Identification of Immune and Viral Correlates of Norovirus Protective Immunity through Comparative Study of Intra-Cluster Norovirus Strains
Autor: | Robert N. Hunter, Makiko Watanabe, Shu Zhu, Danielle Hickman, Shannon M. Kahan, Desyree Murta Jesus, Stephanie M. Karst, Doron Regev, Ian Brierley, Melissa K. Jones, Sawsan Napthine, Divya Devabhaktuni, Nissin Moussatche |
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Jazyk: | angličtina |
Rok vydání: | 2013 |
Předmět: |
CD4-Positive T-Lymphocytes
viruses ved/biology.organism_classification_rank.species Adaptive Immunity medicine.disease_cause Mice fluids and secretions lcsh:QH301-705.5 Immune Response Caliciviridae Infections Mice Knockout 0303 health sciences biology Viral Vaccine virus diseases 3. Good health Cytokines Antibody Research Article lcsh:Immunologic diseases. Allergy Immunology Antigen-Presenting Cells Microbiology Virus Herd immunity Cell Line Immune Activation 03 medical and health sciences Immune system Species Specificity Immunity Virology Genetics medicine Animals Humans Molecular Biology Biology Immunity to Infections 030304 developmental biology 030306 microbiology ved/biology Norovirus Viral Vaccines biochemical phenomena metabolism and nutrition digestive system diseases lcsh:Biology (General) Humoral Immunity biology.protein Parasitology Capsid Proteins lcsh:RC581-607 Immunologic Memory Murine norovirus |
Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 9, Iss 9, p e1003592 (2013) |
ISSN: | 1553-7374 1553-7366 |
Popis: | 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. Author Summary Human noroviruses are a significant cause of gastroenteritis outbreaks worldwide and likely the leading cause of severe childhood diarrhea. An efficacious norovirus vaccine would have a major impact on human health but will undoubtedly be confounded by several roadblocks. First, the norovirus genus is highly genetically, and potentially antigenically, diverse. Second, it is currently unclear whether human noroviruses elicit lasting protective immunity upon natural infection. Here, we test the hypothesis that noroviruses display virus strain-specific differences in their stimulation of protective immunity. Indeed, our results reveal that two highly genetically related murine norovirus strains differ dramatically in their stimulation of protective immune responses. Moreover, we demonstrate that antibody and CD4+ T cells are absolutely essential to protecting from a secondary norovirus infection. Finally, we have revealed two viral correlates of protective immunity induction – VF1-mediated cytokine antagonism and VP2-dependent inhibition of antigen presenting cell maturation. Collectively, this information not only offers a potential explanation for the seemingly discordant results regarding human norovirus protective immunity but it also brings to light a previously unrecognized complexity in developing an efficacious human norovirus vaccine – individual virus strains may differ significantly in their interactions with the host immune system and thus in their immunogenicity. |
Databáze: | OpenAIRE |
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