MyD88-dependent influx of monocytes and neutrophils impairs lymph node B cell responses to chikungunya virus infection via Irf5, Nos2 and Nox2

McCarthy, Mary K.; Reynoso, Glennys V.; Winkler, Emma S.; Mack, Matthias; Diamond, Michael S.; Hickman, Heather D.; Morrison, Thomas E.

IRF5 is expressed constitutively in pDCs, classical or conventional DCs (cDCs), M1 macrophages, and B cells, with further upregulation following activation [41, 59, [62] [63] [64] [65] . Upon activation with TLR ligands, IRF5 expression also can be induced in human monocytes, neutrophils, and macrophages [41, 62, 66] . Thus, many immune cell types can express IRF5, either constitutively or upon activation. Viral infections or agonists of TLR7 or TLR9 can activate IRF5 in DCs in vitro in a MyD88-dependent manner [39] [40] [41] . Following pathogenic CHIKV infection, we observed a partial role for TLR7 in iNOS upregulation, suggesting that recognition of endosomal viral RNA contributes to monocyte activation. However, our data suggest role(s) for other MyD88-dependent TLR(s) in activating IRF5 to promote iNOS expression in infiltrating monocytes. One or more of these TLRs may be activated by endogenous damage-associated molecular patterns (DAMPs) released from damaged or dying cells during the early stages of CHIKV infection, either at the site of inoculation or in the dLN. The cell-intrinsic requirements for TLR(s), IRF5, and IFNAR1 expression in dLN monocyte iNOS upregulation during CHIKV infection remain to be determined through the use of conditional knockout mice.