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.

Type I IFN signaling can modulate monocyte activation and differentiation, with contextdependent pro-inflammatory or anti-inflammatory effects [36, 54, 57, 58] . Although not required for recruitment of monocytes to the dLN after pathogenic CHIKV infection, type I IFN signaling drives iNOS expression in monocytes following entry into the dLN. Furthermore, IRF5, but not IRF3 or IRF7, was responsible for induction of iNOS. IRF3 or IRF7 are required for protection from fatal CHIKV infection, with systemic type I IFN production being driven by the IRF7 response [37, 38] . However, the contribution of type I IFN signaling and additional IRFs in other aspects of alphavirus pathogenesis remains poorly defined. Our work suggests that an IRF5-dependent pathway acts locally in draining lymphoid tissue following infection with CHIKV, whereas IRF3/7-dependent pathways are activated at the site of inoculation. Studies in IRF5-overexpressing cells found that IRF5 induces a distinct subset of IFNα genes compared with other IRFs, such as IRF7 [59] . In addition to IFNα, IRF5 also promotes the transcription of genes encoding proinflammatory cytokines, such as Il12b, Tnfa, and Il6 [41] and several chemokines [60] . Similar to our observations, IRF5 promotes the induction of several proinflammatory cytokines and chemokines, as well as recruitment and activation of lymphocytes in the dLN following West Nile Virus (WNV) infection of mice [61] . However, these IRF5-dependent responses were ultimately protective by limiting viral spread and promoting optimal B cell immunity. In contrast, our data suggest that pathogenic strains of CHIKV trigger an IRF5-dependent inflammatory pathway in the dLN that activates infiltrating monocytes and neutrophils, ultimately causing disruption of dLN architecture and decreased virus-specific B cell responses.