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. Overall design: 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.