Document text
Principal Investigator: Mariah A Hassert
Organization: SAINT LOUIS UNIVERSITY
Fiscal Year: 2020
Award: $30,773
Funding agency: National Institute of Allergy and Infectious Diseases
Zika virus (ZIKV) spread explosively throughout the Americas in 2015, leaving in its wake a devastating and
ever-expanding list of sequela associated with infection. Since this epidemic, substantial effort has been put forth
to understand the emergence of ZIKV in the Americas, the course of disease and importantly, the correlates of
protection. ZIKV is a member of the flavivirus genus which includes other arthropod-borne human pathogens
such as yellow fever virus (YFV), West Nile virus (WNV), and the four serotypes of dengue virus (DENV). In
addition to circulating in mosquito populations in the same geographic regions, flaviviruses share a substantial
degree of genetic, and consequently antigenic similarity. This begs the question: In areas of endemic flavivirus
circulation, how does immunity to one flavivirus shape immunity to the next? Moreover, how does this divergent
immune restriction alter the viral swarms that replicate within the host? These questions are of great importance
due to what we know about DENV. The enhanced disease seen in secondary infection with a heterologous
serotype of DENV has been hypothesized to be mediated by both suboptimal cross-reactive antibody and T cell
responses. The proposed research study is to define how exposure to a heterologous flavivirus shapes the
transcriptional and functional T cell response to ZIKV in a mouse model of infection, and how those T cells in
turn impact viral populations within the host and ultimately pathogenesis.
We have shown previously that CD4+ and CD8+ T cells play important roles in protection from ZIKV disease in a
mouse model of infection and were able to identify specific epitopes to which the responses are directed in this
H2b-restricted model. We have also generated data showing that effector CD8+ T cells generated during infection
with DENV1-4, YFV, Usutu virus, Kunjin virus or WNV functionally cross-react with at least one ZIKV CD8+
epitope, which we are terming a “pan-flavivirus” epitope. We have found that prior infection with a heterologous
flavivirus results in altered phenotypic responses to this cross-reactive epitope during a subsequent ZIKV
infection compared to a homologous ZIKV prime-boost challenge or a primary ZIKV challenge. One specific
example of this is that cross-reactive cells derived from a heterologous infection produce far more Granzyme B
relative to homologously derived cells. However, it is still unknown what drives these functional changes and
how they impact protection from ZIKV-induced disease, which will be evaluated in Aim 1. More recently, it is
being appreciated that different immune selective pressures can impact the viral populations that evolve within
the host during infection, particularly in RNA viruses. How this observed altered T cell function during
heterologous ZIKV infection alters viral quasispecies diversity within the host will be evaluated in Aim 2.
Terms: <Activities of Daily Living><Activities of everyday life><Address><Americas><Animals><Antibodies><Antigenic Determinants><Area><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding Determinants><Blood Circulation><Bloodstream><Breakbone Fever Virus><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cell Body><Cell Function><Cell Process><Cell physiology><Cells><Cellular Function><Cellular Physiology><Cellular Process><Circulation><Costs and Benefits><Culicidae><Cytoplasmic Granules><Data><Dengue><Dengue Virus><Dengue fever virus><Disease><Disease Outcome><Disorder><Egypt 101 virus><Epidemic><Epitopes><Exposure to><Flavivirus><Flavivirus Infections><Gene Transcription><Generations><Genetic><Genetic Transcription><Geographic Area><Geographic Locations><Geographic Region><Geographical Location><Granzyme><Group B Arbovirus><Human><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologics><Incidence><Individual><Infection><Infection Control><KUNV><Kunjin virus><LYT3><Mediating><Memory><Mice><Mice Mammals><Modeling><Modern Man><Mosquitoes><Murine><Mus><NGS Method><NGS system><Outcome><Pathogenesis><Phenotype><Play><Population><Production><RNA Expression><RNA Viruses><RNA vaccine><Role><Serotyping><Shapes><South America><Specificity><Subcellular Process><T cell response><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Transcription><Transcription Alteration><Vaccination><Vaccine Design><Vaccines><Viral><Viral Diseases><Virus><Virus Diseases><WNV><West Nile><West Nile virus><Yellow Fever><Yellow fever virus><ZIKA><ZIKV><ZIKV disease><ZIKV infection><ZIKV positive><Zika Virus><Zika virus disease><Zika virus infection><antigen-specific T cells><arthropod-borne><arthropodborne><base><cross reactivity><daily living functionality><experience><functional ability><functional capacity><geographic site><granule><host response><human pathogen><immunopathology><immunoresponse><improved><in vivo><mRNA vaccine><member><mouse model><murine model><next gen sequencing><next generation sequencing><nextgen sequencing><pathogen><preservation><pressure><research study><response><secondary infection><seropositive><single cell sequencing><social role><thymus derived lymphocyte><viral infection><virus infection><virus-induced disease><zika disease><zika infection><zika viral infection><zikav>