Mast Cell-Derived Proteases Induce Endothelial Permeability and Vascular Damage in Severe Fever with Thrombocytopenia Syndrome

Microbiology Spectrum

Hao Li¹  Yu-Na Wang¹  Ling-Yu Zhang¹  Shuang Li¹  Gang Wang¹  Xiao-Ai Zhang¹  Yun-Fa Zhang¹  Yue Li¹  Heng Ding¹  Jing-Tao Zhang¹  Xue-Fang Peng¹  Hong-Han Ge¹  Wei Liu¹ 

[1] State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, Hebei, China;

关键词: SFTSV;    chymase;    mast cell;    tryptase;    vascular damage;   

DOI  :  10.1128/spectrum.01294-22

来源: DOAJ

【 摘 要 】

ABSTRACT Severe fever with thrombocytopenia syndrome (SFTS) is an emerging hemorrhagic fever acquired by tick bites. Whether mast cells (MCs), the body’s first line of defense against pathogens, might influence immunity or pathogenesis during SFTS virus (SFTSV) infection remained unknown. Here, we found that SFTSV can cause MC infection and degranulation, resulting in the release of the vasoactive mediators, chymase, and tryptase, which can directly act on endothelial cells, break the tight junctions of endothelial cells and threaten the integrity of the microvascular barrier, leading to microvascular hyperpermeability in human microvascular endothelial cells. Local activation of MCs (degranulation) and MC-specific proteases-facilitated endothelial damage were observed in mouse models. When MC-specific proteases were injected subcutaneously into the back skin of mice, signs of capillary leakage were observed in a dose-dependent manner. MC-specific proteases, chymase, and tryptase were tested in the serum collected at the acute phase of SFTS patients, with the higher level significantly correlated with fatal outcomes. By performing receiver operator characteristic curve (ROC) analysis, chymase was determined as a biomarker with the area under the curve value of 0.830 (95% CI = 0.745 to 0.915) for predicting fatal outcomes in SFTS. Our findings highlight the importance of MCs in SFTSV-induced disease progression and outcome. An emerging role for MCs in the clinical prognosis and blocking MC activation as a potential drug target during SFTSV infection was proposed. IMPORTANCE We revealed a pathogenic role for MCs in response to SFTSV infection. The study also identifies potential biomarkers that could differentiate patients at risk of a fatal outcome for SFTS, as well as novel therapeutic targets for the clinical management of SFTS. These findings might shed light on an emerging role for MCs as a potential drug target during infection of other viral hemorrhagic fever diseases with similar host pathology as SFTS.

【 授权许可】

Unknown