection in Nicaragua
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2009 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 81, no 4, 728-735 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2009
Keyword
secretors status; Lewis phenotype; blood groups; Norovirus genogroups
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-68384 (URN)10.1002/jmv.21426 (DOI)000263765900022 ()
Available from: 2011-05-23 Created: 2011-05-23 Last updated: 2012-11-02
3. Human Antibody Responses to Bovine (Newbury-2) Norovirus (GIII.2) and Association to Histo-Blood Group Antigens
Open this publication in new window or tab >>Human Antibody Responses to Bovine (Newbury-2) Norovirus (GIII.2) and Association to Histo-Blood Group Antigens
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2010 (English)In: JOURNAL OF MEDICAL VIROLOGY, ISSN 0146-6615, Vol. 82, no 7, 1241-1246 p.Article in journal (Refereed) Published
Abstract [en]

Serum antibodies to bovine norovirus have been found recently in about 22% of humans. Whether this prevalence reflects limited virulence properties of the virus or that inherited host factors provide protection against bovine norovirus infection in humans remains to be established. To investigate whether histo-blood group antigens correlate with the presence of bovine norovirus (GIII.2) antibody, plasma (n = 105) from Swedish blood donors, genotyped and phenotyped for secretor, Lewis and ABO, were tested and compared for the frequency of IgG antibody and antibody titer to Bo/Newbury2/76/UK. In total, 26.7% (28/105) of Swedish blood donors were antibody-positive. Two non-secretors (2/21, 9.5%) were antibody-positive compared with 26/84 (31%) secretors (P=0.047). While no statistically significant correlation was found between the frequency of antibodies to bovine norovirus and different ABO blood groups, individuals with blood type B presented the highest frequency of antibodies (37.5%) compared with 0-30% among other blood groups. Individuals with Le(a-b+) had not only higher frequency of antibodies (31.3%) compared with Le(a+b-) (11%) (P=0.068) but also higher antibody titer (P=0.085) although this was not significant statistically. No detectable cross-reaction between bovine GIII.2 and human GII.3 NoV VLP was found with human and animal sera. The results of this study suggest that bovine norovirus infections occur in Sweden and that secretor status but not ABO blood groups is a possible risk factor for infection.

Place, publisher, year, edition, pages
John Wiley and Sons, Ltd, 2010
Keyword
secretor status, blood groups, bovine norovirus, histo-blood group antigens, fucosyltransferase
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-57400 (URN)10.1002/jmv.21776 (DOI)000278173400021 ()
Available from: 2010-06-18 Created: 2010-06-18 Last updated: 2011-06-01
4. Characterization of the Bovine Norovirus hemagglutinin
Open this publication in new window or tab >>Characterization of the Bovine Norovirus hemagglutinin
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

In this study we have analyzed the hemagglutination properties of bovine norovirus GIII.2 Newbury-2 virus like particles (VLPs). Hemagglutination (HA) and hemagglutination inhibition (HI) characteristics were investigated and results showed that bovine norovirus hemagglutinated bovine (6/8), pig (9/9) and rabbit (2/3) red blood cells (RBCs) but not RBC from goat, horse, guinea pig, sheep, chicken or humans. HA capacity differed between calfs and was temperature (4-22°C) and pH (4-10) independent. While three synthetic peptides constructed from the P-region of the capsid could not inhibit HA, a rabbit-peptide antiserum towards aa 365-379 inhibited HA. By homology modeling the bovine NoV shows a deletion close to the ligand binding site for Norwalk. This deletion may be responsible for the different binding patterns of the two strains. The peptide 365-379 was surface exposed and possibly located in a binding pocket. A set of 12 glycoconjugates including the proposed bovine receptor αGal1-3β1-4GlcNAc revealed that none could inhibit hemagglutination although αGal could bind the boVLPS. Neuraminidase did not affect HA suggesting that sialic acid is not a constituent of the HA receptor interaction. Trypsin-treatment of bovine RBCs increased HA titers and treatment with αgalactosidase of trypsin treated and non-trypsin treated RBCs eliminated HA activity suggesting that the αGal epitope is a potential receptor structure that might be connected to a glycolipid.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-68746 (URN)
Available from: 2011-06-01 Created: 2011-06-01 Last updated: 2011-06-01Bibliographically approved

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