Mast cell activation in lungs during SARS-CoV-2 infection associated with lung pathology and severe COVID-19
Janessa Y.J. Tan, … , Jörn Karhausen, Ashley L. St. John
Janessa Y.J. Tan, … , Jörn Karhausen, Ashley L. St. John
Published August 10, 2023
Citation Information: J Clin Invest. 2023;133(19):e149834. https://doi.org/10.1172/JCI149834.
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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.

Authors

Janessa Y.J. Tan, Danielle E. Anderson, Abhay P.S. Rathore, Aled O’Neill, Chinmay Kumar Mantri, Wilfried A.A. Saron, Cheryl Q.E. Lee, Chu Wern Cui, Adrian E.Z. Kang, Randy Foo, Shirin Kalimuddin, Jenny G. Low, Lena Ho, Paul Tambyah, Thomas W. Burke, Christopher W. Woods, Kuan Rong Chan, Jörn Karhausen, Ashley L. St. John

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Figure 3

MC-dependent lung pathology in SARS-CoV-2 infection.

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MC-dependent lung pathology in SARS-CoV-2 infection. hACE2-AAV treated W...
hACE2-AAV treated WT or sash mice were inoculated intranasally with 1 × 105 TCID50 of SARS-CoV-2/Australia/Vic/01/20 and observed daily for 5 days. n = 5 (C57BL/6); n = 4 (KitW–sh/W–sh). (A) Three representative examples of lung tissue pathology from 3 different mice during SARS-CoV-2 infection day 5 postinfection. Insets for example 3 show areas of perivascular cuffing. (B) Healthy control tissue showed clear airways with no pathology. For A and B, additional representative images from infected and control groups are provided in Supplemental Figure 5A. (C) Histological score of SARS-CoV-2-infected mice 5 days postinfection determined by Student’s unpaired t test; P = 0.0007. Data points represent biological replicates. Examples of (D) venulitis with perivascular inflammation, (E) bronchial shedding (black arrow) and (F) interstitial pneumonitis in WT/hACE2-AAV infected mice, beside an image showing analogous tissue structures in sash/hACE2-AAV infected mice. (G) Hemorrhaging was only observed in WT/hACE2-AAV SARS-CoV-2-infected mice. (H) Quantification of SARS-CoV-2 genome copies in lung homogenates and nasal turbinate by PCR, which was normally distributed after log-transformation and did not differ significantly by 2-way ANOVA with Holm-Sidak’s post-test. Multiple Mann-Whitney tests on non-transformed data were also non-significant. Data points represent biological replicates. Scale bars for A and B: 50 μM; Scale bars for D–G: 10μM.