Recent Progress in Innate Immune Responses to Enterovirus A71 and Viral Evasion Strategies

Abstract

Enterovirus A71 (EV-A71) is a major pathogen causing hand, foot, and mouth disease (HFMD) in children worldwide. It can lead to severe gastrointestinal, pulmonary, and neurological complications. The innate immune system, which rapidly detects pathogens via pathogen-associated molecular patterns or pathogen-encoded effectors, serves as the first defensive line against EV-A71 infection. Concurrently, the virus has developed various sophisticated strategies to evade host antiviral responses and establish productive infection. Thus, the virus-host interactions and conflicts, as well as the ability to govern biological events at this first line of defense, contribute significantly to the pathogenesis and outcomes of EV-A71 infection. In this review, we update recent progress on host innate immune responses to EV-A71 infection. In addition, we discuss the underlying strategies employed by EV-A71 to escape host innate immune responses. A better understanding of the interplay between EV-A71 and host innate immunity may unravel potential antiviral targets, as well as strategies that can improve patient outcomes.

Keywords: enterovirus; evasion strategies; hand, foot, and mouth disease (HFMD); innate immune response.

Figure 1

Illustration of the EV-A71 life cycle. EV-A71 enters host cells by binding to receptors such as SCARB2 and PSGL-1, allowing the release of its genomic RNA into the cytoplasm through endosomal membrane pores (①–②). The viral RNA undergoes translation, with VPg covalently linked to it (③). The translated polypeptides are then cleaved into 11 major proteins, including VP1-4 for viral capsid assembly and 2A-3D for the replication of viral RNA genome (④). Finally, the viral RNA and capsid are assembled and processed into mature viruses, which are released through extracellular vesicles or the direct lysis of host cells (⑤–⑥). Abbreviations: EV-A71: enterovirus A71; SCARB2: scavenger receptor B2; PSGL-1: P-selectin glycoprotein ligand-1.

Figure 2

Summary of the innate immune response during enterovirus infection. (a) Enterovirus replication activates TLR7 and TLR3/9 through ssRNA and dsRNA, respectively, leading to NF-κB nuclear translocation via TRIF or MyD88 adaptor proteins. (b) Cytoplasmic sensors RIG-I and MDA5 are activated by dsRNA, signaling through mitochondrial-associated MAVS and initiating the nuclear translocation of IRF3/7 and NF-κB transcription factors. Enterovirus infection induces mitochondrial damage, releasing mitochondrial DNA into the cytoplasm and activating STING. (c) Recognition of virus replication activates NLRP3, forming inflammasomes that activate caspase-1 and secrete IL-1β/IL-18. NLRP1 acts as a sensor for dsRNA and viral protease activity, being activated by enterovirus 3C^pro cleavage. (d) The binding of IFN-α/β and IFN-λ to their respective IFNARs triggers downstream kinases JAK1 and TYK2, phosphorylating STAT1 and STAT2. This promotes the formation and nuclear translocation of the STAT1-IRF9-STAT2 complex. Abbreviations: ssRNA: single-stranded RNA; dsRNA: double-stranded RNA; TLR3/7/9: Toll-like receptor 3/7/9; RIG-I: retinoic-acid-activated gene I; MDA5: melanoma differentiation-associated gene 5; TRIF: Toll/ interleukin (IL)-1 receptor domain-containing adaptor-protein-inducing interferon-β; MyD88: myeloid differentiation primary-response protein 88; MAVS: mitochondrial antiviral signaling protein; NF-κB: nuclear factor kappa-B; IRF1/3/7/9: interferon regulatory factor 1/3/7/9; STING: stimulator of interferon genes; NLRP1/3: NOD-like receptor (NLR) family pyrin domain-containing 1/3; IL-1β/18: interleukin-1β/18; IFN-α/β: interferon α/β; IFN-λ: interferon λ; IFNARs: type I interferon receptors; JAK1: Janus kinase 1; TYK2: tyrosine kinase 2; STAT1/2: signal transducer and activator of transcription 1/2; ISGs: IFN-stimulated genes.

Figure 3

Innate immune evasion strategies of EV-A71. EV-A71 infection upregulates USP24, Sox4, and SOCS, which downregulate TBK1 polyubiquitination, inhibit Myd88 activity, and suppress JAK-STAT signaling. The virus also disrupts endosomal structures associated with TLR3/7/8/9. The 2A^pro hydrolyzes key factors involved in innate immune signaling, including MDA5, MAVS, NLRP3, and IFNAR1, blocking signal transduction. The 2C protein targets IKKα and IKKβ, preventing their phosphorylation, reducing p65/p50 heterodimer formation, and inhibiting NF-κB activation. The 3C^pro hydrolyzes RIG-I, NLRP3, TRIF, IRF7, and ISG3, and it upregulates CYLD to inhibit RIG-I ubiquitination. The 3D^pol inhibits MDA5 activity and downregulates IRF1 expression to inhibit IFN-γ signaling. Abbreviations: DDX6: DEAD-box helicase 6; CYLD: CYLD lysine 63 deubiquitinase; USP24: ubiquitin-specific protease 24; Sox4: sex-determining region Y-box 4; SOCS: suppressor of cytokine signaling; TBK1: TANK-binding kinase 1; IKKα/β: inhibitor of kappa B kinase α/β.