A Mouse Model of SARS-CoV-2-Driven Acute Maladaptive Responses and Chronic Systemic Diseases

Kenney, D.; Unali, G.; Tseng, A. E.; Leger, J.; Matsuo, M.; O'Connell, A. K.; McCooney, C.; Good, S.; Norton, J.; Feitosa-Suntheimer, F.; Carossino, M.; Gertje, H. P.; Klose, A.; Paragas, N.; Francis, K. P.; Snyder-Cappione, J. E.; Belkina, A.; Welcker, J.; Albrecht, K.; Corley, R. B.; Harly, C.; Crossland, N. A.; Douam, F.

doi:10.1101/2025.08.13.670105

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bioRxiv · 10.1101/2025.08.13.670105

A Mouse Model of SARS-CoV-2-Driven Acute Maladaptive Responses and Chronic Systemic Diseases

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Abstract

Our understanding of SARS-CoV-2 acute and post-acute pathogenesis is hindered by the lack of adequate small animal models. We present RAB/6N, a mouse model prone to severe disease after exposure to SARS-CoV-2 clinical isolates, with lethal cases showing no widespread brain infection typical of the widely used K18-hACE2 mouse model. Lung viral replication in RAB/6N mice remains steady for several days before a decline in viral titers. Delayed initiation of infection clearance is marked by increased lung T-cell extravasation and type-2 immune responses, leading to maladaptive lung consolidation. While systemic antiviral cytokine responses only correlate with SARS-CoV-2 brain infection in K18-hACE2 mice, they are concomitant with pulmonary immune dynamics in infected RAB/6N mice. Convalescent RAB/6N mice display systemic inflammation and decreased antibody titers against SARS-CoV-2 spike RBD, persistent viral RNA and prolonged lymphoid infiltration in the lungs. These animals also exhibit signatures of multi-organ dysfunction, cognitive impairment, cardiac inflammation, hyper- immunoglobulin production, and various autoimmune disorders, illuminating the molecular correlates of various pathologies associated with post-acute sequelae of COVID-19 (PASC). RAB/6N mice pave the way for dissecting the molecular drivers underlying SARS-CoV-2-induced acute maladaptive responses and subsequent post-acute systemic diseases. This preclinical platform also opens opportunities for the exploration of therapeutic interventions against systemic PASC and for anticipating the emergence of PASC-associated comorbidities. One-sentence summaryWe generated a hACE2-transgenic mouse model that develops maladaptive lung immune responses upon acute SARS-CoV-2 infection, leading to fatal outcomes or post-acute systemic disease syndromes in convalescent animals.

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Kenney, D., Unali, G., Tseng, A. E., Leger, J., Matsuo, M., O'Connell, A. K., McCooney, C., Good, S., Norton, J., Feitosa-Suntheimer, F., Carossino, M., Gertje, H. P., Klose, A., Paragas, N., Francis, K. P., Snyder-Cappione, J. E., Belkina, A., Welcker, J., Albrecht, K., Corley, R. B., Harly, C., Crossland, N. A., Douam, F.. 2025-08-13. A Mouse Model of SARS-CoV-2-Driven Acute Maladaptive Responses and Chronic Systemic Diseases. https://doi.org/10.1101/2025.08.13.670105

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