Influenza Virus Induces Apoptosis via BAD-Mediated Mitochondrial Dysregulation

Tran, Anh; Cortens, John P.; Du, Qiujiang; Wilkins, John A.; Coombs, Kevin M.

doi:10.1128/jvi.02017-12

Cited by 65 publications

(58 citation statements)

References 41 publications

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“…Such low viral protein production may result from a low progeny yield from the initial infection, which then causes reduced viral spread to other cells in the vicinity. Reduction in overall viral protein produced during infection with IAV was also observed in cells that overexpressed Bcl-2 (15) and in Bad-targeted cells (39). Similar observations were reported, in which blocking Bad prevented induction of cell death (39).…”

Section: Discussionsupporting

confidence: 71%

“…Reduction in overall viral protein produced during infection with IAV was also observed in cells that overexpressed Bcl-2 (15) and in Bad-targeted cells (39). Similar observations were reported, in which blocking Bad prevented induction of cell death (39). During synthesis, the influenza A viral envelope proteins HA, NA, and M2 are transported to the ER for glycosylation and folding (40).…”

Section: Discussionsupporting

confidence: 66%

“…Although Bad plays an important role in IAV infection (39), deficiency of Bik was sufficient to cause reduced viral titer and viral gene expression, reduced virus load and lung inflammation in vivo, and increased survival of mice. It is possible that Bik may be upstream of Bad to directly or indirectly affect Bad expression and Bad may play an important role downstream of Bik in IAV infection (39). These possibilities suggest a significant role played by Bik in IAV pathogenesis.…”

Section: Discussionmentioning

confidence: 97%

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Bik Mediates Caspase-Dependent Cleavage of Viral Proteins to Promote Influenza A Virus Infection

Mebratu

Tipper

Chand

et al. 2016

Am J Respir Cell Mol Biol

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Influenza virus induces apoptosis in infected cells to promote viral replication by manipulating the host cell death signaling pathway. Although some Bcl-2 family proteins play a role in the replication of influenza A virus (IAV), the role of cell death pathways in the viral replication cycle is unclear. We investigated whether deficiency of the proapoptotic Bcl-2 family protein, Bik, plays a role in IAV replication. IAV replication was attenuated in mouse airway epithelial cells (MAECs) from bik 2/2 compared with bik Clinical RelevanceThis study identifies Bik as a novel host cell protein that plays an important role in influenza A virus replication. Because Bik promotes influenza A infection through caspase 3 activation and proper cytoplasmic export of viral RNPs, inhibiting Bik expression or caspase 3 activation may be a novel therapeutic approach to reducing influenza A infection.Influenza A virus (IAV) infection is associated with 36,000 deaths and 226,000 hospitalizations annually, with losses in the tens of billions of dollars to the economy of the United States (1). Influenza infections pose serious challenges because of the lack of effective therapeutic interventions and the rapid evolution of viral genomes toward resistance. Therefore, understanding the molecular mechanism by which IAV replicates will help identify targets for effective antiviral drugs that are less susceptible to resistance.Influenza virus induces apoptosis in infected epithelial, lymphocyte, and phagocytic cells (2) and mainly damages epithelial cells of the human respiratory tract (3). Although apoptosis is required for viral replication (3), how the cell death pathways interplay with viral replication is

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Section: Discussionsupporting

confidence: 71%

Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Bik Mediates Caspase-Dependent Cleavage of Viral Proteins to Promote Influenza A Virus Infection

Mebratu

Tipper

Chand

et al. 2016

Am J Respir Cell Mol Biol

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“…1A, 8A). It will be interesting to determine how influenza infection causes mitochondrial damage (28,29) in these cells and clarify the mechanism for activation of the AIM2 inflammasome in the future.…”

Section: Aim2 Is Critical For Iav-induced Inflammasome Activationmentioning

confidence: 99%

AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

Luo

Alcorn

Chen

et al. 2017

The Journal of Immunology

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The absent in melanoma 2 (AIM2) inflammasome plays an important role in many viral and bacterial infections, but very little is known about its role in RNA virus infection, including influenza A virus (IAV). In this study, we have designed in vivo and in vitro studies to determine the role of AIM2 in infections with lethal doses of IAVs A/PR8/34 and A/California/07/09. In wild-type mice, IAV infection enhanced AIM2 expression, induced dsDNA release, and stimulated caspase-1 activation and release of cleaved IL-1β in the lung, which was significantly reduced in AIM2-deficient mice. Interestingly, AIM2 deficiency did not affect the transcription of caspase-1 and IL-1β. In addition, AIM2-deficient mice exhibited attenuated lung injury and significantly improved survival against IAV challenges, but did not alter viral burden in the lung. However, AIM2 deficiency did not seem to affect adaptive immune response against IAV infections. Furthermore, experiments with AIM2-specific small interfering RNA–treated and AIM2-deficient human and mouse lung alveolar macrophages and type II cells indicated a macrophage-specific function of AIM2 in regulation of IAV-stimulated proinflammatory response. Collectively, our results demonstrate that influenza infection activates the AIM2 inflammasome, which plays a critical role in IAV-induced lung injury and mortality. AIM2 might serve as a therapeutic target for combating influenza-associated morbidity and mortality without compromising the host antiviral responses.

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“…Other cellular proteins including UACA, PAWR, FLII, Trim21, IMMT, 14-3-3, EFHD2, DHX9, DDX3, NLRP3 and LRRFIP2 as well as viral factors M2, PB1-F2, NS1, HA and NP may play important roles in Bcl-2-dependent apoptosis by stabilizing or altering the interactions of BH3-domain proteins in infected cells [44,[46][47][48]. However, further studies are required to verify their specific functions in apoptosis.…”

Section: Apoptosis In Iav-infected Cellsmentioning

confidence: 99%

Influenza virus infection, interferon response, viral counter-response and apoptosis

Shim¹,

Kim²,

Min³

et al. 2017

Preprint

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Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here we describe how IAV infection triggers cellular apoptosis, and how this process can be exploited towards development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

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Influenza Virus Induces Apoptosis via BAD-Mediated Mitochondrial Dysregulation

Cited by 65 publications

References 41 publications

Bik Mediates Caspase-Dependent Cleavage of Viral Proteins to Promote Influenza A Virus Infection

Bik Mediates Caspase-Dependent Cleavage of Viral Proteins to Promote Influenza A Virus Infection

AIM2 Inflammasome Is Critical for Influenza-Induced Lung Injury and Mortality

Influenza virus infection, interferon response, viral counter-response and apoptosis

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