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

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 1

Widespread activation of MCs coinciding with lung pathology in NHPs.

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Widespread activation of MCs coinciding with lung pathology in NHPs. (A)...
(A) Cynomolgus macaques were infected intratracheally with SARS-CoV-2 and monitored for 21 days before necropsy. (B) Viral detection was determined by PCR at regular intervals postinfection in swabs from multiple mucosal tissues, lung lavage, and nasal rinses. All NHPs were positive for SARS-CoV-2 infection multiple days after inoculation. (C) Abnormal findings related to lung tissue observed at the time of necropsy were recorded and affected all animals. (D) Images of NHP lungs at the time of necropsy show areas of hemorrhaging and necrotic spots on the lung surface. Boxed region is enlarged. (E) Histological assessment of lung tissues by H&E staining shows hemorrhaging of the tissue and free RBCs within the lung alveolar spaces. Scale bar: 100 μm.(F) Inset corresponding to the boxed region of H. Scale bar: 10 μm. (G) Some RBCs in the tissue proximal to a blood vessel are indicated by arrows and cellular infiltrates are circled. Scale bar: 10 μm. (H) Multiple examples of degranulating or hypogranulated MCs are provided, observed in toluidine blue–stained lung tissue sections. The MCs are enlarged in the red-outlined insets. Scale bars: 10 μm. For I–K, lung sections were stained for MC heparin to indicate the location of MC granules (green) and DAPI to identify cellular nuclei and tissue structures. MCs are indicated with red arrows. (I) MCs were observed degranulating in the lung of SARS-CoV-2 infected primates in sections of a biopsy of lung tissue that did not have overt hemorrhaging visible on the lung surface at necropsy. Scale bar: 50 μm. (J) MCs appear more densely packed in the lung biopsy from a hemorrhagic lobe of the lung and again, degranulation is observed based on staining for MC-heparin. Scale bar: 50 μm. (K) Images of degranulating MCs are presented at higher magnification. Scale bar: 10 μm.