Genetic Susceptibility to Human Norovirus Infection: An Update

Abstract

Noroviruses are the most common etiological agent of acute gastroenteritis worldwide. Despite their high infectivity, a subpopulation of individuals is resistant to infection and disease. This susceptibility is norovirus genotype-dependent and is largely mediated by the presence or absence of human histo-blood group antigens (HBGAs) on gut epithelial surfaces. The synthesis of these HBGAs is mediated by fucosyl- and glycosyltransferases under the genetic control of the FUT2 (secretor), FUT3 (Lewis) and ABO(H) genes. The so-called non-secretors, having an inactivated FUT2 enzyme, do not express blood group antigens and are resistant to several norovirus genotypes, including the predominant GII.4. Significant genotypic and phenotypic diversity of HBGA expression exists between different human populations. Here, we review previous in vivo studies on genetic susceptibility to norovirus infection. These are discussed in relation to population susceptibility, vaccines, norovirus epidemiology and the impact on public health.

The Impact of Human Genetic Polymorphisms on Rotavirus Susceptibility, Epidemiology, and Vaccine Take

“…These individuals express Lewis a if they have a functional FUT3 enzyme that catalyzes the addition of a fucose residue to the H type 1 precursor. Homozygotic inactive FUT3 gene carriers lack Lewis a and b structures and are termed Lewis-negative [9,22].…”

“…The fact that populations vary considerably in relation to HBGA genotype and phenotype raises the question of whether this will affect rotavirus epidemiology at population level. For example, approximately 75-80% of European, North American, Central Asian, and several African populations are secretors [22,25], whereas in Mesoamerica, the prevalence of secretor positives can reach 90-95% [18,26]. The Lewis-negative phenotype, moreover, is significantly more prevalent in several African countries or ethnicities (20-35%) compared to European, North American, and some Asian populations (6-11%) [25] (Figure 1).…”

“…More studies are warranted to understand if and how HBGA phenotype distribution affects rotavirus disease burden at population level. [12,15,16,22,23,[26][27][28]. Studies have suggested that non-secretors have a lower vaccine response but would also be protected against circulating wildtype strains of the same genotypes which predominantly infect secretors.…”

“…Recently, human intestinal enteroids (HIEs), derived from human small intestinal tissue, were used successfully to support human norovirus replication [58,59]. In such studies, there is concordance between the genetic susceptibility of different HIEs to norovirus and in vivo epidemiological data [22]. Accordingly, HIE might be a suitable model for investigating HBGA-mediated rotavirus susceptibility as well.…”

Genetic Manipulation of Human Intestinal Enteroids Demonstrates the Necessity of a Functional Fucosyltransferase 2 Gene for Secretor-Dependent Human Norovirus Infection

“…Secretor status is highly associated with infection and disease caused by many HuNoV strains based upon findings from human experimental infection studies and evaluation of acute gastroenteritis outbreaks (10)(11)(12)(13)(14). Fucosyltransferase 2 (FUT2) is an enzyme expressed in human epithelial cells that catalyzes ␣1,2-fucosylation of the terminal galactose, preferentially on glycan type 1 chain precursors.…”