Article ; Online: SARS-CoV-2 Exploits Sexually Dimorphic and Adaptive IFN and TNFa Signaling to Gain Entry into Alveolar Epithelium
bioRxiv
Abstract: Infection of the alveolar epithelium constitutes a bottleneck in the progression of COVID-19 to SARS presumably due to the paucity of viral entry receptors in alveolar epithelial type 1 and 2 cells. We have found that the male alveolar epithelial cells ... ...
| Abstract | Infection of the alveolar epithelium constitutes a bottleneck in the progression of COVID-19 to SARS presumably due to the paucity of viral entry receptors in alveolar epithelial type 1 and 2 cells. We have found that the male alveolar epithelial cells express twice as many ACE2 and TMPRSS2 entry receptors as the female ones. Intriguingly, IFN and TNF-α signaling are preferentially active in male alveolar cells and induce binding of the cognate transcription factors to the promoters and lung-active enhancers of ACE2 and TMPRSS2. Cotreatment with IFN-I and III dramatically increases expression of the receptors and viral entry in alveolar epithelial cells. TNFα and IFN-II, typically overproduced during the cytokine storm, similarly collaborate to induce these events. Whereas JAK inhibitors suppress viral entry induced by IFN-I/III, simultaneous inhibition of IKK/NF-κB is necessary to block viral entry induced by TNFα and IFN II. In addition to explaining the increased incidence of SARS in males, these findings indicate that SARS-Cov-2 hijacks epithelial immune signaling to promote infection of the alveolar epithelium and suggest that JAK inhibitors, singly and in combination with NF-KB inhibitors, may exhibit efficacy in preventing or treating COVID-19 SARS. |
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| Keywords | covid19 |
| Language | English |
| Publishing date | 2021-07-23 |
| Publisher | Cold Spring Harbor Laboratory |
| Document type | Article ; Online |
| DOI | 10.1101/2021.07.23.453505 |
| Database | COVID19 |
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