Sunday, May 18, 2025
5/18/2025
Defining Long Term Neurological Consequences Following Asymptomatic ZIKV Infection - Project Summary Recent work has underscored the potential for chronic neurological consequences following systemic viral infections. Although mild and asymptomatic cases make up the vast majority of human viral infections, studies in this area to date have overwhelmingly focused on models of severe viral infection and encephalitis. Zika virus is an emerging flavivirus of global concern that is most known for its connection with congenital sequalae following infection in utero. However, despite possessing tropism for neurons, astrocytes, and neural progenitors, infection in healthy adults is asymptomatic in approximately 80% of cases. We have developed an immunocompetent mouse model of systemic ZIKV infection in which infected animals do not display any clinical illness or differences in weight gain, despite ZIKV being detectable in the brain. In this asymptomatic model, we demonstrate leukocyte recruitment into the brain and the establishment of brain tissue resident memory cells (TRMs) up to 32 weeks post infection. Transcriptomic and metabolomic approaches demonstrate dysfunction in pathways related to inflammation, neurodegeneration, and senescence in the postinfectious brain, while computationally driven behavioral approaches illustrate perturbed movement patterns in freely moving mice at 32 weeks post infection. Based on their deleterious role in other neurotropic infections, we propose that CD8 T cell residence in the brain contributes to the induction and maintenance of these deficits. We thus hypothesize that depletion of CD8 T cells during acute infection will prevent these phenotypes. Results from this proposal will define the neurologic consequences of asymptomatic ZIKV infection while describing roles for CD8 T cells in promoting neurologic sequelae in the postinfectious brain.
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