Abstract
Whether or not primary norovirus infections induce protective immunity has become a controversial issue, potentially confounded by the comparison of data from genetically distinct norovirus strains. Early human volunteer studies performed with a norovirus-positive inoculum initially led to the conclusion that primary infection does not generate long-term, protective immunity. More recently though, the epidemiological pattern of norovirus pandemics has led to the extrapolation that primary norovirus infection induces herd immunity. While these are seemingly discordant observations, they may in fact reflect virus strain-, cluster-, or genogroup-specific differences in protective immunity induction. Here, we report that highly genetically related intra-cluster murine norovirus strains differ dramatically in their ability to induce a protective immune response: Primary MNV-3 infection induced robust and cross-reactive protection, whereas primary MNV-1 infection induced modest homotypic and no heterotypic protection. In addition to this fundamental observation that intra-cluster norovirus strains display remarkable differences in protective immunity induction, we report three additional important observations relevant to norovirus:host interactions. First, antibody and CD4+ T cells are essential to controlling secondary norovirus infections. Second, the viral minor structural protein VP2 regulates the maturation of antigen presenting cells and protective immunity induction in a virus strain-specific manner, pointing to a mechanism by which MNV-1 may prevent the stimulation of memory immune responses. Third, VF1-mediated regulation of cytokine induction also correlates with protective immunity induction. Thus, two highly genetically-related norovirus strains displayed striking differences in induction of protective immune responses, strongly suggesting that the interpretation of norovirus immunity and vaccine studies must consider potential virus strain-specific effects. Moreover, we have identified immune (antibody and CD4+ T cells) and viral (VP2 and possibly VF1) correlates of norovirus protective immunity. These findings have significant implications for our understanding of norovirus immunity during primary infections as well as the development of new norovirus vaccines.
Highlights
Noroviruses (NoVs) represent a genus within the Caliciviridae family of viruses, comprised of non-enveloped positive-sense RNA viruses
To test whether intra-cluster NoV strains differ in protective immunity induction, we compared the magnitude of protection elicited by murine NoV (MNV)-1 and MNV-3
Consistent with our previously published results of weak MNV-1 protection in both 129SvEv and B6 mice [37], prior MNV-1 exposure resulted in only modest reductions in secondary titers in the distal ileum and mesenteric lymph nodes (MLNs) upon a homotypic challenge; no protection was observed in the colon (Figure 1A, grey bars)
Summary
Noroviruses (NoVs) represent a genus within the Caliciviridae family of viruses, comprised of non-enveloped positive-sense RNA viruses. Human noroviruses (HuNoVs) are a major cause of gastroenteritis outbreaks worldwide, implicated in over 95% of non-bacterial outbreaks. These highly infectious and ubiquitous viruses spread person-to-person and via fecal-oral contamination, and symptomatically infect people of all ages [6,7]. They are recognized to be an important cause of sporadic diarrheal disease. Emerging evidence indicates that HuNoVs are the leading cause of severe childhood gastroenteritis at least in the United States [8,9], supplanting rotaviruses since the introduction of an effective rotavirus vaccine. One literature review of the association of HuNoVs with severe diarrhea concluded that HuNoVs likely cause over 1 million hospitalizations and 200,000 deaths in children annually [10]
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