Mast cells as rapid innate sensors of cytomegalovirus by TLR3/TRIF signaling-dependent and -independent mechanisms

Abstract

The succinct metaphor, 'the immune system's loaded gun', has been used to describe the role of mast cells (MCs) due to their storage of a wide range of potent pro-inflammatory and antimicrobial mediators in secretory granules that can be released almost instantly on demand to fight invaders. Located at host-environment boundaries and equipped with an arsenal of pattern recognition receptors, MCs are destined to be rapid innate sensors of pathogens penetrating endothelial and epithelial surfaces. Although the importance of MCs in antimicrobial and antiparasitic defense has long been appreciated, their role in raising the alarm against viral infections has been noted only recently. Work on cytomegalovirus (CMV) infection in the murine model has revealed MCs as players in a novel cross-talk axis between innate and adaptive immune surveillance of CMV, in that infection of MCs, which is associated with MC degranulation and release of the chemokine CCL5, enhances the recruitment of protective CD8 T cells to extravascular sites of virus replication, specifically to lung interstitium and alveolar epithelium. Here, we have expanded on these studies by investigating the conditions for MC activation and the consequent degranulation in response to host infection. Surprisingly, the data revealed two temporally and mechanistically distinct waves of MC activation: an almost instant indirect activation that depended on TLR3/TRIF signaling and delayed activation by direct infection of MCs that did not involve TLR3/TRIF signaling. Cell type-specific Cre-recombination that yielded eGFP-expressing reporter virus selectively originating from MCs identified MC as a new in vivo, first-hit target cell of productive murine CMV infection.

Influenza A Viruses Replicate Productively in Mouse Mastocytoma Cells (P815) and Trigger Pro-inflammatory Cytokine and Chemokine Production through TLR3 Signaling Pathway

“…Mast cells used TLR3, RIG-I and MDA5 to sense viral RNA following infection (Kulka et al, 2004; Oldstone and Rosen, 2014; Becker et al, 2015). In a Newcastle disease virus infection model, mast cells produced cytokines and chemokines in a TLR3-dependent manner (To et al, 2001).…”

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.…”

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

“…Mast cells can interact with various immune cells in complex ways, including release of soluble factors and direct contact (11), and are important immune effector and modulatory cells that help to link innate and adaptive immunity in the fight against pathogens (9,(12)(13)(14). They have been shown to be important for host defense against various viruses, such as vesicular stomatitis virus, Sendai virus, hantavirus, reovirus, dengue virus, influenza virus, herpes simplex virus, and murine cytomegalovirus (15)(16)(17)(18)(19)(20)(21)(22)(23). Additionally, mast cells can serve as antigenpresenting cells and participate in traditional immunologic synapse formation with T cells to mediate antigen-specific T cell activation (24).…”