bioRxiv2023
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. Author SummaryThe central nervous system (CNS) is an extraordinarily complex organ system with limited capacity for repair and renewal. When infectious pathogens invade the CNS, resulting immune responses must clear the pathogen while limiting immune-mediated tissue pathology. IL-33 is an "alarmin" cytokine, whose release from dying cells can promote a variety of immune responses. IL-33 is expressed at high levels in the brain, and previous work has implicated signaling by IL-33 in CNS development as well as in the response to parasitic infection of the CNS. Here, we identify IL-33 as a key mediator of disease tolerance in the context of neuroinvasive infection with the flaviviruses West Nile virus and Zika virus. Notably, we find that IL-33 signaling is not involved in the clearance of virus from the brain; rather, IL-33 is required to promote the survival and reprogramming brain-resident immune cells (microglia). When IL-33 signaling is disrupted in mice, flavivirus infection results in defective microglial activation, increased death of both microglia and neurons, increased invasion of the brain by peripheral immune cells, and increased host death. This work suggests that IL-33 is a key mediator of host tolerance upon neuroinvasive flavivirus infection.