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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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Research Article Article has an altmetric score of 43

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

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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 2

Degranulation of MCs in SARS-CoV-2 infected mice.

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Degranulation of MCs in SARS-CoV-2 infected mice.
(A) Experimental desig...
(A) Experimental design of hACE2-AAV inoculation and SARS-CoV-2 infection in mice. C57BL/6J mice were inoculated intranasally with hACE2-AAV to induce hACE2 expression in the airways. SARS-CoV-2 (2 × 107 TCID50) was inoculated intranasally into hACE2-AAV C57BL/6J mice. Blood was taken on days 1, 3, 5, and 7, and organs were harvested after 5 or 7 days for histology and virus quantification. (B) Virus quantification from the organs harvested shows detection in the lung, spleen, liver, kidney, brain, and bone marrow from both days 5 and 7. n = 5 (5 days postinfection); n = 5 (7 days postinfection) (C) Representative histology images of toluidine blue–stained trachea sections from uninfected and SARS-CoV-2 infected hACE2-AAV mice (scale bar: 20 μm) and (D) mean tracheal thickness quantitated from multiple tissue sections. Degranulating MCs (red arrow) could be observed in SARS-CoV-2 infected mice as well as tissue edema and airway narrowing. (E) MCPT1 detection in serum Days 3, 5, and 7 postinfection shows systemic elevation of MCPT1, which was quantitated by densitometry from Western blots of 5 individual mouse samples (biological replicates) and presented as fold increase over uninfected controls. Error bars represent the SEM. MCPT1 was significantly elevated in serum of infected mice compared with uninfected controls, determined by 1-way ANOVA with Dunnett’s posthoc test where the values for each day were compared with the uninfected control; *P < 0.05, **P < 0.01. (F) Representative Western blot images from panel E. Western blots showing additional replicates are provided in Supplemental Figure 4. Expected molecular weight for MCPT1 is 28 kDa. (G) Dose-dependent MC degranulation in response to SARS-CoV-2 Spike protein is reduced by treatment with MC-stabilizing drug cromolyn. Purified recombinant Spike protein from SARS-CoV-2 was conjugated to 1 μm carboxylate microspheres. Significant and dose-dependent MC degranulation was induced by Spike-coated beads, but not in MCs treated with the MC-stabilizing drug cromolyn (10μM). Significance was determined by 1-way ANOVA with Tukey’s posthoc test; *P <0.05, ***P <0.001.

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