Infectious diseases have influenced population genetics and the evolution of the structure of the human genome in part by selecting for host susceptibility alleles that modify pathogenesis. Norovirus infection is associated with ∼90% of epidemic non-bacterial acute gastroenteritis worldwide. Here, we show that resistance to Norwalk virus infection is multifactorial. Using a human challenge model, we showed that 29% of our study population was homozygous recessive for the α(1,2)fucosyltransferase gene (FUT2) in the ABH histo-blood group family and did not express the H type-1 oligosaccharide ligand required for Norwalk virus binding. The FUT2 susceptibility allele was fully penetrant against Norwalk virus infection as none of these individuals developed an infection after challenge, regardless of dose. Of the susceptible population that encoded a functional FUT2 gene, a portion was resistant to infection, suggesting that a memory immune response or some other unidentified factor also affords protection from Norwalk virus infection.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Mead, P.S. et al. Food-related illness and death in the United States. Emerg. Infect. Dis. 5, 607–625 (1999).
Fankhauser, R.L., Noel, J.S., Monroe, S.S., Ando, T. & Glass, R.I. Molecular epidemiology of “Norwalk-like viruses” in outbreaks of gastroenteritis in the United States. J. Infect. Dis. 178, 1571–1578 (1998).
Ho, M.S. et al. Viral gastroenteritis aboard a cruise ship. Lancet 2, 961–965 (1989).
Koopmans, M. et al. Molecular epidemiology of human enteric caliciviruses in the Netherlands. J. Infect. Dis. 181, S262–S269 (2000).
Glass, R.I. et al. The epidemiology of enteric caliciviruses from humans: a reassessment using new diagnostics. J. Infect. Dis. 181 (suppl. 2), S254–S261 (2000).
Marie-Cardine, A. et al. Epidemiology of acute viral gastroenteritis in children hospitalized in Rouen, France. Clin. Infect. Dis. 34, 1170–1178 (2002).
Herwaldt, B.L. et al. Characterization of a variant strain of Norwalk virus from a food-borne outbreak of gastroenteritis on a cruise ship in Hawaii. J. Clin. Microbiol. 32, 861–866 (1994).
Matsui, S.M. & Greenberg, H.B. Immunity to calicivirus infection. J. Infect. Dis. 181 (suppl. 2), S331–S335 (2000).
Johnson, P.C., Mathewson, J.J., DuPont, H.L. & Greenberg, H.B. Multiple-challenge study of host susceptibility to Norwalk gastroenteritis in US adults. J. Infect. Dis. 161, 18–21 (1990).
Hutson, A.M., Atmar, R.L., Graham, D.Y. & Estes, M.K. Norwalk virus infection and disease is associated with ABO histo-blood group type. J. Infect. Dis. 185, 1335–1337 (2002).
Marionneau, S. et al. Norwalk virus binds to histo-blood group antigens present on gastroduodenal epithelial cells of secretor individuals. Gastroenterology 122, 1967–1977 (2002).
Rouquier, S. et al. Molecular cloning of a human genomic region containing the H blood group α(1,2)fucosyltransferase gene and two H locus-related DNA restriction fragments. Isolation of a candidate for the human Secretor blood group locus. J. Biol. Chem. 270, 4632–4639 (1995).
Marionneau, S. et al. ABH and Lewis histo-blood group antigens, a model for the meaning of oligosaccharide diversity in the face of a changing world. Biochimie 83, 565–573 (2001).
Harrington, P.R., Lindesmith, L., Yount, B., Moe, C.L. & Baric, R.S. Binding of Norwalk virus-like particles to ABH histo-blood group antigens is blocked by antisera from infected human volunteers or experimentally vaccinated mice. J. Virol. 76, 12335–12343 (2002).
Oriol, R., Candelier, J.J. & Mollicone, R. Molecular genetics of H. Vox Sang. 78, 105–108 (2000).
Wyatt, R.G. et al. Comparison of three agents of acute infectious nonbacterial gastroenteritis by cross-challenge in volunteers. J. Infect. Dis. 129, 709–714 (1974).
Parrino, T.A., Schreiber, D.S., Trier, J.S., Kapikian, A.Z. & Blacklow, N.R. Clinical immunity in acute gastroenteritis caused by Norwalk agent. N. Engl. J. Med. 297, 86–89 (1977).
Moe, C.L. et al. Application of PCR to detect Norwalk virus in fecal specimens from outbreaks of gastroenteritis. J. Clin. Microbiol. 32, 642–648 (1994).
Carrington, M., Dean, M., Martin, M.P. & O'Brien, S.J. Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences. Hum. Mol. Genet. 8, 1939–1945 (1999).
Dean, M. et al. Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273, 1856–1862 (1996).
Boren, T., Falk, P., Roth, K.A., Larson, G. & Normark, S. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science 262, 1892–1895 (1993).
Schaeffer, A.J. et al. Host pathogenesis in urinary tract infections. Internal J. Antimicrob. Agents 17, 245–251 (2001).
Saadi, A.T. et al. Isolation of an adhesin from Staphlococcus aureus that binds Lewis a blood group antigen and its relevance to sudden infant death syndrome. FEMS Immunol. Med. Microbiol. 8, 315–320 (1994).
Hutson, A.M., Atmar, R.L., Marcus, D.M. & Estes, M.K. Norwalk virus-like particle hemagglutination by binding to H histo- blood group antigens. J. Virol. 77, 405–415 (2003).
Okhuysen, P.C., Jiang, X., Ye, L., Johnson, P.C. & Estes, M.K. Viral shedding and fecal IgA response after Norwalk virus infection. J. Infect. Dis. 171, 566–569 (1995).
Graham, D.Y. et al. Norwalk virus infection of volunteers: new insights based on improved assays. J. Infect. Dis. 170, 34–43 (1994).
Ball, J.M. et al. Recombinant Norwalk virus-like particles given orally to volunteers: phase I study. Gastroenterology 117, 40–48 (1999).
Harrington, P.R. et al. Systemic, mucosal, and heterotypic immune induction in mice inoculated with Venezuelan equine encephalitis replicons expressing Norwalk virus-like particles. J. Virol. 76, 730–742 (2002).
Dolin, R. et al. Biological properties of Norwalk agent of acute infectious nonbacterial gastroenteritis. Proc. Soc. Exp. Biol. Med. 140, 578–583 (1972).
Wyatt, R.G. et al. In vitro cultivation in human fetal intestinal organ culture of a reovirus-like agent associated with nonbacterial gastroenteritis in infants and children. J. Infect. Dis. 130, 523–528 (1974).
Ando, T. et al. Epidemiologic applications of novel molecular methods to detect and differentiate small round structured viruses (Norwalk-like viruses). J. Med. Virol. 47, 145–152 (1995).
Monroe, S.S., Stine, S.E., Jiang, X., Estes, M.K. & Glass, R.I. Detection of antibody to recombinant Norwalk virus antigen in specimens from outbreaks of gastroenteritis. J. Clin. Microbiol. 31, 2866–2872 (1993).
Sidmann, F.K. (ed.) Appendix 2: saliva testing for ABH and Lewis inTechnical Manual of the American Association of Blood Banks, 122–123 (J.B. Lippincott, Philadelphia, 1981).
Svensson, L., Petersson, A. & Henry, S.M. Secretor genotyping for A385T, G428A, C571T, C628T, 685delTGG, G849A, and other mutations from a single PCR. Transfusion 40, 856–860 (2000).
Friedman, M.G. Radioimmunoassay for the detection of virus-specific IgA antibodies in saliva. J. Immunol. Meth. 54, 203–211 (1982).
Baric, R.S. et al. Expression and self-assembly of Norwalk virus capsid protein from Venezuelan equine encephalitis virus replicons. J. Virol. 76, 3023–3030 (2003).
Ward, R.L. et al. Salivary antibody titers in adults challenged with a human rotavirus. J. Med. Virol. 36, 222–225 (1992).
Simell, B., Korkeila, M., Pursiainen, H., Kilpi, T.M. & Kayhty, H. Pneumococcal carriage and otitis media induce salivary antibodies to pneumococcal surface adhesin a, pneumolysin, and pneumococcal surface protein a in children. J. Infect. Dis. 183, 887–896 (2001).
We thank S. Hutton and S. Hooper for additional statistical support; J. Herrmann, N. Blacklow, R. Calderon and the staff of the UNC General Clinical Research Center for their contributions to the human challenge studies; S. Fout for his support of the salivary assay development; and P. Harrington for critical reading of the manuscript. This work was supported by grants from the US Environmental Protection Agency (STAR grant R826139 and R-82936501), National Institutes of Health (AI23946 and GM63228, and RR00046 to the UNC General Clinical Research Center), the North Carolina Biotechnology Center (2000-ARG-0040) and Glaxo Wellcome, and by the Institut National de la Santé et de la Recherche Médicale.
The authors declare no competing financial interests.
About this article
Cite this article
Lindesmith, L., Moe, C., Marionneau, S. et al. Human susceptibility and resistance to Norwalk virus infection. Nat Med 9, 548–553 (2003). https://doi.org/10.1038/nm860
NKT cells are responsible for the clearance of murine norovirus through the virus-specific secretory IgA pathway
Biochemistry and Biophysics Reports (2020)
Bile acids and ceramide overcome the entry restriction for GII.3 human norovirus replication in human intestinal enteroids
Proceedings of the National Academy of Sciences (2020)
Sera Antibody Repertoire Analyses Reveal Mechanisms of Broad and Pandemic Strain Neutralizing Responses after Human Norovirus Vaccination
Current HIV/AIDS Reports (2019)
Human Norovirus Cultivation in Nontransformed Stem Cell-Derived Human Intestinal Enteroid Cultures: Success and Challenges