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

• Published in: PLoS pathogens Vol. 16; no. 1; p. e1008292
• Main Authors: McCarthy, Mary K., Reynoso, Glennys V., Winkler, Emma S., Mack, Matthias, Diamond, Michael S., Hickman, Heather D., Morrison, Thomas E.
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.01.2020; Public Library of Science (PLoS)
• Subjects: Animals; Antigens; Antiviral drugs; Arthritis; B-Lymphocytes - immunology; Biology and Life Sciences; Cell activation; Chikungunya Fever - immunology; Chikungunya Fever - virology; Chikungunya virus; Chikungunya virus - physiology; Chronic infection; CYBB protein; Funding; Humans; Immune response; Immune response (humoral); Immunology; Infections; Infectious diseases; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - immunology; Laboratories; Leukocytes (neutrophilic); Lymph nodes; Lymph Nodes - immunology; Lymph Nodes - virology; Lymphatic system; Lymphocytes; Medicine; Medicine and Health Sciences; Mice, Inbred C57BL; Mice, Knockout; Monocytes; Monocytes - immunology; Mosquitoes; MyD88 protein; Myeloid Differentiation Factor 88 - genetics; Myeloid Differentiation Factor 88 - immunology; NAD(P)H oxidase; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - immunology; Neutrophils; Neutrophils - immunology; Nitric oxide; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - immunology; Nitric-oxide synthase; Pathogenesis; Recruitment; Research and Analysis Methods; RNA viruses; Supervision; TLR7 protein; Toll-like receptors; Vector-borne diseases; Viral infections; Viruses; United States > US; Maryland; Colorado; Missouri
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1008292

Humoral immune responses initiate in the lymph node draining the site of viral infection (dLN). Some viruses subvert LN B cell activation; however, our knowledge of viral hindrance of B cell responses of important human pathogens is lacking. Here, we define mechanisms whereby chikungunya virus (CHIKV), a mosquito-transmitted RNA virus that causes outbreaks of acute and chronic arthritis in humans, hinders dLN antiviral B cell responses. Infection of WT mice with pathogenic, but not acutely cleared CHIKV, induced MyD88-dependent recruitment of monocytes and neutrophils to the dLN. Blocking this influx improved lymphocyte accumulation, dLN organization, and CHIKV-specific B cell responses. Both inducible nitric oxide synthase (iNOS) and the phagocyte NADPH oxidase (Nox2) contributed to impaired dLN organization and function. Infiltrating monocytes expressed iNOS through a local IRF5- and IFNAR1-dependent pathway that was partially TLR7-dependent. Together, our data suggest that pathogenic CHIKV triggers the influx and activation of monocytes and neutrophils in the dLN that impairs virus-specific B cell responses.