Sequence-Based Classification of Select Agents: A Brighter Line (2010)

Virus-host interactions play a critical role in regulating disease severity and distribution in human populations. Moreover, it is likely that pathogenic microorganisms have shaped the genetic population structure of humans. For example, noroviruses are category B biodefense pathogens and the primary etiologic agent responsible for epidemic viral gastroenteritis worldwide. Members of this diverse family of viruses are the most common causes of sporadic diarrhea in community settings and a major burden on the military, restaurant services, the cruise-ship industry, university campuses, hospitals, and retirement communities. Humans encode a highly diverse set of histo-blood group (HBGA) carbohydrates on mucosal surfaces that are regulated by several highly polymorphic fucosyltransferase genes designated FUT1, FUT2, and FUT3 and by the enzymes that regulate A and B carbohydrate expression, resulting in dramatic differences in HBGA expression in human populations. Several studies have indicated that different HBGAs function as the receptors or coreceptors for productive norovirus infection in humans. People who cannot express HB-GAs on mucosal surfaces (FUT2^–/–) are highly resistant to Norwalk virus (NV) and perhaps other noroviruses, whereas people who express O type HBGAs on mucosal surfaces are more susceptible to NV. The most prevalent strains (GII.4) caused global pandemics of severe gastroenteritis in 1996, 2002, and 2006. Epidemic GII.4 viruses appear to have evolved two techniques to maintain their high prevalence in human populations. First, new epidemic GII.4 variants have emerged from ancestral strains and have altered HBGA-receptor binding profiles, allowing new strains to target unique susceptible human population groups that were probably resistant to ancestral strains. Second, like influenza viruses, exigent GII.4 norovirus variants undergo antigenic variation and so escape herd immunity. Thus, it is clear that host genetics have profound

influences in regulating susceptibility to and virulence of viruses (Norovirus pathogenesis: mechanisms of persistence and immune evasion in human populations. Donaldson EF, Lindesmith LC, Lobue AD, Baric RS. Immunol Rev. 2008 Oct;225:190-211; Human susceptibility and resistance to Norwalk virus infection (Lindesmith, Moe et al. 2003).