NEUROPATHOGENESIS OF ZIKA VIRUS INFECTIONS

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SUMMARY Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus of global public health concern due to its ability to cause severe congenital abnormalities during infections of pregnant women2, and meningoencephalitis or post-infectious autoimmune demyelination in infected, non-pregnant adults. Host-viral interactions that control infection and dissemination of ZIKV remain poorly characterized, as are post-infectious effects on brain development and function in congenital and adult infections, respectively. We have developed both congenital and adult models of ZIKV infection that have been instrumental in defining many pathogenic features of ZIKV infection. In preliminary studies, mice with deficiencies in lymphocytes (Rag1-/-), B cells (μMT-/-) or T cell function (TCR-/-) exhibited differential abilities to clear virus depending on the manner of exposure. Thus, μMT-/- mice exhibited increased pathogenesis in congenital models of ZIKV infection while Rag1-/- and TCR-/- adult mice exhibited decreased survival after intracranial infection with ZIKV. We hypothesize that antigen-specific T cells are required to eliminate ZIKV from the brain of adult mice, whereas humoral immunity plays the dominant role in clearance of ZIKV during congenital infection. Aim 1 we will define mechanisms of immune-mediated clearance during congenital and adult ZIKV infection of the CNS. While 30% of congenitally infected fetuses exhibit morphological abnormalities by ultrasound (e.g., microcephaly or brain calcifications)12, the majority of congenitally infected humans exhibit no morphological or structural abnormalities. Cognitive impairment and neurodevelopmental abnormalities are likely to occur after congenital ZIKV infection, but there may also be important effects on neurodevelopment after in utero infection. In addition, memory disturbances in adults that have recovered from acute ZIKV infection have recently been reported in the literature. One possible mechanism involves ZIKV infection of neural stem cells and early neural cell type progenitors. However, in preliminary studies of ZIKV-recovered adult mice, we observed persistent microglial activation, decreased SGZ neurogenesis and severe spatial learning defects, the latter of which is ameliorated by lack of signaling via the interferon-γ receptor (IFNγR). These studies suggest adaptive immune mechanisms may also contribute to memory dysfunction in adults recovering from ZIKV encephalitis. We hypothesize that congenital infection with ZIKV leads to alterations in cognition due to direct effects on neuronal progenitors and indirect disruption of radial glial function, leading to abnormalities in functional connectivity. We further hypothesize that the persistence of CD8+IFNγ+ T cells within the CNS of adult ZIKV- recovered animals promotes microglial activation, which alter neural correlates of learning and memory such as synaptic plasticity and adult neurogenesis. Aims 2 and 3 will define the mechanisms of spatial memory dysfunction during adult and congenital infection with ZIKV and determine the effects of congenital ZIKV infection on cerebral functional connectivity using optical neuroimaging.