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Review
. 2022 Jan 7:12:797789.
doi: 10.3389/fmicb.2021.797789. eCollection 2021.

Molecular Events Involved in Influenza A Virus-Induced Cell Death

Rui Gui  1   2 , Quanjiao Chen  1
Affiliations
Review

Molecular Events Involved in Influenza A Virus-Induced Cell Death

Rui Gui et al. Front Microbiol. .

Abstract

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.

Keywords: apoptosis; cell death; influenza A virus; necroptosis; pyroptosis; viral infection.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Viral proteins involved in intrinsic apoptosis and necroptosis during influenza A virus (IAV) infection. The IAV progeny ribonucleoprotein complex (vRNP) is sensed by DAI via recruitment of RIPK3 to activate MLKL. NS1 directly interacts with MLKL and induces its oligomerization. NS1 also can induce apoptosis; however, the underlying mechanism is not well understood. NA interacts with CEACAM6 and increases the phosphorylation of Src, AKT, and Bcl-2, thereby inhibiting apoptosis. When M1 binds with Hsp70, apoptosome formation is blocked. When NP interacts with CLU and RNF43, its ability to resist apoptosis is weakened by interference with the mitochondrial translocation of Bax. NP also promotes apoptosis by down-regulating API5 expression, thereby inhibiting E2F1 recruitment to the Apaf-1 promoter. The expression of Apaf-1 is then blocked, and apoptosome formation is impaired. PB1-F2 interacts with ANT3 and VDAC1, resulting in increased permeability of the mitochondrial outer membrane and induction of cytochrome c release.
FIGURE 2
FIGURE 2
Extrinsic apoptosis and necroptosis pathways during IAV infection. IAV infection can lead to upregulation of the death receptor ligands TNFα and FasL and the pattern recognition receptors TLR3/4 as well as downregulation of cFLIP.
FIGURE 3
FIGURE 3
Pyroptosis pathways induced by IAV. The IAV progeny ribonucleoprotein complex (vRNP) is sensed by DAI via recruitment of RIPK3 to activate caspase-8. Caspase-8 may cleave GSDMD, and the N-terminal GSDMD fragment then activates NLRP3-dependent caspase-1. PB1-F2 can induce ASC speck formation, NLRP3 activation, and cleavage of caspase-1. M2 is translocated to the Golgi apparatus as a proton ion channel to alter the pH of intracellular compartments and activate inflammasomes.
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