Journal article
Cells that survive acute SARS-CoV-2 infection contribute to inflammation and lung regeneration in mice
mBio, Vol.16(3), e03693-24
03/12/2025
DOI: 10.1128/mbio.03693-24
PMCID: PMC11898547
PMID: 39878483
Abstract
Post-acute sequelae of COVID-19 involves several organs, but its basis remains poorly understood. Some infected cells in mice survive the acute infection and persist for extended periods in the respiratory tract but not in other tissues. Here, we describe two experimental models of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection to assess the effect of viral virulence on previously infected cells. Both approaches use lineage tracking of previously infected cells. In mice infected with a highly pathogenic mouse-adapted SARS-CoV-2, alveolar type 2 cells (AT2) but not alveolar type 1 (AT1) cells survived the acute infection. These cells became activated, differentiated into an AT2-to-AT1 transitional cell state (KRT8
pre-alveolar type 1 transitional cell state). Additionally, nearby uninfected AT2 cells upregulated the transitional marker KRT8, thereby contributing to lung regeneration. In mice sensitized to infection by transduction with Ad5-hACE2, the infection is nonlethal, and AT1 cells survived the infection. Consequently, recovery in these mice was more rapid. Taken together, these results provide an explanation for how SARS-CoV-2 virulence contributes to poor outcomes and affects clinical recovery and lung regeneration. We also identified a new mechanism by which SARS-CoV-2 impacts lung recovery, even at times when infectious virus cannot be detected.
A major consequence of the COVID-19 pandemic is that many survivors have long-term sequelae, which are not well understood. These involve many organs, with the respiratory tract being a common site of long-term effects. Many of these sequelae can be found in mice infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In this study, we have focused on the lungs, with particular interest in the fate and role of cells that were infected with SARS-CoV-2 and survived the acute infection. We found that some infected cells survive acute SARS-CoV-2 infection and that these surviving cells both contribute to the immune response in the lungs and are involved in lung recovery. These findings illustrate previously unexplored aspects of recovery from SARS-CoV-2 induced pneumonia and may be relevant for understanding aspects of post-acute sequelae of COVID-19.
Details
- Title: Subtitle
- Cells that survive acute SARS-CoV-2 infection contribute to inflammation and lung regeneration in mice
- Creators
- Ruangang Pan - University of IowaDavid K Meyerholz - University of IowaStanley Perlman - University of Iowa
- Resource Type
- Journal article
- Publication Details
- mBio, Vol.16(3), e03693-24
- DOI
- 10.1128/mbio.03693-24
- PMID
- 39878483
- PMCID
- PMC11898547
- NLM abbreviation
- mBio
- ISSN
- 2150-7511
- eISSN
- 2150-7511
- Publisher
- AMER SOC MICROBIOLOGY
- Grant note
- Vice President for Research & Economic DevelopmentHolden Comprehensive Cancer CenterCarver College of Medicine
We thank Dr. Luis Enjuanes for providing the original SARS-CoV-2 Bac cDNA clone and Drs. Jian Zheng, Abhishek Verma, and Pengfei Li for valuable discussion. We thank Drs. Jian Zheng, Lei Lei, and Lok-Yin Roy Wong for critical reading of the manuscript. We acknowledge the use of the University of Iowa Central Microscopy Research Facility and Flow Cytometry Facility, a core resource supported by the Vice President for Research & Economic Development, the Holden Comprehensive Cancer Center, and the Carver College of Medicine.
- Language
- English
- Electronic publication date
- 01/29/2025
- Date published
- 03/12/2025
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Infectious Disease (Pediatrics)
- Record Identifier
- 9984781374102771
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