Loss of the TAM Receptor Axl Ameliorates Severe Zika Virus Pathogenesis and Reduces Apoptosis in Microglia

The TAM receptor, Axl, has been implicated as a candidate entry receptor for Zika virus (ZIKV) infection but has been shown as inessential for virus infection in mice. To probe the role of Axl in murine ZIKV infection, we developed a mouse model lacking the Axl receptor and the interferon alpha/beta receptor (Ifnar−/−Axl−/−), conferring susceptibility to ZIKV. This model validated that Axl is not required for murine ZIKV infection and that mice lacking Axl are resistant to ZIKV pathogenesis. This resistance correlates to lower pro-interleukin-1β production and less apoptosis in microglia of ZIKV-infected mice. This apoptosis occurs through both intrinsic (caspase 9) and extrinsic (caspase 8) manners, and is age dependent, as younger Axl-deficient mice are susceptible to ZIKV pathogenesis. These findings suggest that Axl plays an important role in pathogenesis in the brain during ZIKV infection and indicates a potential role for Axl inhibitors as therapeutics during viral infection. [Display omitted] •IFNAR−/−Axl−/− mice show Axl unnecessary for Zika virus replication in mice•Mice lacking Axl receptor are significantly resistant to Zika virus neuropathogenesis•IFNAR−/−Axl−/− mice have less ZIKV-driven caspase-dependent apoptosis in brain•Axl deficient mice have fewer apoptotic microglia after ZIKV infection Biological Sciences; Neurotoxicology; Virology