Mast cell activation in lungs during SARS-CoV-2 infection associated with lung pathology and severe COVID-19

Abstract

Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens and often promote inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and nonhuman primates. Using a mouse model of MC deficiency, MC-dependent interstitial pneumonitis, hemorrhaging, and edema in the lung were observed during SARS-CoV-2 infection. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype in severe disease. MC activation in humans was confirmed through detection of MC-specific proteases, including chymase, the levels of which were significantly correlated with disease severity and with biomarkers of vascular dysregulation. These results support the involvement of MCs in lung tissue damage during SARS-CoV-2 infection in animal models and the association of MC activation with severe COVID-19 in humans, suggesting potential strategies for intervention.

Mast cell activation triggered by SARS-CoV-2 causes inflammation in brain microvascular endothelial cells and microglia

“…Other than brain, the rapidly induced MC degranulation in various tissues, including lung, trachea, heart, and intestines, could offer an explanation of multi-focal SARS-CoV-2–induced inflammation and damages (our submitted data). Our research, along with others’, has recently reported that SARS-CoV-2–induced MC massive accumulation and rapid degranulation caused lung inflammation and injury in mice and nonhuman primates ( Wu et al., 2021 , 2022 ; Tan et al., 2023 ). The severity of SARS-CoV-2 infection is associated with high number of alveolar MCs and their degranulation ( Krysko et al., 2022 ).…”

“…In SARS-CoV-2 infection, the post-mortem lung biopsies of COVID-19 patients show a massive increase in the density of perivascular and septal MCs ( Motta Junior et al., 2020 ; Budnevsky et al., 2022 ; Schaller et al., 2022 ). Our research, along with others’, has recently reported that SARS-CoV-2–induced massive MC accumulation and rapid degranulation caused lung inflammation and damage both in mice and nonhuman primate models ( Wu et al., 2021 , 2022 ; Tan et al., 2023 ). The severity of SARS-CoV-2 infection is associated with high number of alveolar MCs and their degranulation ( Krysko et al., 2022 ).…”

ATP/IL-33-Co-Sensing by Mast Cells (MCs) Requires Activated c-Kit to Ensure Effective Cytokine Responses

“…In addition to such allergic reactions, we suggest that the co-sensing of ATP and IL-33 by MCs also contributes to the development of pulmonary diseases such as COVID-19. Interestingly, in lung tissues of SARS-CoV2-infected humans and mice, hyperactivated MCs were found [19][20][21]. Thereby, the presence of hyperactivated MCs correlated with the strongly elevated levels of IL-33 [22,23], ATP [24] and MC proteases [19] in the serum of COVID-19 patients.…”

Potential Pathways and Pathophysiological Implications of Viral Infection-Driven Activation of Kallikrein–Kinin System (KKS)

“…In this context, degranulating mast cells, as well as elastase and NET-secreting neutrophils, are potential candidates for KKS amplification during SARS-CoV-2 infection ( Figure 3 , panel 1). Mast cell degranulation was detected in the lungs of mouse and nonhuman primate models of COVID-19 [ 158 ]. Also, increased levels of circulating chymase were detected in hospitalized patients in comparison with healthy donors or individuals with mild disease.…”