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Review
. 2020 Jul 14;12(7):755.
doi: 10.3390/v12070755.

Innate Immune Sensing of Influenza A Virus

Gaurav Malik  1   2 , Yan Zhou  1   2
Affiliations
Review

Innate Immune Sensing of Influenza A Virus

Gaurav Malik et al. Viruses. .

Abstract

Influenza virus infection triggers host innate immune response by stimulating various pattern recognition receptors (PRRs). Activation of these PRRs leads to the activation of a plethora of signaling pathways, resulting in the production of interferon (IFN) and proinflammatory cytokines, followed by the expression of interferon-stimulated genes (ISGs), the recruitment of innate immune cells, or the activation of programmed cell death. All these antiviral approaches collectively restrict viral replication inside the host. However, influenza virus also engages in multiple mechanisms to subvert the innate immune responses. In this review, we discuss the role of PRRs such as Toll-like receptors (TLRs), Retinoic acid-inducible gene I (RIG-I), NOD-, LRR-, pyrin domain-containing protein 3 (NLRP3), and Z-DNA binding protein 1 (ZBP1) in sensing and restricting influenza viral infection. Further, we also discuss the mechanisms influenza virus utilizes, especially the role of viral non-structure proteins NS1, PB1-F2, and PA-X, to evade the host innate immune responses.

Keywords: influenza virus; innate immune response; pattern recognition receptors.

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Conflict of interest statement

The authors declare no conflict of interest. This article is published with the permission of the VIDO-InterVac Director and was assigned a manuscript no. 901.

Figures

Figure 1
Figure 1
Toll-like receptor (TLR) signaling in response to viral infection. The TLRs engage the viral RNA signal in a MyD88-dependent (TLR7 and TLR8) and TRIF-dependent manner (TLR3). The MyD88 dependent pathway proceeds via formation of “Mydossome” with TRAF6 activating TAK1 kinase via polyubiquitination. The activated TAK1 activates IKK kinase complex and various MAP kinases by phosphorylation. The activation of IKK complex leads to the activation and nuclear translocation of NF-κB (by targeting inhibitor IκBα for proteasomal degradation) and IRF7; the MAPK kinases, however, activate AP-1 family of transcription factors followed by their nuclear translocation. The TRIF-dependent pathway, on the other hand, directly recruits TRAF3 and TRAF6. The TRAF6 then activates RIPK1 by polyubiquitination, which in turn activates TAK1 by phosphorylation leading to activation and nuclear translocation of NF-κB, IRF7, and AP-1 family of transcription factors. TRAF3 on the other hand activates IKK complex by polyubiquitination which in turn activates IKKε/TBK1 by phosphorylation leading to activation and nuclear translocation of IRF3. Of note, TLR4 recognizes endogenous danger-associated molecular patterns (DAMPs) secreted by influenza-infected cells and signal via both adaptors, MyD88 and TRIF. Signaling by various TLRs thus culminates with the induction of interferons and proinflammatory cytokines.
Figure 2
Figure 2
RIG-I signaling in response to viral infection. Under sterile conditions, RIG-I is generally present in closed conformation with the CARD2 domain interacting with the Helicase domain. However, on binding to immunostimulatory RNA, the CARDs are released and undergo K63Ub by ubiquitin ligases such as TRIM25 and Riplet. This drives RIG-I oligomerization and interaction with MAVS which leads to MAVS activation and oligomerization into MAVS filaments. Activated/oligomerized MAVS then interacts with TRAF3 and TRADD which itself exists in a complex with RIPK1 and FADD. The TRAF3 then activates RIPK1 by polyubiquitination which in turn activates IKK kinase complex by phosphorylation leading to activation and nuclear translocation of NF-κB. The activated IKK complex also activates TBK1/IKKε by phosphorylation which results in activation and nuclear translocation of IRF3 and IRF7. Signaling via this axis eventually induces the production of IFNs and proinflammatory cytokines. Notably, the nuclear resident RIG-I after recognizing the viral RNA in the nucleus is proposed to undergo oligomerization in the nucleus itself and interact with MAVS in the regions of proximity between the nuclear and mitochondrial membrane and thus inducing the antiviral signaling pathways.
Figure 3
Figure 3
ZBP1 signaling in response to viral infection. ZBP1 on recognizing viral RNA in the cytoplasm interacts with RIPK1 and RIPK3 via their RHIM domains. Signaling via the ZBP1-RIPK1 axis results in activation and nuclear translocation of NF-κB. Signaling via ZBP1-RIPK3 axis, in turn, drives necroptosis via phosphorylation of MLKL by RIPK3 and apoptosis and NLRP3 inflammasome activation (thus pyroptosis) via ZBP1-RIPK3-RIPK1-FADD-Casapse8 axis (RIPK3 interacts with RIPK1 via RHIM domain which in turn interacts with FADD via death domain (DD), which subsequently interacts with Caspase 8 via death effector domain (DED)). KD: Kinase domain. The pathways are also initiated on the recognition of immunostimulatory RNA by ZBP1 in the nucleus.
Figure 4
Figure 4
Priming and activation of NLRP3 inflammasome in response to viral infection. NLRP3 inflammasome in response to viral infection is primed by the cytokines such as TNFα and IL-1β or through viral recognition by PRRs such as RIG-I, TLRs, and ZBP-1. The signals converge at NF-κB activation and nuclear translocation leading to the gene transcription of NLPR3, caspase 1, IL-1β, and IL-18. The priming is followed by the activation of the inflammasome in response to a variety of upstream signals such as K+/Cl− efflux and Ca2+ Flux, either due to the opening of plasma membrane channels or release from the endoplasmic reticulum (ER). Mitochondrial disruption and release of mtDNA and mtROS into the cytoplasm, lysosomal rupture and release of cathepsins, dispersion of trans Golgi network (dTGN) can also activate inflammasome. The activated inflammasome leads to the cleavage of pro-caspase 1 to generate activated form of caspase 1, which then cleaves pro-IL-1β and pro-IL-18 to their mature form of IL-1β and IL-18. Active caspase 1 also cleaves GSDMD into a 31 kDa N-terminal fragment (GSDMDNterm) and a 22 kDa C-terminal fragment. GSDMDNterm then permeabilizes the plasma membrane and induces pyroptosis.
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