Abstract
51 Activation of complement in a mouse model of severe COVID-19
Immunobiology (1979), Vol.228(5), p.152505
09/2023
DOI: 10.1016/j.imbio.2023.152505
Abstract
Background: Research has demonstrated complement activation is a hallmark of severe COVID-19. While the association between COVID-19 and complement has been studied extensively in humans, it has yet to be investigated in an animal model. Here using a mouse model of severe COVID-19 lung disease, we find evidence of complement activation and describe its possible role in lung injury.
Methods: To characterize the complement response to SARS-CoV-2 infection, 6-8 week old BALB/c mice were inoculated intranasally with 5x103 PFU of mouse-adapted SARS-CoV-2 virus (SARS-CoV-2MA30), which reliably recapitulates key phenotypic features of severe COVID-19 seen in humans1. We next utilized C3-/- mice on a C57BL/6J background to evaluate the response to infection in the absence of complement activity. Mice were euthanized, with organs and serum collected for analysis of complement response and evaluation of disease phenotype.
Results: BALB/c mice develop exuberant complement activation in response to SARS-CoV-2, with increases in serum C3, C4, and CH50 activity levels by 2 days post-infection (d.p.i.). Immunofluorescence (IF) staining demonstrates pronounced C3 deposition in the lungs by 4 d.p.i. Colocalization by IF staining suggests direct interaction with type I alveolar, ciliated, and endothelial cells, with immunoblot and IF for C3b/iC3b/C3c confirming presence of C3 fragments consistent with activation. In C57BL/6J mice, the complement response to SARS-CoV-2MA30 was diminished compared to BALB/c mice. Surprisingly, in C3-/- mice the absence of C3 resulted in no significant difference in weight loss or mortality. Indeed, C3 appears to have a protective role early in disease course. In its absence, mice have increased viral burden in lung tissue, delayed viral clearance, increased lung injury, and increased early cytokine markers of systemic inflammation.
Conclusion: We have successfully produced a reliable mouse model of severe COVID-19. Similar to humans, mice infected with SARS-CoV-2MA30 develop significant complement response with pulmonary activation. Despite strain differences in the degree of complement activity, our results indicate that complement activation in the lung plays an important role in the immune response to this deadly virus.
Details
- Title: Subtitle
- 51 Activation of complement in a mouse model of severe COVID-19
- Creators
- Peter Szachowicz - University of IowaChristine Wohlford-Lenane - University of IowaYuzhou Zhang - University of IowaPaul McCray - University of IowaRichard Smith
- Resource Type
- Abstract
- Publication Details
- Immunobiology (1979), Vol.228(5), p.152505
- DOI
- 10.1016/j.imbio.2023.152505
- ISSN
- 0171-2985
- eISSN
- 1878-3279
- Language
- English
- Date published
- 09/2023
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Microbiology and Immunology; Pulmonary Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984458258502771
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