Depletion of cytotoxic lymphocytes shifts brain immune response, promoting blood-brain barrier integrity and survival in Venezuelan equine encephalitis virus infection 3984

Abstract Description The neuropathology observed during Venezuelan equine encephalitis virus (VEEV) infection, including blood-brain barrier (BBB) breakdown, is linked to an overwhelming immune response in the brain, but the roles of specific cell types are not fully elucidated. Here we temporally profiled the immune response to VEEV by performing single cell RNA sequencing on brains of infected mice. This data revealed activation of microglia subsets and their sequential decline in abundance concurrent with infiltration of immune cells, including cytotoxic lymphocytes NK cells and CD8+ T cells. Targeting these cells, we found depletion of NK cells and CD8+ T cells synergistically improved BBB integrity and survival. NK cell-depleted brains have fewer CD8+ T cells and both NK cell-depleted and double-depleted brains have increased microglia. NK cell-depleted infected brains had similar levels of elevated cytokines IFN-a, CCL2, CCL5, and IFN-g, chemokines CXCL1 and CXCL10, and interleukins IL-6 and IL-1b, while having higher IFN-b. Double-depleted brains had strikingly higher levels of each of these proteins, in addition to IL-10, IL-12, GM-CSF, and TNF. Through this work, we have begun profiling immune signatures associated with improved outcomes of VEEV infection, underscoring the utility in understanding complex immune responses for the development of immunomodulatory therapies aimed at limiting BBB dysfunction and improving infection outcomes. Funding Sources [1] This work was performed under the auspices of the U.S. Department of Energy by Lawrence Livermore National Security, LLC, Lawrence Livermore National Laboratory under Contract DEAC52-07NA27344. Topic Categories Viral Immunology (VIR)