CONICET | Buscador de Institutos y Recursos Humanos

Coxsackievirus B3 (CVB3) is a globally prevalent enterovirus of the Picornaviridae family that is frequently associated with viral myocarditis (VM). The mechanism underlying the pathogenesis of VM is not well established. Neutrophils, as first-responders, may be key cells in determining viral disease outcome; however, neutrophils have been poorly studied with respect to viral infection. Although neutrophils have been ascribed to have a relevant role in early cardiac inflammation, their precise role in CVB3 infection has not yet been evaluated. In this study, we aimed to determine if the interaction of human neutrophils with CVB3 could lead to viral replication, modulation of neutrophil survival and biological functions, and whether neutrophil depletion in a murine model has a beneficial or harmful effect on CVB3 infection. Our results showed that CVB3 interacted with but did not replicate in human neutrophils. Neutrophils recognized CVB3 mainly through endosomal TLR-8, and infection triggered NFκB activation. Virus internalization resulted in an increased cell survival, an up-regulation of CD11b, an adhesion to fibrinogen and fibronectin, and the secretion of pro-inflammatory cytokines IL-6, IL-1β, TNF-α, and chemokine IL-8. Supernatants from infected neutrophils exerted chemotactic activity mediated by IL-8. The infected neutrophils released myeloperoxidase and triggered neutrophil extracellular traps formation, which was further increased in the presence of TNF-α. In mice infected with CVB3, viral RNA was detected in neutrophils as well as in mononuclear cells. After neutrophil depletion, mice showed a reduced myocarditis reflected by reduction of: viral titers, cell exudate, levels of CCL-2 mRNA and abrogation of the reactive cardiomyocyte hyperthrophy. Our results indicate that neutrophils have relevant direct and indirect roles in the pathogenesis of viral myocarditis.