Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

ACC 2024 Congress

Catch up on all the top stories and latest evidence in cardiology research with our ACC 2024 Congress hub page.
ADVANCED SEARCH
Log in
Top
Virology Journal
Published in: Virology Journal 1/2023

Open Access 01-12-2023 | Influenza | Research

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

Authors: Sourabh Soni, Stephanie Walton-Filipczak, Richard S. Nho, Yohannes Tesfaigzi, Yohannes A. Mebratu

Published in: Virology Journal | Issue 1/2023

Login to get access

Abstract

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.
Appendix
Available only for authorised users
Literature
1.
2.
3.
4.
5.
Caliendo V, Lewis NS, Pohlmann A, Baillie SR, Banyard AC, Beer M, Brown IH, Fouchier RAM, Hansen RDE, Lameris TK, et al. Transatlantic spread of highly pathogenic avian influenza H5N1 by wild birds from Europe to North America in 2021. Sci Rep. 2022;12:11729.PubMedPubMedCentralCrossRef
6.
7.
McLean JE, Datan E, Matassov D, Zakeri ZF. Lack of bax prevents influenza a virus-induced apoptosis and causes diminished viral replication. J Virol. 2009;83:8233–46.PubMedPubMedCentralCrossRef
8.
McLean JE, Ruck A, Shirazian A, Pooyaei-Mehr F, Zakeri ZF. Viral manipulation of cell death. Curr Pharm Des. 2008;14:198–220.PubMedCrossRef
9.
Takizawa T, Matsukawa S, Higuchi Y, Nakamura S, Nakanishi Y, Fukuda R. Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells. J Gen Virol. 1993;74(Pt 11):2347–55.PubMedCrossRef
10.
Brydon EW, Morris SJ, Sweet C. Role of apoptosis and cytokines in influenza virus morbidity. FEMS Microbiol Rev. 2005;29:837–50.PubMedCrossRef
11.
Wurzer WJ, Planz O, Ehrhardt C, Giner M, Silberzahn T, Pleschka S, Ludwig S. Caspase 3 activation is essential for efficient influenza virus propagation. EMBO J. 2003;22:2717–28.PubMedPubMedCentralCrossRef
12.
Mebratu YA, Tipper J, Chand HS, Walton S, Harrod KS, Tesfaigzi Y. Bik mediates caspase-dependent cleavage of viral proteins to promote influenza a virus infection. Am J Respir Cell Mol Biol. 2016;54:664–73.PubMedPubMedCentralCrossRef
13.
Zhirnov OP, Syrtzev VV. Influenza virus pathogenicity is determined by caspase cleavage motifs located in the viral proteins. J Mol Genet Med. 2009;3:124–32.PubMedPubMedCentralCrossRef
14.
Zhirnov OP, Klenk HD. Alterations in caspase cleavage motifs of NP and M2 proteins attenuate virulence of a highly pathogenic avian influenza virus. Virology. 2009;394:57–63.PubMedCrossRef
15.
Zhirnov OP, Matrosovich TY, Matrosovich MN, Klenk HD. Aprotinin, a protease inhibitor, suppresses proteolytic activation of pandemic H1N1v influenza virus. Antivir Chem Chemother. 2011;21:169–74.PubMedCrossRef
16.
Xia C, Wolf JJ, Sun C, Xu M, Studstill CJ, Chen J, Ngo H, Zhu H, Hahm B. PARP1 Enhances Influenza A Virus Propagation by Facilitating Degradation of Host Type I Interferon Receptor.J Virol2020,94.
17.
Man SM, Kanneganti TD. Converging roles of caspases in inflammasome activation, cell death and innate immunity. Nat Rev Immunol. 2016;16:7–21.PubMedCrossRef
18.
Galluzzi L, Lopez-Soto A, Kumar S, Kroemer G. Caspases connect cell-death signaling to Organismal Homeostasis. Immunity. 2016;44:221–31.PubMedCrossRef
19.
20.
21.
Zhirnov OP, Isaeva EI. NSP protein encoded in negative NS RNA strand of Influenza A Virus induces Cellular Immune response in infected animals. Dokl Biochem Biophys. 2019;486:201–5.PubMedCrossRef
22.
Zhirnov OP, Klenk HD. Influenza a virus proteins NS1 and hemagglutinin along with M2 are involved in stimulation of autophagy in infected cells. J Virol. 2013;87:13107–14.PubMedPubMedCentralCrossRef
23.
Lowy RJ. Influenza virus induction of apoptosis by intrinsic and extrinsic mechanisms. Int Rev Immunol. 2003;22:425–49.PubMedCrossRef
24.
25.
Muhlbauer D, Dzieciolowski J, Hardt M, Hocke A, Schierhorn KL, Mostafa A, Muller C, Wisskirchen C, Herold S, Wolff T, et al. Influenza virus-induced caspase-dependent enlargement of nuclear pores promotes nuclear export of viral ribonucleoprotein complexes. J Virol. 2015;89:6009–21.PubMedPubMedCentralCrossRef
26.
Nencioni L, Iuvara A, Aquilano K, Ciriolo MR, Cozzolino F, Rotilio G, Garaci E, Palamara AT. Influenza a virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2. FASEB J. 2003;17:758–60.PubMedCrossRef
27.
Whitacre CM, Zborowska E, Willson JK, Berger NA. Detection of poly(ADP-ribose) polymerase cleavage in response to treatment with topoisomerase I inhibitors: a potential surrogate end point to assess treatment effectiveness. Clin Cancer Res. 1999;5:665–72.PubMed
28.
Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995;376:37–43.PubMedCrossRef
29.
Lazebnik YA, Kaufmann SH, Desnoyers S, Poirier GG, Earnshaw WC. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature. 1994;371:346–7.PubMedCrossRef
30.
Bortz E, Westera L, Maamary J, Steel J, Albrecht RA, Manicassamy B, Chase G, Martinez-Sobrido L, Schwemmle M, Garcia-Sastre A. Host- and strain-specific regulation of influenza virus polymerase activity by interacting cellular proteins.mBio2011,2.
31.
Westera L, Jennings AM, Maamary J, Schwemmle M, Garcia-Sastre A, Bortz E. Poly-ADP ribosyl polymerase 1 (PARP1) regulates Influenza A Virus polymerase. Adv Virol. 2019;2019:8512363.PubMedPubMedCentralCrossRef
32.
Rabi SA, Laird GM, Durand CM, Laskey S, Shan L, Bailey JR, Chioma S, Moore RD, Siliciano RF. Multi-step inhibition explains HIV-1 protease inhibitor pharmacodynamics and resistance. J Clin Invest. 2013;123:3848–60.PubMedPubMedCentralCrossRef
33.
Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour H Jr, Martin P, Pol S, Londono MC, Hassanein T, et al. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015;386:1537–45.PubMedCrossRef
34.
Jacobson IM, Lawitz E, Kwo PY, Hezode C, Peng CY, Howe AYM, Hwang P, Wahl J, Robertson M, Barr E, Haber BA. Safety and efficacy of Elbasvir/Grazoprevir in patients with Hepatitis C virus infection and compensated cirrhosis: an Integrated Analysis. Gastroenterology. 2017;152:1372–1382e1372.PubMedCrossRef
35.
Coultas L, Bouillet P, Stanley EG, Brodnicki TC, Adams JM, Strasser A. Proapoptotic BH3-only Bcl-2 family member Bik/Blk/Nbk is expressed in hemopoietic and endothelial cells but is redundant for their programmed death. Mol Cell Biol. 2004;24:1570–81.PubMedPubMedCentralCrossRef
36.
Lundberg AS, Randell SH, Stewart SA, Elenbaas B, Hartwell KA, Brooks MW, Fleming MD, Olsen JC, Miller SW, Weinberg RA, Hahn WC. Immortalization and transformation of primary human airway epithelial cells by gene transfer. Oncogene. 2002;21:4577–86.PubMedCrossRef
37.
Braun-Fahrlander C, Riedler J, Herz U, Eder W, Waser M, Grize L, Maisch S, Carr D, Gerlach F, Bufe A, et al. Environmental exposure to endotoxin and its relation to asthma in school-age children. N Engl J Med. 2002;347:869–77.PubMedCrossRef
38.
Fulcher ML, Gabriel S, Burns KA, Yankaskas JR, Randell SH. Well-differentiated human airway epithelial cell cultures. Methods Mol Med. 2005;107:183–206.PubMed
39.
You Y, Richer EJ, Huang T, Brody SL. Growth and differentiation of mouse tracheal epithelial cells: selection of a proliferative population. Am J Physiol Lung Cell Mol Physiol. 2002;283:L1315–1321.PubMedCrossRef
40.
Ling MT, Tu W, Han Y, Mao H, Chong WP, Guan J, Liu M, Lam KT, Law HK, Peiris JS, et al. Mannose-binding lectin contributes to deleterious inflammatory response in pandemic H1N1 and avian H9N2 infection. J Infect Dis. 2012;205:44–53.PubMedCrossRef
41.
Reed LJMH. A simple method of estimating fifty-percent endpoints. Am J Hyg. 1938;27:493–7.
42.
Wang L, He G, Zhang P, Wang X, Jiang M, Yu L. Interplay between MDM2, MDMX, Pirh2 and COP1: the negative regulators of p53. Mol Biol Rep. 2011;38:229–36.PubMedCrossRef
43.
van den Brand JM, Stittelaar KJ, van Amerongen G, Rimmelzwaan GF, Simon J, de Wit E, Munster V, Bestebroer T, Fouchier RA, Kuiken T, Osterhaus AD. Severity of pneumonia due to new H1N1 influenza virus in ferrets is intermediate between that due to seasonal H1N1 virus and highly pathogenic avian influenza H5N1 virus. J Infect Dis. 2010;201:993–9.PubMedCrossRef
44.
Song F, Yu X, Zhong T, Wang Z, Meng X, Li Z, Zhang S, Huo W, Liu X, Zhang Y, et al. Caspase-3 inhibition attenuates the Cytopathic Effects of EV71 infection. Front Microbiol. 2018;9:817.PubMedPubMedCentralCrossRef
45.
Valionyte E, Yang Y, Griffiths SA, Bone AT, Barrow ER, Sharma V, Lu B, Luo S. The caspase-6-p62 axis modulates p62 droplets based autophagy in a dominant-negative manner. Cell Death Differ. 2022;29:1211–27.PubMedCrossRef
46.
Kanellis DC, Espinoza JA, Zisi A, Sakkas E, Bartkova J, Katsori AM, Bostrom J, Dyrskjot L, Broholm H, Altun M et al. The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output.Sci Adv2021,7.
47.
Melnikov VY, Faubel S, Siegmund B, Lucia MS, Ljubanovic D, Edelstein CL. Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice. J Clin Invest. 2002;110:1083–91.PubMedPubMedCentralCrossRef
48.
Mebratu YA, Dickey BF, Evans C, Tesfaigzi Y. The BH3-only protein Bik/Blk/Nbk inhibits nuclear translocation of activated ERK1/2 to mediate IFNgamma-induced cell death. J Cell Biol. 2008;183:429–39.PubMedPubMedCentralCrossRef
49.
Baburamani AA, Miyakuni Y, Vontell R, Supramaniam VG, Svedin P, Rutherford M, Gressens P, Mallard C, Takeda S, Thornton C, Hagberg H. Does Caspase-6 have a role in Perinatal Brain Injury? Dev Neurosci. 2015;37:321–37.PubMedCrossRef
50.
Kawasaki M, Kuwano K, Hagimoto N, Matsuba T, Kunitake R, Tanaka T, Maeyama T, Hara N. Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor. Am J Pathol. 2000;157:597–603.PubMedPubMedCentralCrossRef
51.
Jaeschke H, Fisher MA, Lawson JA, Simmons CA, Farhood A, Jones DA. Activation of caspase 3 (CPP32)-like proteases is essential for TNF-alpha-induced hepatic parenchymal cell apoptosis and neutrophil-mediated necrosis in a murine endotoxin shock model. J Immunol. 1998;160:3480–6.PubMedCrossRef
52.
Dursun B, He Z, Somerset H, Oh DJ, Faubel S, Edelstein CL. Caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis. Am J Physiol Renal Physiol. 2006;291:F578–587.PubMedCrossRef
53.
Zheng M, Karki R, Vogel P, Kanneganti TD. Caspase-6 is a Key Regulator of Innate Immunity, Inflammasome activation, and host defense. Cell. 2020;181:674–687e613.PubMedPubMedCentralCrossRef
54.
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O’Connor MJ, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123–34.PubMedCrossRef
55.
Kim G, Ison G, McKee AE, Zhang H, Tang S, Gwise T, Sridhara R, Lee E, Tzou A, Philip R, et al. FDA approval Summary: Olaparib Monotherapy in patients with deleterious germline BRCA-Mutated Advanced Ovarian Cancer treated with three or more lines of Chemotherapy. Clin Cancer Res. 2015;21:4257–61.PubMedCrossRef
56.
Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, et al. Niraparib maintenance therapy in Platinum-Sensitive, recurrent ovarian Cancer. N Engl J Med. 2016;375:2154–64.PubMedCrossRef
57.
58.
Coleman MD, Ha SD, Haeryfar SMM, Barr SD, Kim SO. Cathepsin B plays a key role in optimal production of the influenza a virus. J Virol Antivir Res. 2018;2018:1–20.
59.
Gunther SC, Martinez-Romero C, Sempere Borau M, Pham CTN, Garcia-Sastre A, Stertz S. Proteomic identification of potential target proteins of cathepsin W for its development as a drug target for Influenza. Microbiol Spectr. 2022;10:e0092122.PubMedCrossRef
60.
Bestle D, Limburg H, Kruhl D, Harbig A, Stein DA, Moulton H, Matrosovich M, Abdelwhab EM, Stech J, Bottcher-Friebertshauser E. Hemagglutinins of avian influenza viruses are Proteolytically activated by TMPRSS2 in Human and Murine Airway cells. J Virol. 2021;95:e0090621.PubMedCrossRef
61.
Hatesuer B, Bertram S, Mehnert N, Bahgat MM, Nelson PS, Pohlmann S, Schughart K. Tmprss2 is essential for influenza H1N1 virus pathogenesis in mice. PLoS Pathog. 2013;9:e1003774.PubMedPubMedCentralCrossRef
62.
Tarnow C, Engels G, Arendt A, Schwalm F, Sediri H, Preuss A, Nelson PS, Garten W, Klenk HD, Gabriel G, Bottcher-Friebertshauser E. TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza a virus in mice. J Virol. 2014;88:4744–51.PubMedPubMedCentralCrossRef
63.
Sakai K, Ami Y, Tahara M, Kubota T, Anraku M, Abe M, Nakajima N, Sekizuka T, Shirato K, Suzaki Y, et al. The host protease TMPRSS2 plays a major role in in vivo replication of emerging H7N9 and seasonal influenza viruses. J Virol. 2014;88:5608–16.PubMedPubMedCentralCrossRef
64.
Lambertz RLO, Gerhauser I, Nehlmeier I, Gartner S, Winkler M, Leist SR, Kollmus H, Pohlmann S, Schughart K. H2 influenza A virus is not pathogenic in Tmprss2 knock-out mice. Virol J. 2020;17:56.PubMedPubMedCentralCrossRef
65.
Nencioni L, De Chiara G, Sgarbanti R, Amatore D, Aquilano K, Marcocci ME, Serafino A, Torcia M, Cozzolino F, Ciriolo MR, et al. Bcl-2 expression and p38MAPK activity in cells infected with influenza a virus: impact on virally induced apoptosis and viral replication. J Biol Chem. 2009;284:16004–15.PubMedPubMedCentralCrossRef
Metadata
Title
Independent role of caspases and Bik in augmenting influenza A virus replication in airway epithelial cells and mice
Authors
Sourabh Soni
Stephanie Walton-Filipczak
Richard S. Nho
Yohannes Tesfaigzi
Yohannes A. Mebratu
Publication date
01-12-2023
Publisher
BioMed Central
Keyword
Influenza
Published in
Virology Journal / Issue 1/2023
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-023-02027-w

Other articles of this Issue 1/2023

Virology Journal 1/2023 Go to the issue

Research

Immune escape of SARS-CoV-2 variants to therapeutic monoclonal antibodies: a system review and meta-analysis

Case Report

A fatal case of neonatal viral sepsis caused by human parainfluenza virus type 3

Case Report

The presence of human respiratory syncytial virus in the cerebrospinal fluid of a child with Anti-N-methyl-D-aspartate receptor encephalitis of unknown trigger

Methodology

Global mpox lineage discovery and rapid outbreak tracking with nanopore sequencing

Research

The features of high-risk human papillomavirus infection in different female genital sites and impacts on HPV-based cervical cancer screening

Comment

Trajectory of confirmed cases and deaths: fourth wave of COVID-19 epidemic in Myanmar

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits