Severity of SARS-CoV-2 infection is associated with high numbers of alveolar mast cells and their degranulation

Abstract

BackgroundThe systemic inflammatory response post-SARS-CoV-2 infection increases pro-inflammatory cytokine production, multi-organ damage, and mortality rates. Mast cells (MC) modulate thrombo-inflammatory disease progression (e.g., deep vein thrombosis) and the inflammatory response post-infection.ObjectiveTo enhance our understanding of the contribution of MC and their proteases in SARS-CoV-2 infection and the pathogenesis of the disease, which might help to identify novel therapeutic targets.MethodsMC proteases chymase (CMA1), carboxypeptidase A3 (CPA3), and tryptase beta 2 (TPSB2), as well as cytokine levels, were measured in the serum of 60 patients with SARS-CoV-2 infection (30 moderate and 30 severe; severity of the disease assessed by chest CT) and 17 healthy controls by ELISA. MC number and degranulation were quantified by immunofluorescent staining for tryptase in lung autopsies of patients deceased from either SARS-CoV-2 infection or unrelated reasons (control). Immortalized human FcεR1+c-Kit+ LUVA MC were infected with SARS-CoV-2, or treated with its viral proteins, to assess direct MC activation by flow cytometry.ResultsThe levels of all three proteases were increased in the serum of patients with COVID-19, and strongly correlated with clinical severity. The density of degranulated MC in COVID-19 lung autopsies was increased compared to control lungs. The total number of released granules and the number of granules per each MC were elevated and positively correlated with von Willebrand factor levels in the lung. SARS-CoV-2 or its viral proteins spike and nucleocapsid did not induce activation or degranulation of LUVA MC in vitro.ConclusionIn this study, we demonstrate that SARS-CoV-2 is strongly associated with activation of MC, which likely occurs indirectly, driven by the inflammatory response. The results suggest that plasma MC protease levels could predict the disease course, and that severe COVID-19 patients might benefit from including MC-stabilizing drugs in the treatment scheme.

Mechanisms of COVID-19 Associated Pulmonary Thrombosis: A Narrative Review

“…Proteases released from MCs further enhance cell viral entry, as MC-derived chymase interacts with SARS-CoV-2 S protein [ 71 ]. The MC degranulation degree rather than their total number is associated with the prothrombotic phenotype typical of COVID-19 [ 72 ]. Under IL-4 expression, early recruiting of CD 117 + MC progenitors in the alveolar septa will lead to MC proliferation/differentiation, and once activated, they will orchestrate the crosstalk between proinflammatory and procoagulative networks, such as the complement and the plasma kallikrein-kinin system [ 73 ].…”

“…MC activation with subsequent degranulation in the respiratory tract submucosa will release high levels of IL-1, IL-6, and TNF-α, but also other proteins such as matrix metalloproteinase 9 (MMP-9), PAF, substance P, transforming growth factor beta (TGF-β), TXB2, and vascular endothelial growth factor (VEGF), which will contribute to the pathogenesis as proinflammatory and prothrombotic molecular factors [ 77 , 78 ]. MCs and their associated proteases, chymase (CMA1), carboxypeptidase A3, and tryptase beta 2, also modulate indirectly the systemic thrombo–inflammatory response in patients with SARS-CoV-2 pneumonia, as they induce thrombosis through activation of clotting factors and platelets, and this may affect the relatively high incidence of pulmonary thrombotic events in COVID-19 [ 69 , 72 ].…”

“…Immune cells, such as macrophages, monocytes, MCs, T cells, DCs, NK cells, and neutrophils, “orchestrate” the crosstalk between proinflammatory and procoagulative networks [ 4 , 18 , 43 , 44 , 45 , 46 , 47 , 48 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 113 , 114 , 115 , 129 , 131 ].…”

“…Cytokines, especially IL-1 and IL-6, and chemokines are involved in all phases of inflammation and thrombosis, using multiple biological pathways [ 18 , 29 , 43 , 44 , 45 , 50 , 51 , 58 , 59 , 60 , 61 , 62 , 66 , 69 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 93 , 94 , 101 , 103 , 129 , 132 , 136 , 137 , 138 ].…”

“…Activated clotting factors from extrinsic, common, and intrinsic coagulation pathways are involved in SARS-CoV-2-associated immunothrombosis [ 11 , 18 , 19 , 39 , 47 , 48 , 66 , 69 , 72 , 73 , 77 , 78 , 81 , 88 , 89 , 94 , 128 , 129 , 130 , 131 ].…”