Mechanism by which porcine transmissible gastroenteritis virus disrupts host innate immunity

Abstract

Innate immune evasion is a critical aspect of viral infections, as it disrupts the host's defense mechanisms.The innate immune system, as the primary defense against pathogens, detects pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs). This recognition triggers the production of interferons (IFNs) and pro-inflammatory factors, initiating the antiviral immune response. During evolution, viruses have found many ways to evade innate immune response in order to increase the replication efficiency, transmission ability and to establish persistent infection through co-evolution with hosts. Pigs act as natural hosts for a variety of significant viruses, including both DNA and RNA viruses. These viruses not only jeopardize animal health but also present a potential risk of interspecies transmission. Among these, porcine transmissible gastroenteritis virus (TGEV) stands out as a highly prevalent and severely detrimental enterovirus in the global swine industry. This review aims to comprehensively analyze the interaction between TGEV and host cells, emphasizing the molecular underpinnings of its immune evasion strategies. In addition, we will describe the programmed cell death types induced by TGEV, including autophagy, apoptosis and pyroptosis. Compared with existing reviews, this article not only provides a systematic integration of the multilayered immune evasion mechanisms of TGEV but also, for the first time, offers a comprehensive overview of its interactions with various forms of programmed cell death. This perspective highlights the complex regulatory networks underlying TGEV's adaptive evolution in the host, thereby enhancing our understanding of the pathogenic mechanisms of porcine coronaviruses and offering novel theoretical foundations for the development of vaccines and antiviral therapeutics.

Keywords: IFN; PAMPS; PRRs; TGEV; immune response; innate immune escape.

Figure 1

Genomic organization of TGEV and host innate immune responses. TGEV is an enveloped, positive-sense single-stranded RNA virus whose genome is organized as 5′UTR–ORF1a–ORF1b–S–ORF3a/3b–E–M–N–ORF7–3′UTR. It encodes four structural proteins,namely the spike (S), envelope (E), membrane (M), and nucleocapsid (N)—as well as several accessory proteins. In piglets less than 10 days of age, infection typically causes severe diarrhea and is often fatal, with mortality rates reaching 80–100%. The figure also illustrates the recognition of viral RNA by host pattern recognition receptors (TLRs, RLRs, and NLRs), along with the activation of downstream interferon signaling pathways. These pathways induce antiviral gene expression and contribute to host defense.

Figure 2

Schematic representation of NLRP3 inflammasome and cGAS-STING pathway activation. This figure illustrates the activation mechanisms and downstream effects of the NLRP3 inflammasome (on the left) and the cGAS-STING pathway (on the right), highlighting their interconnections in innate immune responses. The left panel shows that priming signals, which are mediated by TNFR, TLR, and IL-1R upon stimulation with TNF, PAMPs, and IL-1β, lead to NF-κB activation and NLRP3 inflammasome assembly. This assembly process involves nucleotide - binding oligomerization domain - containing protein 2 (NOD2), muramyl dipeptide (MDP), ATP, K⁺ efflux, and ROS, ultimately inducing caspase - 11 (CASP11) and interferon - β (IFNB) expression, pyroptosis, and IL-1β release. The right panel illustrates cyclic GMP - AMP synthase (cGAS) binding to cytosolic DNA to generate cGAMP, which activates STING translocation from the endoplasmic reticulum (ER)to the Golgi and subsequently triggers the activation of interferon regulatory factor 3 (IRF3) and NF-κB, resulting in antiviral responses and pro-inflammatory cytokine production. Shared regulatory elements include ROS and Ca²⁺ perturbations, mitochondrial damage, and lysosomal rupture, with organelles such as lysosomes, mitochondria, and autophagosomes contributing to inflammasome activation, pyroptosis, and cytokine synthesis.

Figure 3

Mechanisms by which TGEV evades host PRRs-mediated innate immune responses. In uninfected cells, viral RNA is recognized by endosomal Toll-like receptors (TLR3/TLR7) or cytoplasmic sensors such as Melanoma Differentiation - Associated Gene 5 (MDA5). This recognition triggers downstream signaling cascades via adaptor kinases and transcription factors, ultimately leading to the production of type I interferons and pro - inflammatory cytokines.However, during TGEV infection, viral non-structural proteins (NS) inhibit key signaling nodes by promoting protein degradation or functional inactivation, thereby disrupting the TLR/RLR signaling pathways. This results in impaired nuclear translocation of IRF3 and NF-κB,along with reduced cytokine expression. In addition, TGEV evades MDA5 recognition by modifying the viral RNA cap structure through 2’-O methylation (m⁷GpppNm), which prevents MDA5 binding and subsequent activation of downstream signaling.

Figure 4

TGEV-induced disruption of intestinal barrier and modulation of Notch signaling. TGEV infection activates NF-κB and MAPK pathways, promoting inflammatory cytokine release (TNF-α, IL-6, IL-8) and downregulating tight junction proteins (ZO-1, Occludin, Claudin-1), leading to barrier dysfunction. Excess ROS impairs mitochondrial function, reduces TEER, and inhibits Dll4 and Hes5 expression in the Notch pathway, causing aberrant differentiation of GI stem cells into goblet cells, which may facilitate viral replication and spread.