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Mast Cells and Influenza a Virus: Association With Allergic Responses and Beyond

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Review

Mast Cells and Influenza a Virus: Association With Allergic Responses and Beyond

Amy C Graham et al. Front Immunol.

Abstract

Influenza A virus (IAV) is a widespread infectious agent commonly found in mammalian and avian species. In humans, IAV is a respiratory pathogen that causes seasonal infections associated with significant morbidity in young and elderly populations, and has a large economic impact. Moreover, IAV has the potential to cause both zoonotic spillover infection and global pandemics, which have significantly greater morbidity and mortality across all ages. The pathology associated with these pandemic and spillover infections appear to be the result of an excessive inflammatory response leading to severe lung damage, which likely predisposes the lungs for secondary bacterial infections. The lung is protected from pathogens by alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. The importance of mast cells during bacterial and parasitic infections has been extensively studied; yet, the role of these hematopoietic cells during viral infections is only beginning to emerge. Recently, it has been shown that mast cells can be directly activated in response to IAV, releasing mediators such histamine, proteases, leukotrienes, inflammatory cytokines, and antiviral chemokines, which participate in the excessive inflammatory and pathological response observed during IAV infections. In this review, we will examine the relationship between mast cells and IAV, and discuss the role of mast cells as a potential drug target during highly pathological IAV infections. Finally, we proposed an emerging role for mast cells in other viral infections associated with significant host pathology.

Keywords: degranulation; dengue virus; inflammation; influenza A virus; mast cell; mast cell activation; viral immunology; viral infection.

Figures

Figure 1
Figure 1
Mast cell activation in response to viral infection. Mast cells are classically known for their response to polyvalent cross-linking of IgE in the FcϵR1 receptor, which is important in protective immunity to helminth worm infection and pathologically associated with allergic disease. However, mast cells also are important tissue sentinel cells for initiating inflammatory response to pathogens. Mast cells can recognize and respond to viruses through several different receptors. These receptors include TLR signaling, such as TLR3 detection of dsRNA, sphingosin-1-phosphate (S1P) binding to its receptor S1PR, and RIG-I recognition of uncapped vRNA. Engagement of these receptors results in mast cell activation leading to immediate degranulation, the de novo synthesis of eicosanoids within minutes of activation, and the de novo synthesis of numerous cytokines, chemokines, and growth factors within hours of activation.
Figure 2
Figure 2
The effects of mast cell activation on the inflammatory environment induced by viruses. Within the tissues, mast cells can be activated by viruses (i) resulting in the secretion of effector molecules (ii). Mast cell-derived effector molecules act within the local tissue environment or at distal site to mediate the accumulation of mast cell progenitors (iii) and leukocytes (iv) to the site of infection. Mast cell accumulation in the infected tissues could be due to either the recruitment and differentiation of mast cell progenitors to the infected tissue and/or proliferation of the tissue-resident mast cell population. Mast cell activation can participate in limiting viral replication in the local tissue and viral dissemination, but if left unchecked can cause significant tissue damage, vascular leakage, and tissue edema. Finally, activated mast cells can survive the pathogenic insult and replenish mast cell granules to return the mast cell to a basal state to survey the tissue for future pathogenic insults (v).
Figure 3
Figure 3
Mast cell inhibitors. Various classes of mast cell inhibitors already exist for the treatment of various conditions. (i) Uninhibited, activated mast cells will degranulate and synthesize eicosanoids, cytokines, and chemokines which are released into the surrounding tissue. (ii) The mast cell stabilizing drugs (e.g., ketotifen, cromolyn, and quercetin) block the release of mast cell granules following activation. (iii) Second broad class of mast cell inhibitors target the activity of specific mast cell mediators. These includes anti-TNF-α compounds, anti-histamines (e.g., hydroxyzine, desloratadine, diphenhydramine, fexofenadine, loratadine), protease antagonists, and leukotriene antagonists (e.g., montelukast, zafirlukast, zileuton). (iv) A potential third class of mast cell inhibitors could target the recruitment of mast cells to inflamed tissue following infection.

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