Role of neutrophils in CVB3 infection and viral myocarditis

Abstract

Coxsackievirus B3 (CVB3) is a globally prevalent enterovirus of the Picornaviridae family that is frequently associated with viral myocarditis (VM). Neutrophils, as first responders, may be key cells in determining viral disease outcomes; however, neutrophils have been poorly studied with respect to viral infection. Although neutrophils have been ascribed 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 between human neutrophils and CVB3 could lead to viral replication and/or 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 show 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 increased cell survival, up-regulation of CD11b, enhanced adhesion to fibrinogen and fibronectin, and the secretion of IL-6, IL-1β, TNF-α, and IL-8. Supernatants from infected neutrophils exerted chemotactic activity partly mediated by IL-8. The infected neutrophils released myeloperoxidase and triggered neutrophil extracellular trap formation 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 reduced VM reflected by a reduction in viral titers, cell exudates, and CCL-2 mRNA levels, as well as the abrogation of reactive cardiomyocyte hypertrophy. Our results indicate that neutrophils have relevant direct and indirect roles in the pathogenesis of CVB3-induced VM.

IL-6 and IL-8 secreted by tumour cells impair the function of NK cells via the STAT3 pathway in oesophageal squamous cell carcinoma

“…For instance, IL-6 inhibits the anticancer response by dampening the IL27/STAT1 signalling pathway [51]. IL-8 is mainly responsible for the recruitment of neutrophils, basophils and T cells [52, 53]. Moreover, accumulated evidence has revealed that IL-8 promotes angiogenesis and metastasis in tumour cells [54].…”

Pathogenic Role of an IL-23/γδT17/Neutrophil Axis in Coxsackievirus B3–Induced Pancreatitis

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Myocarditis and inflammatory cardiomyopathy: current evidence and future directions

“…This mobilization occurs earlier than that of any other infiltrated innate immune cells. Depletion of neutrophils in CVB3-infected mice results in reduced myocarditis 92 . Neutrophils can maintain inflammation by a specific process called NETosis, which involves the formation of neutrophil extracellular traps.…”