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Complement expression determines disease severity in mouse models of SARS-CoV-2 and influenza pneumonia
Abstract   Open access   Peer reviewed

Complement expression determines disease severity in mouse models of SARS-CoV-2 and influenza pneumonia

Peter Szachowicz, Alexander Watson, Christine Wohlford-Lenane, Boopathi Sownthirarajan, Jeffery Dubert, Yuzhou Zhang, Balaji Manicassamy, Paul McCray and Richard Smith
Immunobiology (1979), Vol.230(4), 152931
07/2025
DOI: 10.1016/j.imbio.2025.152931
url
https://doi.org/10.1016/j.imbio.2025.152931View
Published (Version of record) Open Access

Abstract

The role of complement in the host response to respiratory viral infections is debated, with evidence suggesting it can either promote an effective immune response, or induce excessive inflammation and acute lung injury. During the COVID-19 pandemic, complement was implicated in disease pathobiology and complement C5 inhibition was granted emergency use approval in severe cases. Currently, virulent strains of both SARS-CoV-2 and influenza still result in thousands of deaths annually, and new variants which could produce another pandemic event are an ever present threat. Thus, it is vitally important that we understand the mechanisms by which these respiratory viruses induce severe disease and identify new therapeutic options for the future. We intranasally inoculated Balb/c WT, C3-/+, C3-/- mice with lethal doses of mouse-adapted SARS-CoV-2 (SARS2-N501YMA30) and PR8 influenza (5,000 PFU and 100 PFU, respectively) to determine whether varying degrees of complement expression altered the observed disease phenotype. Mice were monitored for weight loss and survival and euthanized on days 2 and 4 post-infection for sample collection. We found that both viruses induced a significant complement response in the lungs of wild-type mice by lung homogenate western blot for C3, C9, and FB. Interestingly, we found that mouse genotype directly influenced severity of illness, with homozygous mice having the best outcome and wild-type mice the worst, based on differences in weight-loss (p > 0.05) and survival (p < 0.05). This data confirms that complement contributes to the pathobiology in mouse models of both SARS-CoV-2 and influenza pneumonia, suggesting that the mechanisms by which complement drives pathogenesis is conserved across various human pathologic respiratory viruses. This data will serve to support future research investigating the specific mechanisms by which complement influences the host response to these infections, and complement inhibition as a broad spectrum treatment option for severe viral pneumonia.

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