Alveolar type II (ATII) pneumocytes as defenders of the alveolus are critical to repairing lung injury. We investigated the ATII reparative response in COVID-19 pneumonia, because the initial proliferation of ATII cells in this reparative process should provide large numbers of target cells to amplify SARS-CoV-2 virus production and cytopathological effects to compromise lung repair. We show that both infected and uninfected ATII cells succumb to tumor necrosis factor-α (TNF)-induced necroptosis, Bruton's tyrosine kinase (BTK)-induced pyroptosis and a new PANoptotic hybrid form of inflammatory cell death mediated by a PANoptosomal latticework that generates distinctive COVID-19 pathologies in contiguous ATII cells. Identifying TNF and BTK as the initiators of programmed cell death and SARS-CoV-2 cytopathic effects provides a rationale for early antiviral treatment combined with inhibitors of TNF and BTK to preserve ATII cell populations, reduce programmed cell death and associated hyperinflammation, and restore functioning alveoli in COVID-19 pneumonia.
The Defenders of the Alveolus Succumb in COVID-19 Pneumonia to SARS-CoV-2 and Necroptosis, Pyroptosis and Panoptosis / L. Schifanella, J. Anderson, G. Wieking, P. J Southern, S. Antinori, M. Galli, M. Corbellino, A. Lai, N. Klatt, T. W Schacker, A. T Haase. - In: THE JOURNAL OF INFECTIOUS DISEASES. - ISSN 0022-1899. - (2023), pp. jiad056.1-jiad056.9. [Epub ahead of print] [10.1093/infdis/jiad056]
The Defenders of the Alveolus Succumb in COVID-19 Pneumonia to SARS-CoV-2 and Necroptosis, Pyroptosis and Panoptosis
L. Schifanella
Primo
Writing – Original Draft Preparation
;S. Antinori;M. Galli;A. Lai;
2023
Abstract
Alveolar type II (ATII) pneumocytes as defenders of the alveolus are critical to repairing lung injury. We investigated the ATII reparative response in COVID-19 pneumonia, because the initial proliferation of ATII cells in this reparative process should provide large numbers of target cells to amplify SARS-CoV-2 virus production and cytopathological effects to compromise lung repair. We show that both infected and uninfected ATII cells succumb to tumor necrosis factor-α (TNF)-induced necroptosis, Bruton's tyrosine kinase (BTK)-induced pyroptosis and a new PANoptotic hybrid form of inflammatory cell death mediated by a PANoptosomal latticework that generates distinctive COVID-19 pathologies in contiguous ATII cells. Identifying TNF and BTK as the initiators of programmed cell death and SARS-CoV-2 cytopathic effects provides a rationale for early antiviral treatment combined with inhibitors of TNF and BTK to preserve ATII cell populations, reduce programmed cell death and associated hyperinflammation, and restore functioning alveoli in COVID-19 pneumonia.File | Dimensione | Formato | |
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