Roles of RNA Sensors in Host Innate Response to Influenza Virus and Coronavirus Infections

Abstract

Influenza virus and coronavirus are two important respiratory viruses, which often cause serious respiratory diseases in humans and animals after infection. In recent years, highly pathogenic avian influenza virus (HPAIV) and SARS-CoV-2 have become major pathogens causing respiratory diseases in humans. Thus, an in-depth understanding of the relationship between viral infection and host innate immunity is particularly important to the stipulation of effective control strategies. As the first line of defense against pathogens infection, innate immunity not only acts as a natural physiological barrier, but also eliminates pathogens through the production of interferon (IFN), the formation of inflammasomes, and the production of pro-inflammatory cytokines. In this process, the recognition of viral pathogen-associated molecular patterns (PAMPs) by host pattern recognition receptors (PRRs) is the initiation and the most important part of the innate immune response. In this review, we summarize the roles of RNA sensors in the host innate immune response to influenza virus and coronavirus infections in different species, with a particular focus on innate immune recognition of viral nucleic acids in host cells, which will help to develop an effective strategy for the control of respiratory infectious diseases.

Keywords: RNA sensors; coronavirus; influenza virus; innate immune response; viral RNA.

Figure 1

Schematic diagram of innate immune response caused by IAV RNA. Upon IAV infection, viral ssRNA in the endosome is sensed by TLR7/8 and recruits the MyD88 adapter. Activated MyD88 induces the production of inflammatory cytokines through the TAK1-IKK-NF-κB signaling pathway. Viral double-stranded RNA in the endosome is sensed by TLR3, which further recruits TRIF and PI3K adapters, inducing the production of IFN through the TAK1-IRFs signaling pathway. Viral dsRNA in the cytoplasm is sensed by RIG-I and IFI16, leading to activation of NF-κB and phosphorylation of IRFs by binding to MAVS on mitochondria. Furthermore, IAV RNA can be sensed by NLRP3, which promotes the formation of inflammasomes, causing pyroptosis and secreting the IL-1β and IL-18. Of note, there is no direct evidence to demonstrate that IAV RNA can be recognized by DDX3X and MDA5 in mammals, which is indicated by dotted lines. Abbreviation: ROS, reactive oxygen species; MLKL, mixed lineage kinase domain-like pseudokinase. Other abbreviations are shown in the legend to Figure 2.

Figure 2

Schematic diagram of signaling transduction pathways in host response induced by recognition of PAMPs by PRRs. Sensing PAMPs, the PRRs recruit and activate MyD88, TRIF, TIRAP, and other adapters. These adapters transduce activating signals, which finally induce activation of transcriptional regulators NF-κB and IRFs, leading to the expression of IFNs and proinflammatory cytokines or mediators, such as IL-1, IL-6, IL-12, TNF-α, NO, etc. Abbreviation: MyD88, myeloid differentiation factor 88; TRIF, TIR domain-containing adapter-inducing IFN-β; TIRAP, TIR domain-containing adapter protein; IRAK, IL-1 receptor kinase; TRAF, tumor necrosis factor receptor-associated factor; MALT1, mucosa-associated lymphoid tissue lymphoma translocation gene 1; Syk, spleen tyrosine kinase; TAK, TGF-β activated kinase; NEMO, NF-κB essential modulator; IKK, inhibitor of NF-κB kinase; IκB, inhibitor of NF-κB; MAVS, mitochondrial antiviral signaling protein; PI3K, phosphoinositol-3 kinase; NF-κB, nuclear factor kappa enhancer binding protein; IRF, interferon regulatory factor; RIG-I, retinoic acid-inducible gene I; MDA5, melanoma differentiation-associated gene 5; STING, stimulator of interferon genes; LPS, Lipopolysaccharide; GSDMD, gasdermin D.

Figure 3

Schematic diagram of innate immune response induced by coronavirus RNA. Viral dsRNA is sensed by TLR3 in endosomes, triggering the innate immune response, while ssRNA in endosomes is sensed by TLR7/8 and induces the production of inflammatory cytokines through the MyD88-TAK1-IKK-NF-κB signaling pathway. Viral dsRNA is recognized by MDA5 and NOD1, and then interacts with MAVS on mitochondria, which further activates the NF-κB and IRFs signaling pathways. Viral GU-rich ssRNA is sensed by TLR8, causing the activation of NLRP3 inflammasomes through the Caspase-8-RIPK1 signaling pathway, leading to the secretion of mature IL-1β and IL-18. Importantly, it is not clear whether viral dsRNA is recognized by RIG-I to initiate IFN response or whether viral RNA induces inflammasome formation; thus, the associated pathway is indicated by dotted lines. Abbreviation: RIPK, Receptor interacting protein kinase; other abbreviations are shown in the legend to Figure 2.