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.

We next evaluated the molecular pathways that promote iNOS expression in monocytes infiltrating the dLN. Many inflammatory stimuli can induce iNOS expression, including type I IFNs [36] . Indeed, type I IFN receptor signaling was required for expression of iNOS in dLN monocytes following CHIKV infection (Fig 7A and 7B) . Type I IFN signaling and either IRF3 or IRF7 are required for protection from fatal CHIKV infection, with IRF7 responsible for systemic type I IFN production [37, 38] . Unexpectedly, both IRF3 and IRF7 were dispensable for iNOS induction in dLN monocytes (Fig 7A and 7B) . Instead, Irf3 -/-Irf5 -/-Irf7 -/triple knockout mice showed diminished monocyte iNOS expression similar to that of Ifnar1 -/mice, suggesting a requirement for IRF5. The dependency on IRF5 for monocyte iNOS expression was confirmed in Irf5 -/mice (Fig 7C and 7D) . Together, these data suggest that IRF5-and IFNAR1-dependent signals act locally in the dLN to induce iNOS expression in infiltrating monocytes during pathogenic CHIKV infection.