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Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice

Caspases and poly (ADP-ribose) polymerase 1 (PARP1) have been shown to promote influenza A virus (IAV) replication. However, the relative importance and molecular mechanisms of specific caspases and their downstream substrate PARP1 in regulating viral replication in airway epithelial cells (AECs) re...

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Autores principales: Soni, Sourabh, Walton-Filipczak, Stephanie, Nho, Richard S., Tesfaigzi, Yohannes, Mebratu, Yohannes A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127399/
https://www.ncbi.nlm.nih.gov/pubmed/37095508
http://dx.doi.org/10.1186/s12985-023-02027-w
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author Soni, Sourabh
Walton-Filipczak, Stephanie
Nho, Richard S.
Tesfaigzi, Yohannes
Mebratu, Yohannes A.
author_facet Soni, Sourabh
Walton-Filipczak, Stephanie
Nho, Richard S.
Tesfaigzi, Yohannes
Mebratu, Yohannes A.
author_sort Soni, Sourabh
collection PubMed
description Caspases and poly (ADP-ribose) polymerase 1 (PARP1) have been shown to promote influenza A virus (IAV) replication. However, the relative importance and molecular mechanisms of specific caspases and their downstream substrate PARP1 in regulating viral replication in airway epithelial cells (AECs) remains incompletely elucidated. Here, we targeted caspase 2, 3, 6, and PARP1 using specific inhibitors to compare their role in promoting IAV replication. Inhibition of each of these proteins caused significant decline in viral titer, although PARP1 inhibitor led to the most robust reduction of viral replication. We previously showed that the pro-apoptotic protein Bcl-2 interacting killer (Bik) promotes IAV replication in the AECs by activating caspase 3. In this study, we found that as compared with AECs from wild-type mice, bik-deficiency alone resulted in ~ 3 logs reduction in virus titer in the absence of treatment with the pan-caspase inhibitor (Q-VD-Oph). Inhibiting overall caspase activity using Q-VD-Oph caused additional decline in viral titer by ~ 1 log in bik(-/-) AECs. Similarly, mice treated with Q-VD-Oph were protected from IAV-induced lung inflammation and lethality. Inhibiting caspase activity diminished nucleo-cytoplasmic transport of viral nucleoprotein (NP) and cleavage of viral hemagglutinin and NP in human AECs. These findings suggest that caspases and PARP1 play major roles to independently promote IAV replication and that additional mechanism(s) independent of caspases and PARP1 may be involved in Bik-mediated IAV replication. Further, peptides or inhibitors that target and block multiple caspases or PARP1 may be effective treatment targets for influenza infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12985-023-02027-w.
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spelling pubmed-101273992023-04-26 Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice Soni, Sourabh Walton-Filipczak, Stephanie Nho, Richard S. Tesfaigzi, Yohannes Mebratu, Yohannes A. Virol J Research Caspases and poly (ADP-ribose) polymerase 1 (PARP1) have been shown to promote influenza A virus (IAV) replication. However, the relative importance and molecular mechanisms of specific caspases and their downstream substrate PARP1 in regulating viral replication in airway epithelial cells (AECs) remains incompletely elucidated. Here, we targeted caspase 2, 3, 6, and PARP1 using specific inhibitors to compare their role in promoting IAV replication. Inhibition of each of these proteins caused significant decline in viral titer, although PARP1 inhibitor led to the most robust reduction of viral replication. We previously showed that the pro-apoptotic protein Bcl-2 interacting killer (Bik) promotes IAV replication in the AECs by activating caspase 3. In this study, we found that as compared with AECs from wild-type mice, bik-deficiency alone resulted in ~ 3 logs reduction in virus titer in the absence of treatment with the pan-caspase inhibitor (Q-VD-Oph). Inhibiting overall caspase activity using Q-VD-Oph caused additional decline in viral titer by ~ 1 log in bik(-/-) AECs. Similarly, mice treated with Q-VD-Oph were protected from IAV-induced lung inflammation and lethality. Inhibiting caspase activity diminished nucleo-cytoplasmic transport of viral nucleoprotein (NP) and cleavage of viral hemagglutinin and NP in human AECs. These findings suggest that caspases and PARP1 play major roles to independently promote IAV replication and that additional mechanism(s) independent of caspases and PARP1 may be involved in Bik-mediated IAV replication. Further, peptides or inhibitors that target and block multiple caspases or PARP1 may be effective treatment targets for influenza infection. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12985-023-02027-w. BioMed Central 2023-04-24 /pmc/articles/PMC10127399/ /pubmed/37095508 http://dx.doi.org/10.1186/s12985-023-02027-w Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Soni, Sourabh
Walton-Filipczak, Stephanie
Nho, Richard S.
Tesfaigzi, Yohannes
Mebratu, Yohannes A.
Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice
title Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice
title_full Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice
title_fullStr Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice
title_full_unstemmed Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice
title_short Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice
title_sort independent role of caspases and bik in augmenting influenza a virus replication in airway epithelial cells and mice
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10127399/
https://www.ncbi.nlm.nih.gov/pubmed/37095508
http://dx.doi.org/10.1186/s12985-023-02027-w
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