Benefits and Perils of Necroptosis in Influenza Virus Infection

Balachandran, Siddharth; Rall, Glenn F.

doi:10.1128/jvi.01101-19

Cited by 48 publications

(41 citation statements)

References 78 publications

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“…It has been reported that influenza virus infection triggers both apoptosis and necroptosis in the lung as redundant cell death processes resulting in immune responses to restrict viral replication. 11 However, when these two pathways were triggered to a hyper-activation status, IAV infection leads to severe lung damage and fatal infection outcome. 11 Similar with IAV, the SARS-CoV-2 induced a dual mode of cell death pathways in the lung epithelial cells, which may pose anti-viral responses or immune pathogenesis depending on the activation status.…”

Section: Discussionmentioning

confidence: 99%

“… 11 However, when these two pathways were triggered to a hyper-activation status, IAV infection leads to severe lung damage and fatal infection outcome. 11 Similar with IAV, the SARS-CoV-2 induced a dual mode of cell death pathways in the lung epithelial cells, which may pose anti-viral responses or immune pathogenesis depending on the activation status. Many factors may contribute to the level of cell death activation, including initial dose of viral infection, the underlying co-morbidity in the patient, age factor, etc.…”

Section: Discussionmentioning

confidence: 99%

“… 10 The benefits of necroptosis to the host, however, may sometimes be outweighed by the potentially deleterious hyper-inflammatory consequences of activating this death pathway in pulmonary and other tissues. 11 For example, the influenza A virus (IAV) infection-induced necroptosis in airway epithelial cells is associated with lung damage and hyper-inflammatory responses. Similar with IAV, SARS-CoV-2 can cause severe lung damage and disease-associated hyper-inflammatory responses.…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

Zhang

Guan

et al. 2020

Sig Transduct Target Ther

335

346

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to respiratory illness and multi-organ failure in critically ill patients. Although the virus-induced lung damage and inflammatory cytokine storm are believed to be directly associated with coronavirus disease 2019 (COVID-19) clinical manifestations, the underlying mechanisms of virus-triggered inflammatory responses are currently unknown. Here we report that SARS-CoV-2 infection activates caspase-8 to trigger cell apoptosis and inflammatory cytokine processing in the lung epithelial cells. The processed inflammatory cytokines are released through the virus-induced necroptosis pathway. Virus-induced apoptosis, necroptosis, and inflammation activation were also observed in the lung sections of SARS-CoV-2-infected HFH4-hACE2 transgenic mouse model, a valid model for studying SARS-CoV-2 pathogenesis. Furthermore, analysis of the postmortem lung sections of fatal COVID-19 patients revealed not only apoptosis and necroptosis but also massive inflammatory cell infiltration, necrotic cell debris, and pulmonary interstitial fibrosis, typical of immune pathogenesis in the lung. The SARS-CoV-2 infection triggered a dual mode of cell death pathways and caspase-8-dependent inflammatory responses may lead to the lung damage in the COVID-19 patients. These discoveries might assist the development of therapeutic strategies to treat COVID-19.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

Zhang

Guan

et al. 2020

Sig Transduct Target Ther

335

346

View full text Add to dashboard Cite

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“…The molecular mechanisms of IAV subversion of cellular defenses and programmed cell death continue to be investigated ( Yeganeh et al, 2013 ; Balachandran and Rall, 2020 ). Only recently has it become apparent that necroptosis is essential for the control of virus replication during infection ( Nogusa et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

“…Along such lines, RIPK3 activation is necessary to establish an efficient response to the virus. ( Nailwal and Chan, 2019 ; Nogusa et al, 2016 ; Balachandran and Rall, 2020 ). Our research group has shown that during bacterial pneumonia, initiation of necroptosis (i.e., MLKL-activity) is detrimental and exacerbates bacterial outgrowth, pulmonary injury, and loss of alveolar-capillary integrity ( González-Juarbe et al, 2015a ; González-Juarbe et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Influenza-Induced Oxidative Stress Sensitizes Lung Cells to Bacterial-Toxin-Mediated Necroptosis

et al. 2020

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SUMMARY Pneumonias caused by influenza A virus (IAV) co- and secondary bacterial infections are characterized by their severity and high mortality rate. Previously, we have shown that bacterial pore-forming toxin (PFT)-mediated necroptosis is a key driver of acute lung injury during bacterial pneumonia. Here, we evaluate the impact of IAV on PFT-induced acute lung injury during co- and secondary Streptococcus pneumoniae ( Spn ) infection. We observe that IAV synergistically sensitizes lung epithelial cells for PFT-mediated necroptosis in vitro and in murine models of Spn co-infection and secondary infection. Pharmacological induction of oxidative stress without virus sensitizes cells for PFT-mediated necroptosis. Antioxidant treatment or inhibition of necroptosis reduces disease severity during secondary bacterial infection. Our results advance our understanding on the molecular basis of co- and secondary bacterial infection to influenza and identify necroptosis inhibition and antioxidant therapy as potential intervention strategies.

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Cell pyroptosis in picornavirus and its potential for treating viral infection

Zheng

Zhuang

et al. 2022

Journal of Medical Virology

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Cell pyroptosis has received increased attention due to the associations between innate immunity and disease, and it has become a major focal point recently due to in‐depth studies of cancer. With increased research on pyroptosis, scientists have discovered that it has an essential role in viral infections, especially in the occurrence and development of some picornavirus infections. Many picornaviruses, including Coxsackievirus, a71 enterovirus, human rhinovirus, encephalomyocarditis virus, and foot‐and‐mouth disease virus induce pyroptosis to varying degrees. This review summarized the mechanisms by which these viruses induce cell pyroptosis, which can be an effective defense against pathogen infection. However, excessive inflammasome activation or pyroptosis also can damage the host's health or aggravate disease progression. Careful approaches that acknowledge this dual effect will aid in the exploration of picornavirus infections and the mechanisms that produce the inflammatory response. This information will promote the development of drugs that can inhibit cell pyroptosis and provide new avenues for future clinical treatment.

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Benefits and Perils of Necroptosis in Influenza Virus Infection

Cited by 48 publications

References 78 publications

SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation

Influenza-Induced Oxidative Stress Sensitizes Lung Cells to Bacterial-Toxin-Mediated Necroptosis

Cell pyroptosis in picornavirus and its potential for treating viral infection

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