Signatures of mast cell activation are associated with severe COVID-19
Tan J., Anderson D.E. et al. (MedRxiv) DOI: 10.1101/2021.05.31.21255594v1
The authors identified strong and persistent mast cell activation in animal models during both acute and convalescent SARS-CoV-2 infection, with widespread lung pathology. Enrichment of mast cell or mast cell/basophil-associated transcriptional signatures in severe but not mild COVID-19 patients coincided with respiratory distress levels and elevated chymase levels in the sera, providing a link to mast cells as potentiators of severe disease, tissue damage, and vascular pathologies.
Underutilization of animal models – direct immune cell characterization via flow cytometry, single cell RNA-seq, etc. could have strengthened the story by revealing the contribution of other immune cells in the lung niche and directly phenotyping the mast cells, versus assessing correlates of mast cell activation. Mild vs severe disease models could have also been applied to the animal models as well to mirror the clinical cohorts.
Identification of a causal pathway or mechanism – are other cells in the lung environment activating mast cells? Does SARS-CoV-2 directly activate mast cells? How are mast cell products affecting other immune cells?
Harmonization of techniques across models – application of the same whole blood transcriptomics analyses and serology done on clinical samples to the animal models would have been powerful confirmatory evidence that what was seen in animal models is recapitulated in humans as well.
Although the findings are novel for immunologists, the preprint has broader implications for the medical field since attenuation of mast cell and/or other granulocytes via drugs or monoclonal antibodies are potential avenues of treatment for patients with severe COVID-19. The paper also provides an accessible diagnostic (serum chymase levels) for assessing if aberrant mast cell activation and degranulation is occurring so clinicians can take the appropriate steps for treatment.
The preprint reveals a previously understudied player in the lung immune niche, mast cells, as contributors to lung pathology in respiratory viral infections such as COVID-19. Findings were confirmed across murine, non-human primate, and human clinical samples. The preprint opens many avenues of potential future investigation, such as mechanistically understanding the causal pathway of mast cell activation and what other immune cells are involved in this process, whether this activation phenotype is observed during other severe respiratory viral infections, and if SARS-CoV-2 variants can induce different levels of mast cell activation depending on virulence. For patients and clinicians, the preprint demonstrates chymase levels as a potential diagnostic and suggests that mast cell/granulocyte degranulation-attenuating drugs or monoclonal antibodies could be viable treatments for severe COVID-19.
Reviewed by Lauren A. Chang as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.