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Poldip2 deficiency attenuates disease severity in a mouse model of COVID-19

Hu, R.; Valdivia, A.; White, T.; Ju, W.; Brockman, M. L.; Zhang, Z.; Qu, H.; Gafford, G.; Joseph, G.; Burton, S.; Bassit, L.; Charles, T. P.; Levit, R. D.; Derdeyn, C. A.; Griendling, K. K.; Lassegue, B.; Hernandes, M. S.

2025-06-18 pathology
10.1101/2025.06.17.657579 bioRxiv
Show abstract

The lungs are the primary target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2), with the infection resulting in lung inflammation, pulmonary vascular leakage and diffuse alveolar damage. Polymerase delta-interacting protein-2 (Poldip2) mediates lung inflammation and vascular permeability after lipopolysaccharide-induced acute respiratory distress syndrome; however, its role in regulating lung permeability, vascular inflammation and tissue damage following SARS-CoV-2 infection is completely unknown. Here, we assessed the role of Poldip2 in inflammation, immune cell infiltration and lung tissue damage in response to SARS-CoV-2 infection. Our data shows that while deletion of Poldip2 does not affect the susceptibility to SARS- CoV-2 infection, mice heterozygous for Poldip2 exhibit reduced lung tissue damage, reduced cytokine and chemokine induction and decreased infiltration of myeloperoxidase (MPO)-positive neutrophils into inflamed lung tissue. These data reveal that Poldip2 depletion mitigates inflammation and immune cell infiltration following SARS-CoV-2 infection, highlighting the therapeutic potential of Poldip2 inhibition to attenuate severe lung injury.

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