Single-cell transcriptomic profiling of brain immune infiltration following Venezuelan equine encephalitis virus infection

Neurotropic alphaviruses such as Venezuelan equine encephalitis virus (VEEV) are critical human pathogens that continually expand to naïve populations and for which there are no licensed vaccines or therapeutics. The neuropathology of VEEV has been attributed to the immune response in the brain yet the underlying mechanisms and specific immune cell populations involved are not fully elucidated. In this study, a murine model of lethal VEEV infection is paired with single-cell RNA sequencing to transcriptionally profile the immune response longitudinally in the brain following infection. Infection-induced immune changes in the brain was also compared to changes in peripheral blood mononuclear cells (PBMCs). The results define an inflammatory response involving transcriptionally distinct subpopulations of activated microglia and infiltrating proinflammatory myeloid populations and cytotoxic lymphocytes. This study advances our understanding of the immune mechanisms underlying viral encephalitis toward the goal of identifying new therapeutic targets. Overall design: Single-cell RNA sequencing was performed on immune cells isolated from the brains and blood of C3H/HeN mice infected intranasally with VEEV TC-83 at 2, 4, and 6 days post infection or from brains of uninfected control mice.