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Type I interferon signaling induces a delayed antiproliferative response in Calu-3 cells during SARS-CoV-2 infection (preprint)
biorxiv; 2023.
Препринт
в английский
| bioRxiv | ID: ppzbmed-10.1101.2023.02.28.530557
ABSTRACT
Disease progression during SARS-CoV-2 infection is tightly linked to the fate of lung epithelial cells, with severe cases of COVID-19 characterized by direct injury of the alveolar epithelium and an impairment in its regeneration from progenitor cells. The molecular pathways that govern respiratory epithelial cell death and proliferation during SARS-CoV-2 infection, however, remain poorly understood. We now report a high-throughput CRISPR screen for host genetic modifiers of the fitness of SARS-CoV-2-infected Calu-3 respiratory epithelial cells. The top 4 genes identified in our screen encode components of the same type I interferon signaling complex - IFNAR1, IFNAR2, JAK1, and TYK2. The 5th gene, ACE2, was an expected control encoding the SARS-CoV-2 viral receptor. Surprisingly, despite the antiviral properties of IFN-I signaling, its disruption in our screen was associated with an increase in Calu-3 cell fitness. We validated this effect and found that IFN-I signaling did not sensitize SARS-CoV-2-infected cultures to cell death but rather inhibited the proliferation of surviving cells after the early peak of viral replication and cytopathic effect. We also found that IFN-I signaling alone, in the absence of viral infection, was sufficient to induce this delayed antiproliferative response. Together, these findings highlight a cell autonomous antiproliferative response by respiratory epithelial cells to persistent IFN-I signaling during SARS-CoV-2 infection. This response may contribute to the deficient alveolar regeneration that has been associated with COVID-19 lung injury and represents a promising area for host-targeted therapeutic development.
Полный текст:
Имеется в наличии
Коллекция:
Препринты
база данных:
bioRxiv
Основная тема:
Virus Diseases
/
Carcinoma, Renal Cell
/
Adenocarcinoma, Bronchiolo-Alveolar
/
Severe Acute Respiratory Syndrome
/
COVID-19
/
Lung Diseases
Язык:
английский
Год:
2023
Тип:
Препринт
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