Human susceptibility and resistance to Norwalk virus infection

Abstract

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.

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Figure 1: Norwalk VLPs bind to saliva from Se+ volunteers.
Figure 2: Norwalk virus–specific salivary IgA response is predictive of infection.
Figure 3: Model of Norwalk virus challenge outcomes.

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Acknowledgements

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.

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Correspondence to Ralph Baric.

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The authors declare no competing financial interests.

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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

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