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.

Keywords: histo-blood group antigens; norovirus; secretor status; susceptibility.

Figure 1

Biosynthesis pathway of histo-blood group antigens (HBGAs) by stepwise addition of monosaccharides to precursor structures. The FUT2 (secretor) gene encodes an α1,2-fucosyltransferase which adds a fucose residue in α1,2 linkage to the terminal galactose of the H type 1 precursor. Non-secretors, having a non-functional FUT2 enzyme, cannot synthesize the H type 1 antigen from its precursor and lack α1,2-linked fucose HBGAs in the intestinal mucosa and other secretions. The synthesis of the A and B antigens by the corresponding enzymes requires the presence of the H type 1 antigen, adding an N-acetylgalactosamine (A) or a galactose (B) in a α1,4 linkage on the galactose residue of the H type 1 antigen. The Lewis antigens are synthesized with the FUT3 enzyme which adds a α1,4-linked fucose residue on the N-acetylglucosamine of the H antigen or the H antigen precursor, generating Lewis a or Lewis b antigens respectively. Abbreviations: Gal: galactose; GlcNAc: N-acetylglucosamine; Fuc: fucose.

Figure 2

A simplistic overview of secretor status in different population groups. Secretors (green) are susceptible to secretor-dependent norovirus genotypes, including the globally predominant GII.4 genotype. Secretors are also further susceptible to secretor-independent genotypes. Non-secretors (red) are only susceptible to secretor-independent genotypes. As of yet, no genotypes have been observed to exclusively infect non-secretors. Weak-secretors (mix red or green) are common in East Asian populations, having a reduced expression of secretor antigens, and would thus be partially susceptible to secretor-specific genotypes. The prevalence of secretors is particularly high in Meso-American populations, which may lead to a higher disease burden in the population due to (1) higher rates of GII.4 infection and (2) a larger portion of the population being susceptible to both secretor and secretor-independent genotypes.