ZBP1/DAI-Dependent Cell Death Pathways in Influenza A Virus Immunity and Pathogenesis

AbstractProgrammed cell death pathways are triggered by various stresses or stimuli, including viral infections. The mechanism underlying the regulation of these pathways upon Influenza A virus IAV infection is not well characterized. We report that a cytosolic DNA sensor IFI16 is essential for the activation of programmed cell death pathways in IAV infected cells. We have identified that IFI16 functions as an RNA sensor for influenza A virus by binding to genomic RNA. The activation of IFI16 triggers the production of type I, III interferons, and also other pro-inflammatory cytokines via the STING-TBK1 and Pro-caspase-1 signaling axis, thereby promoting cell death (apoptosis and pyroptosis in IAV infected cells). Whereas, IFI16 knockdown cells showed reduced inflammatory responses and also prevented cell mortality during IAV infection. These results demonstrate the pivotal role of IFI16-mediated IAV sensing and its essential role in activating programmed cell death pathways.

Download Full-text

DAI Senses Influenza A Virus Genomic RNA and Activates RIPK3-Dependent Cell Death

Cell Host & Microbe ◽

10.1016/j.chom.2016.09.014 ◽

2016 ◽

Vol 20 (5) ◽

pp. 674-681 ◽

Cited By ~ 138

Author(s):

Roshan J. Thapa ◽

Justin P. Ingram ◽

Katherine B. Ragan ◽

Shoko Nogusa ◽

David F. Boyd ◽

...

Keyword(s):

Cell Death ◽

Influenza A Virus ◽

Influenza A ◽

Genomic Rna ◽

Dependent Cell

Download Full-text

Faculty Opinions recommendation of A novel influenza A virus mitochondrial protein that induces cell death.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1002844.32105 ◽

2002 ◽

Author(s):

Barry Rouse

Keyword(s):

Cell Death ◽

Influenza A Virus ◽

Influenza A ◽

Mitochondrial Protein ◽

Novel Influenza A

Download Full-text

Molecular Events Involved in Influenza A Virus-Induced Cell Death

Frontiers in Microbiology ◽

10.3389/fmicb.2021.797789 ◽

2022 ◽

Vol 12 ◽

Author(s):

Rui Gui ◽

Quanjiao Chen

Keyword(s):

Cell Death ◽

Influenza A Virus ◽

Influenza A ◽

Regulatory Networks ◽

Molecular Mechanisms ◽

Tissue Destruction ◽

Inflammatory Reactions ◽

Molecular Events ◽

Host Death

Viral infection usually leads to cell death. Moderate cell death is a protective innate immune response. By contrast, excessive, uncontrolled cell death causes tissue destruction, cytokine storm, or even host death. Thus, the struggle between the host and virus determines whether the host survives. Influenza A virus (IAV) infection in humans can lead to unbridled hyper-inflammatory reactions and cause serious illnesses and even death. A full understanding of the molecular mechanisms and regulatory networks through which IAVs induce cell death could facilitate the development of more effective antiviral treatments. In this review, we discuss current progress in research on cell death induced by IAV infection and evaluate the role of cell death in IAV replication and disease prognosis.

Download Full-text

Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1609316113 ◽

2016 ◽

Vol 113 (42) ◽

pp. 11931-11936 ◽

Cited By ~ 88

Author(s):

Wenqian He ◽

Gene S. Tan ◽

Caitlin E. Mullarkey ◽

Amanda J. Lee ◽

Mannie Man Wai Lam ◽

...

Keyword(s):

Influenza Virus ◽

Influenza A Virus ◽

Neutralizing Antibodies ◽

Influenza A ◽

Critical Role ◽

Host Cells ◽

Viral Glycoprotein ◽

Effector Functions ◽

Dependent Cell

The generation of strain-specific neutralizing antibodies against influenza A virus is known to confer potent protection against homologous infections. The majority of these antibodies bind to the hemagglutinin (HA) head domain and function by blocking the receptor binding site, preventing infection of host cells. Recently, elicitation of broadly neutralizing antibodies which target the conserved HA stalk domain has become a promising “universal” influenza virus vaccine strategy. The ability of these antibodies to elicit Fc-dependent effector functions has emerged as an important mechanism through which protection is achieved in vivo. However, the way in which Fc-dependent effector functions are regulated by polyclonal influenza virus-binding antibody mixtures in vivo has never been defined. Here, we demonstrate that interactions among viral glycoprotein-binding antibodies of varying specificities regulate the magnitude of antibody-dependent cell-mediated cytotoxicity induction. We show that the mechanism responsible for this phenotype relies upon competition for binding to HA on the surface of infected cells and virus particles. Nonneutralizing antibodies were poor inducers and did not inhibit antibody-dependent cell-mediated cytotoxicity. Interestingly, anti-neuraminidase antibodies weakly induced antibody-dependent cell-mediated cytotoxicity and enhanced induction in the presence of HA stalk-binding antibodies in an additive manner. Our data demonstrate that antibody specificity plays an important role in the regulation of ADCC, and that cross-talk among antibodies of varying specificities determines the magnitude of Fc receptor-mediated effector functions.

Download Full-text

The Zα2 domain of ZBP1 is a molecular switch regulating influenza-induced PANoptosis and perinatal lethality during development

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013752 ◽

2020 ◽

Vol 295 (24) ◽

pp. 8325-8330 ◽

Cited By ~ 14

Author(s):

Sannula Kesavardhana ◽

R. K. Subbarao Malireddi ◽

Amanda R. Burton ◽

Shaina N. Porter ◽

Peter Vogel ◽

...

Keyword(s):

Cell Death ◽

Nucleic Acids ◽

Influenza A Virus ◽

Nlrp3 Inflammasome ◽

Influenza A ◽

Defense Responses ◽

Innate Immune ◽

Inflammasome Activation ◽

Perinatal Lethality

Z-DNA-binding protein 1 (ZBP1) is an innate immune sensor of nucleic acids that regulates host defense responses and development. ZBP1 activation triggers inflammation and pyroptosis, necroptosis, and apoptosis (PANoptosis) by activating receptor-interacting Ser/Thr kinase 3 (RIPK3), caspase-8, and the NLRP3 inflammasome. ZBP1 is unique among innate immune sensors because of its N-terminal Zα1 and Zα2 domains, which bind to nucleic acids in the Z-conformation. However, the specific role of these Zα domains in orchestrating ZBP1 activation and subsequent inflammation and cell death is not clear. Here we generated Zbp1ΔZα2/ΔZα2 mice that express ZBP1 lacking the Zα2 domain and demonstrate that this domain is critical for influenza A virus–induced PANoptosis and underlies perinatal lethality in mice in which the RIP homotypic interaction motif domain of RIPK1 has been mutated (Ripk1mRHIM/mRHIM). Deletion of the Zα2 domain in ZBP1 abolished influenza A virus–induced PANoptosis and NLRP3 inflammasome activation. Furthermore, deletion of the Zα2 domain of ZBP1 was sufficient to rescue Ripk1mRHIM/mRHIM mice from perinatal lethality caused by ZBP1-driven cell death and inflammation. Our findings identify the essential role of the Zα2 domain of ZBP1 in several physiological functions and establish a link between Z-RNA sensing via the Zα2 domain and promotion of influenza-induced PANoptosis and perinatal lethality.

Download Full-text

Mitochondrial dynamics in yeast cell death and aging

Biochemical Society Transactions ◽

10.1042/bst0391520 ◽

2011 ◽

Vol 39 (5) ◽

pp. 1520-1526 ◽

Cited By ~ 33

Author(s):

Ralf J. Braun ◽

Benedikt Westermann

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Mitochondrial Dynamics ◽

Progressive Increase ◽

Mitochondrial Morphology ◽

Aging Research ◽

Yeast Saccharomyces Cerevisiae ◽

Cell Death Pathways ◽

Dependent Cell ◽

Mitochondrial Networks

Mitochondria play crucial roles in programmed cell death and aging. Different stimuli activate distinct mitochondrion-dependent cell death pathways, and aging is associated with a progressive increase in mitochondrial damage, culminating in oxidative stress and cellular dysfunction. Mitochondria are highly dynamic organelles that constantly fuse and divide, forming either interconnected mitochondrial networks or separated fragmented mitochondria. These processes are believed to provide a mitochondrial quality control system and enable an effective adaptation of the mitochondrial compartment to the metabolic needs of the cell. The baker's yeast, Saccharomyces cerevisiae, is an established model for programmed cell death and aging research. The present review summarizes how mitochondrial morphology is altered on induction of cell death or on aging and how this correlates with the induction of different cell death pathways in yeast. We highlight the roles of the components of the mitochondrial fusion and fission machinery that affect and regulate cell death and aging.

Download Full-text