Rotavirus (RV) infects small intestinal epithelial cells, inducing severe diarrhea in children, resulting in over 500,000 deaths annually. Relatively little is known about how innate immunity contains acute infection and drives adaptive immune responses that afford complete clearance of RV and protection against future infection. Hence, we examined the consequence of the absence of MyD88, known to be central to innate immunity, in a mouse model of RV infection. The absence of MyD88, but not combined blockade of IL-1β and IL-18 signaling, resulted in greater infectivity, as reflected by levels of RV in feces, intestinal lysates and viremia. Such increased RV levels correlated with an increase in incidence and duration of diarrhea. Loss of MyD88 also impaired humoral immunity to RV. Specifically, MyD88 knockout generated less RV-specific IgA and exhibited profoundly reduced RV-specific IgG2c/IgG1 ratios suggesting that MyD88 signaling drives RV-induced Th1 responses. A study of MyD88 bone marrow chimeras indicated that MyD88-dependent control of acute RV infection was mediated by both hemopoietic and non-hemopoietic cells, while generation of RV-specific humoral immunity was driven by MyD88 signaling in hemopoietic cells, which reflected the loss of IL-1β and IL-18 expression by these cells. Thus, TLR signaling and inflammasome cytokines drive innate and adaptive immunity to RV.
Keywords: MyD88; Rotavirus; Toll-like receptors; antibody; inflammasome.
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