Influence of Mast Cells on Dengue Protective Immunity and Immune Pathology

Mast cells (MCs) are sentinels for pathogens. They are situated in the skin and mucosae where pathogen encounter is common and surround blood vessels. MCs pre-store vasoactive mediators and cytokines in granules, such as histamine, heparin, proteases, and TNF [1]. Degranulation occurs virtually instantaneously after MC activation by certain pathogen-derived or endogenous products signifying infection or inflammation. While MC activation through pattern recognition receptors, such as TLRs, alone is not usually a sufficient cause for degranulation, degranulationinitiating receptors have been identified for bacterial pathogens (e.g., CD48 for E. coli, M. tuberculosis) [2]. Some viruses trigger degranulation, including dengue, through yet-unknown receptors [2]. MCs also express Fc receptors for binding antibodies, such as FceR1 that binds IgE. MC binding of IgE, or sensitization, heightens degranulation responses to IgE-specific antigens when antibodies are present, as occurs during reinfection [1]. MCs also de novo synthesize products, including leukotrienes, prostaglandins, cytokines, and chemokines [1]. MCs promote protective immunity against pathogens but, paradoxically, they are best characterized for contributing to pathology when they are chronically activated (as in the context of allergy) or when substantial acute activation causes systemic excess of their products (e.g., during anaphylaxis, which can lead to shock). Thus, when misdirected, such as to environmental antigens, or when excessive, prolonged, or systemic, MC responses can harm the host, causing vascular leakage or tissue damage. The potential for MCs to promote a spectrum of disease outcomes, ranging from protective immunity to immune pathology, is apparent during bacterial peritonitis, where MCs either protect from or promote death, depending on the severity of the experimental model [3]. To date, we know little about the role of MCs during acute viral infections [1]. However, evidence has emerged that MCs significantly influence immunity and pathogenesis during dengue virus (DENV) infection.