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1.
Cell Rep ; 31(4): 107566, 2020 04 28.
Article in English | MEDLINE | ID: mdl-32348763

ABSTRACT

The underlying mechanisms by which prior immunity to dengue virus (DENV) affords cross-protection against the related flavivirus Zika virus (ZIKV) are poorly understood. Here, we examine the ability of DENV/ZIKV-cross-reactive CD4+ T cells to protect against versus exacerbate ZIKV infection by using a histocompatibility leukocyte antigen (HLA)-DRB1∗0101 transgenic, interferon α/ß receptor-deficient mouse model that supports robust DENV and ZIKV replication. By mapping the HLA-DRB1∗0101-restricted T cell response, we identify DENV/ZIKV-cross-reactive CD4+ T cell epitopes that stimulate interferon gamma (IFNγ) and/or tumor necrosis factor (TNF) production. Vaccination of naive HLA-DRB1∗0101 transgenic mice with these peptides induces a CD4+ T cell response sufficient to reduce tissue viral burden following ZIKV infection. Notably, this protective response requires IFNγ and/or TNF secretion but not anti-ZIKV immunoglobulin G (IgG) production. Thus, DENV/ZIKV-cross-reactive CD4+ T cells producing canonical Th1 cytokines can suppress ZIKV replication in an antibody-independent manner. These results may have important implications for increasing the efficacy and safety of DENV/ZIKV vaccines and for developing pan-flavivirus vaccines.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , Cross Reactions/immunology , Dengue Virus/immunology , Zika Virus/immunology , Animals , Dengue/immunology , Dengue/virology , Disease Models, Animal , Humans , Mice , Zika Virus Infection/immunology , Zika Virus Infection/virology
3.
PLoS Pathog ; 15(1): e1007474, 2019 01.
Article in English | MEDLINE | ID: mdl-30677097

ABSTRACT

Several Zika virus (ZIKV) vaccines designed to elicit protective antibody (Ab) responses are currently under rapid development, but the underlying mechanisms that control the magnitude and quality of the Ab response remain unclear. Here, we investigated the CD4+ T cell response to primary intravenous and intravaginal infection with ZIKV. Using the LysMCre+Ifnar1fl/fl (myeloid type I IFN receptor-deficient) C57BL/6 mouse models, we identified six I-Ab-restricted ZIKV epitopes that stimulated CD4+ T cells with a predominantly cytotoxic Th1 phenotype in mice primed with ZIKV. Intravenous and intravaginal infection with ZIKV effectively induced follicular helper and regulatory CD4+ T cells. Treatment of mice with a CD4+ T cell-depleting Ab reduced the plasma cell, germinal center B cell, and IgG responses to ZIKV without affecting the CD8+ T cell response. CD4+ T cells were required to protect mice from a lethal dose of ZIKV after infection intravaginally, but not intravenously. However, adoptive transfer and peptide immunization experiments showed a role for memory CD4+ T cells in ZIKV clearance in mice challenged intravenously. These results demonstrate that CD4+ T cells are required mainly for the generation of a ZIKV-specific humoral response but not for an efficient CD8+ T cell response. Thus, CD4+ T cells could be important mediators of protection against ZIKV, depending on the infection or vaccination context.


Subject(s)
Zika Virus Infection/immunology , Zika Virus/immunology , Adoptive Transfer , Animals , Antibodies, Viral/blood , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Immunity, Humoral/immunology , Mice , Mice, Inbred C57BL , Vaccination , Viral Vaccines/immunology , Virus Diseases/metabolism , Zika Virus Infection/virology
4.
Cell Host Microbe ; 24(5): 743-750.e5, 2018 11 14.
Article in English | MEDLINE | ID: mdl-30439343

ABSTRACT

Antibody (Ab)-dependent enhancement can exacerbate dengue virus (DENV) infection due to cross-reactive Abs from an initial DENV infection, facilitating replication of a second DENV. Zika virus (ZIKV) emerged in DENV-endemic areas, raising questions about whether existing immunity could affect these related flaviviruses. We show that mice born with circulating maternal Abs against ZIKV develop severe disease upon DENV infection. Compared with pups of naive mothers, those born to ZIKV-immune mice lacking type I interferon receptor in myeloid cells (LysMCre+Ifnar1fl/fl) exhibit heightened disease and viremia upon DENV infection. Passive transfer of IgG isolated from mice born to ZIKV-immune mothers resulted in increased viremia in naive recipient mice. Treatment with Abs blocking inflammatory cytokine tumor necrosis factor linked to DENV disease or Abs blocking DENV entry improved survival of DENV-infected mice born to ZIKV-immune mothers. Thus, the maternal Ab response to ZIKV infection or vaccination might predispose to severe dengue disease in infants.


Subject(s)
Antibodies, Viral/immunology , Antibody-Dependent Enhancement/immunology , Dengue Virus/immunology , Dengue/immunology , Zika Virus Infection/immunology , Zika Virus/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/immunology , Antibody Formation , Cell Line , Cross Reactions/immunology , Culicidae , Cytokines/metabolism , Dengue Virus/pathogenicity , Disease Models, Animal , Female , Humans , Immunity , Immunoglobulin G , Male , Mice , Mice, Inbred C57BL , Myeloid Cells , Receptor, Interferon alpha-beta/metabolism , Tumor Necrosis Factor-alpha/metabolism , Viremia , Virus Internalization , Zika Virus/pathogenicity , Zika Virus Infection/virology
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