Zika virus infection in the brains of lymphocyte-deficient mice does not lead to neurological symptoms despite sustained high viral load.

Zika virus (ZIKV) infections have been linked to severe neurological disorders, including microcephaly and Guillain-Barré syndrome in humans as well as mouse models of ZIKV infection. Despite the association, the mechanisms underlying ZIKV-induced neuropathology remain incompletely understood. We have recently shown that antigen independent CD8+ T cells mediate neurological disease in ZIKV-infected mice independent of the amount of infectious virus in the CNS. To further investigate the role of brain viral load and lymphocytes in ZIKV infection we studied the viral kinetics, pathology, and immune responses of ZIKV-infected NOD-Rag1-/-Il2rg-/- mice, which are deficient in lymphoid cells. Despite prolonged high viral titers in the brain, NOD-Rag1-/-IL2rg-/- mice did not develop neurological symptoms following ZIKV infection, contrasting with the infection outcomes of Ifnar1-/- mice which exhibit paralysis despite lower viral load. Notably, we observed significant differences in brain myeloid cells in the presence or absence of lymphoid cells. While Ifnar1-/- mice showed robust infiltration of CD45hiCD11b+ cells in the brain, lymphocyte-deficient NOD-Rag1-/-IL2rg-/- mice exhibited reduced recruitment and activation of these cells. Additionally, we found that CD45hiCD11b+ cells displayed a more inflammatory phenotype in Ifnar1-/- mice compared to NOD-Rag1-/-IL2rg-/- mice. Our study highlights the complex interplay between the immune system and viral infection in ZIKV-induced neuropathology and underscores the importance of considering immune responses in the development of therapeutic interventions for ZIKV.