Abstract
Author summary Elucidating mechanisms by which viruses subvert B cell immunity and establish persistent infection is essential for the development of new therapeutic strategies against chronic viral infections. The humoral immune response initiates in the lymph node draining the site of viral infection. However, how persistent viruses evade B cell responses is poorly understood. In this study, we ...
Abstract
Author summary Elucidating mechanisms by which viruses subvert B cell immunity and establish persistent infection is essential for the development of new therapeutic strategies against chronic viral infections. The humoral immune response initiates in the lymph node draining the site of viral infection. However, how persistent viruses evade B cell responses is poorly understood. In this study, we find that infection with pathogenic, persistent chikungunya virus triggers rapid recruitment of neutrophils and monocytes to the draining lymph node, which impair structural organization, lymphocyte accumulation, and downstream virus-specific B cell responses that are important for control of infection. This work enhances our understanding of the pathogenesis of acute and chronic CHIKV disease and highlights how local innate immune responses in draining lymphoid tissue dictate the effectiveness of downstream adaptive immunity. 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.
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