Abstract
SARS-CoV-2 infection-induced hyper-inflammation links to the acute lung injury and COVID-19 severity. Identifying the primary mediators that initiate the uncontrolled hypercytokinemia is essential for treatments. Mast cells (MCs) are strategically located at the mucosa and beneficially or detrimentally regulate immune inflammations. In this study, we showed that SARS-CoV-2-triggered MC degranulation initiated alveolar epithelial inflammation and lung injury. SARS-CoV-2 challenge induced MC degranulation in ACE-2 humanized mice and rhesus macaques, and a rapid MC degranulation could be recapitulated with Spike-RBD binding to ACE2 in cells; MC degranulation altered various signaling pathways in alveolar epithelial cells, particularly, the induction of pro-inflammatory factors and consequential disruption of tight junctions. Importantly, the administration of clinical MC stabilizers for blocking degranulation dampened SARS-CoV-2-induced production of pro-inflammatory factors and prevented lung injury. These findings uncover a novel mechanism for SARS-CoV-2 initiating lung inflammation, and suggest an off-label use of MC stabilizer as immunomodulators for COVID-19 treatments.
Highlights
The Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic
To seek drug candidates that may modulate Mast cells (MCs) degranulation MC stabilizers reduce SARS-CoV-2-induced lung inflammation and and consequential cytokine release, we examined the known MC prevent lung injury in mice stabilizer Sodium cromoglicate (Sod. crom.), and the histamine To test whether the above observation derived from in vitro study receptor 1 (HR1) antagonists Ketotifen Fumarate (Ket.), Ebastine could be applied to the actual infection in vivo, we went back to (Eba.) and Loratadine (Lor.), which are routinely used for treating human allergy
In this study, we demonstrate a pivotal role of MCs in SARS-CoV-2induced epithelial inflammation and lung injury in vivo and elucidate its possible mechanisms in vitro
Summary
The Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. The pathological damage of both alveoli epithelial cells and capillary endothelial score was assessed according to the degree of lung tissue lesions cells during SARS-CoV-2 infection,[36,37,38] during which infected and MC count in lung sections was calculated (Fig. 1i). The pathological score was assessed according to the degree cells in allergy, MCs can interact with various immune cells of lung tissue lesions and MC count in lung sections was through release of soluble factors or direct contact to beneficially or detrimentally regulate immune inflammations.[41,42,43] A variety of calculated (Supplementary Fig. 2i) Taken together, these data demonstrate convincingly that SARS-CoV-2 infection induces MC pathogens including DNA/RNA virus, fungi, bacteria or their accumulation and degranulation around the area of lung lesion products can activate MCs, and induce secretion of cytokines and in ACE2-humanized mice.
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