Abstract
Abstract Mast cells (MCs) promote immunosurveillance for pathogens in peripheral tissues and line the host vasculature. We observe that MC are activated by dengue virus (DENV), a flavivirus that is spread by mosquito vectors. MC activation by DENV during viremia elevates systemic levels of their vasoactive products, including the MC-specific protease, chymase, and promotes vascular leakage. Symptoms of DENV infection in humans include widespread vascular leakage, pooling of fluid within internal organs and, occasionally, severe hemorrhaging; however, the processes that underlie the immune-mediated vascular pathology during dengue infection are largely unknown. A component of dengue-induced vascular leakage is MC-dependent since mice that lack MCs have greatly reduced vascular permeability during infection. We show that treatment of infected animals with MC-stabilizing drugs restores vascular integrity during experimental DENV infection. Validation of these findings using human clinical samples revealed a direct correlation between MC activation and DENV disease severity based on the measurement of chymase as a serum biomarker. Our findings reveal that MCs mediate DENV-induced vascular pathology, and suggest MC-stabilizing drugs should be evaluated for their effectiveness in improving disease outcomes during viral hemorrhagic fevers.
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