Complement is primarily activated in the lung in a mouse model of severe COVID-19
<i>In vitro</i> studies and observational human disease data suggest the complement system contributes to SARS-CoV-2 pathogenesis, although how complement dysregulation develops in severe COVID-19 is unknown. Here, using a mouse-adapted SARS-CoV-2 virus (SARS2-N501Y<sub>MA30</sub>) and a mouse model of COVID-19, we identify significant serologic and pulmonary complement activation post-infection. We observed C3 activation in airway and alveolar epithelia, and pulmonary vascular endothelia. Our evidence suggests the alternative pathway is the primary route of complement activation, however, components of both the alternative and classical pathways are produced locally by respiratory epithelial cells following infection, and increased in primary cultures of human airway epithelia following cytokine and SARS-CoV-2 exposure. This tissue-specific complement response appears to precede lung injury and inflammation. Our results suggest that complement activation is a defining feature of severe COVID-19 in mice, agreeing with previous publications, and provide the basis for further investigation into the role of complement in COVID-19.
Authors
- Yuzhou Zhang (ORCID: https://orcid.org/0000-0003-2627-6956)
- Peter J. Szachowicz (ORCID: https://orcid.org/0000-0003-1735-297X)
- Christine Wohlford-Lenane
- Richard J. Smith (ORCID: https://orcid.org/0000-0003-1201-6731)
- Abhishek Verma (ORCID: https://orcid.org/0000-0002-2374-5254)
- Shreya Ghimire (ORCID: https://orcid.org/0000-0001-8975-7998)
- Stanley Perlman (ORCID: https://orcid.org/0000-0003-4213-2354)
- Alejandro A. Pezzulo (ORCID: https://orcid.org/0000-0001-7544-5109)
- Biyun Xue
- Tayyab Rehman (ORCID: https://orcid.org/0000-0001-7792-201X)
- Jennifer Bermick (ORCID: https://orcid.org/0000-0002-0245-946X)
- David Kyle Meyerholz (ORCID: https://orcid.org/0000-0003-1552-3253)
- Timothy J. Boly (ORCID: https://orcid.org/0000-0002-8892-8086)
- Andrew L. Thurman (ORCID: https://orcid.org/0000-0002-7777-4165)
- Paul B. McCray (ORCID: https://orcid.org/0000-0002-4067-577X)
- Leila MašinoviĆ
- Cobey J. H. Donelson
Institutions
- University of Iowa (US)
- University of Michigan (US)
- Michigan Medicine (US)
Publication Details
- Journal
- iScience
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.isci.2025.111930
- Citations
- 5
- Primary Topic
- COVID-19 Impact on Reproduction
- Type
- article
- Field-Weighted Citation Impact
- 10.29
Funders
- Roy J. Carver Charitable Trust
- National Institutes of Health
- Roy J. and Lucille A. Carver College of Medicine, University of Iowa
- National Heart, Lung, and Blood Institute