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.

Our results demonstrate that a rapid influx of Ly6C hi monocytes and neutrophils into the dLN triggered by infection with pathogenic, persistent strains of CHIKV reduces the accumulation of lymphocytes, disrupts lymphocyte organization, and impairs the development of virus-specific B cell responses. Preventing the early influx of Ly6C hi monocytes and neutrophils into the dLN improved accumulation of lymphocytes and follicular organization and enhanced dLN GC formation, plasma cell differentiation, and CHIKV-specific serum neutralizing antibody responses. Lymphocyte accumulation and dLN organization was improved in CHIKVinfected mice lacking Nos2 (iNOS) or the phagocyte NADPH oxidase Nox2. Monocytes, but not other cell types, upregulated iNOS following entry into the dLN in a manner dependent on IFNAR1, IRF5, and MyD88, and partially dependent on TLR7. Although IRF3/IRF7-dependent type I IFN production is required for protection from fatal CHIKV infection [37, 46] , we identified an IRF5-dependent pathway acting locally within the dLN following pathogenic CHIKV infection that drives activation of infiltrating monocytes.