Oligodendrocyte-derived IL-33 functions as a microglial survival factor during neuroinvasive flavivirus infection

In order to recover from infection, organisms must balance robust immune responses to pathogens with the tolerance of immune-mediated pathology. This balance is particularly critical within the central nervous system, whose complex architecture, essential function, and limited capacity for self-renewal render it susceptible to both pathogen- and immune-mediated pathology. Here, we identify the alarmin IL-33 and its receptor ST2 as critical for host survival to neuroinvasive flavivirus infection. We identify oligodendrocytes as the critical source of IL-33, and microglia as the key cellular responders. Notably, we find that the IL-33/ST2 axis does not impact viral control or adaptive immune responses; rather, it is required to promote the activation and survival of microglia. In the absence of intact IL-33/ST2 signaling in the brain, neuroinvasive flavivirus infection triggered aberrant recruitment of monocyte-derived peripheral immune cells, increased neuronal stress, and neuronal cell death, effects that compromised organismal survival. These findings identify IL-33 as a critical mediator of CNS tolerance to pathogen-initiated immunity and inflammation. To study the contribution of Il33 to CNS immune responses to flavivirus infection, we used wildtype and IL33 knockout mouse model that were intracranially infected with the attenuated WNV-E218A strain. At 7 days post infection, brains were collected for anti F4/80 MACS mediated isolation of microglia and peripheral monocyte derived macrophages for RNA-seq. The RNA-seq data generated was used to perform a comparative analysis beween Il33 knockout and wildtype CNS immune responses to WNV-E218A infection.