Towards a Comprehensive Understanding of Human Norovirus Immunity.

Noroviruses (NVs) cause most outbreaks of acute gastroenteritis and account for 267 million infections and more than 200,000 deaths each year. Strains belonging to genotype GII.4 have led to 6 pandemics since 1995 and pose a major health and economic burden. Numerous challenges have hampered the study of NVs and the development of an effective vaccine. Such challenges include the inability to propagate NVs in established cell lines; the rapid emergence of novel GII.4 strains that escape herd immunity; and the complexity of host exposure histories and determinants of susceptibility, which complicate the interpretation of immunologic studies. Consequently, key questions, such as what constitutes an effective and durable NV immune response, remain unanswered.

In this issue of Cellular and Molecular Gastroenterology and Hepatology, Lindesmith et al address a particularly important and understudied area of human NV research: the cellular immune response following acute infection. Most studies to date have focused on humoral immunity and have shown that antibodies that block NV attachment to host histoblood group antigens (HBGAs) are associated with protection from reinfection. However, such antibodies are highly strain-specific and may be short-lived; moreover, a robust antibody response is not always sufficient or necessary for protection against NV, suggesting that additional immune mechanisms may be at play. Indeed, innate immunity and T cells are critical during mouse NV infection, but have received little attention in human studies.,

Lindesmith et al prospectively investigate a unique cohort of NV-infected subjects with an inactivating mutation in the gene encoding α-1,2-fucosyltransferase, an enzyme involved in HBGA synthesis. Known as “nonsecretors,” such subjects have a limited repertoire of HBGAs and are naturally resistant to most NV strains, including GII.4 variants. The authors carry out broad phenotypic and functional analysis of the immune response at days 8, 30, and 180 following natural infection with a GII.2 virus, focusing on both adaptive and innate immune responses. Moreover, they take advantage of the limited exposure history of this cohort to interrogate the cross-reactivity of GII.2-specific T cells against GII.4 virus-like particles. Because most adults have had multiple NV exposures, this is a clever approach to address the issue of preexisting versus cross-protective immunity. Lastly, the authors investigate why nonsecretors are susceptible to GII.2 infection even though these viruses fail to bind HBGAs in vitro.

The findings presented here suggest broad immune activation following acute NV infection. Like serologic responses, cellular responses vary considerably across the cohort and are even Th2-biased in 1 subject. Given the small size of this cohort and the absence of preinfection data (the authors used an independent cohort of healthy donors for comparison), there are limitations to the interpretation of the results. Nevertheless, this is a comprehensive first attempt at broadly characterizing the immune response following natural NV infection. Importantly, T cells elicited by the GII.2 virus were cross-reactive against GII.4 virus-like particles, suggesting that such cells may target conserved epitopes and provide broad protection, a finding with important implications for vaccine design. Finally, in line with recent discoveries, the authors show that bile is necessary for GII.2 attachment to nonsecretor HBGAs.

Developing an effective NV vaccine will be facilitated by a detailed understanding of immune correlates of protection. This study is a step in the right direction, and a reminder of the challenges inherent in human NV research. Samples from larger human cohorts, preferably pre- and post-NV infection, are needed to define the full breadth and durability of the T-cell immune response. Such studies should focus on the differentiation, functionality, and tissue localization of NV-specific T cells, particularly within the intestine. To that end, recent efforts to map HLA-restricted NV epitopes are noteworthy, because such knowledge could enable the tracking of virus-specific T cells at baseline and following infection or vaccination.