Inflammatory Response of Mast Cells during Influenza A Virus Infection Is Mediated by Active Infection and RIG-I Signaling

Abstract

Influenza A virus (IAV) is a major respiratory pathogen of both humans and animals. The lung is protected from pathogens by alveolar epithelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. The role of alveolar epithelial cells, endothelial cells, and alveolar macrophages during IAV infection has been previously studied. Here we address the role of mast cells during IAV infection. Respiratory infection with A/WSN/33 causes significant disease and immunopathology in C57BL/6 mice, but not B6.Cg-KitW-sh mice that lack mast cells. During in vitro co-culture, A/WSN/33 caused mast cells to release histamine, secrete cytokines and chemokines, and produce leukotrienes. Moreover, when mast cells were infected with IAV, the virus did not replicate within mast cells. Importantly, human H1N1, H3N2, and influenza B virus isolates could also activate mast cells in vitro. Mast cell production of cytokines and chemokines occurs in a RIG-I/MAVS-dependent mechanism; in contrast, histamine production occurred through a RIG-I/MAVS-independent mechanism. Our data highlight that following IAV infection the response of mast cells is controlled by multiple receptors. In conclusion, we have identified a unique inflammatory cascade activated during IAV infection that could potentially be targeted to limit morbidity following IAV infection.

Human Mucosal Mast Cells Capture HIV-1 and Mediate Viral trans -Infection of CD4 + T Cells

“…These dengue virus-activated mast cells recruit natural killer and natural killer T cells to infection sites for viral clearance (18). Mast cells have been demonstrated to play a role in the inflammatory pathology induced by influenza A virus (IAV), as IAV-induced mast cells trigger RIG-I signaling-dependent production of cytokines and chemokines, resulting in a cytokine storm and systemic disease in mice during viral infection (52). Further investigations into whether HIV-1 or other retroviruses can also trigger mast cell activation could be very helpful for the elucidation of host immune responses during primary viral infection.…”

Delayed Inflammatory and Cell Death Responses Are Associated with Reduced Pathogenicity in Lujo Virus-Infected Cynomolgus Macaques

“…Notably, the delay of cell death-related pathways may contribute to improved survival of distinct populations of immune cells, which in turn can alter pathogenesis in the host. The specific induction of mast cell apoptosis early following LUJV infection may partly explain the milder pathology, as mast cells have been associated with inflammatory pathology in response to virus infection (36)(37)(38)(39)(40)(41)(42)(43)(44), including vascular leakage associated with dengue hemorrhagic fever (45). The early selective depletion of mast cells may account for immune responses associated with controlled antiviral responses rather than uncontrolled inflammation and consequent mild disease during LUJV infection.…”

Mast Cells, Basophils and Mucosal Immunity

“…In mice lacking mast cells, influenza virus causes less lung pathology than in mast cell-sufficient mice (Graham et al, 2013). The mast cell mediators tryptase and TNF increase in the nasal mucosa, trachea, lungs, and regional lymph nodes in mice infected with H5N1 influenza, and inhibition of mast cell degranulation decreased lung pathology and improved efficacy of antiviral medications (Hu et al, 2012).…”

“…Certain strains of influenza virus can activate mast cells to release cytokines through a RIG-I-dependent pathway and preformed mediators through a RIG-I-independent pathway, but the virus does not replicate in murine mast cells (Graham et al, 2013). The virus infects human mast cells lines and primary cultured mast cells and starts to replicate, but there is no release of infectious particles, perhaps because the cells may lack the machinery to assemble the virus or because of active antiviral mechanisms (Marcet et al, 2013).…”