International Journal of Molecular Veterinary Research, 2025, Vol.15, No.1, 32-42 http://animalscipublisher.com/index.php/ijmvr 34 3 Mechanisms of PRRSV Infection and Pathogenesis 3.1 Viral entry mechanisms and receptor recognition PRRSV has a very limited cell tropism and infects predominantly porcine alveolar macrophages. The first requirement for entry is adhesion to the cellular receptor CD163, which is a scavenger receptor with cysteines and is strictly necessary for PRRSV-1 and PRRSV-2 infection. CD163 promotes viral uncoating and genome release, and gene-editing studies suggest that pigs deficient in CD163 or its SRCR5 domain are resistant to infection. Sialoadhesin (Siglec-1/CD169) may act as an accessory receptor, i.e., for genotype I PRRSV, but is not essential for productive infection. Other molecules, e.g., heparan sulfate, vimentin, CD151, and DC-SIGN, are involved in viral attachment and ingestion. PRRSV is able to exploit alternative entry mechanisms, e.g., clathrin-mediated endocytosis and apoptotic mimicry via macropinocytosis, in order to further facilitate host cell invasion and immune detection evasion (Liu et al., 2024). 3.2 Viral replication and interactions with host cells When it invades, PRRSV unwraps its positive-sense RNA genome into the cytoplasm and is translated and replicated. PRRSV takes over the host cell machinery, which forms replication complexes on rearranged intracellular membranes, particularly in CD163-expressing macrophages. PRRSV nonstructural proteins such as NSP2 exhibit interaction with a wide range of host proteins involved in translation, metabolism, signal transduction, and innate immunity to enable efficient viral replication and regulation of apoptosis. Viral glycoprotein 5 (GP5) plays a role in destabilizing mitochondria and endoplasmic reticulum structure, enhancing ER-mitochondria contact, and stimulating mitochondrial Ca2+ uptake and reactive oxygen species (ROS) generation. The changes induce autophagy and NLRP3 inflammasome activation, enhancing viral replication and host immune regulation. PRRSV has also been shown to hijack host proteins such as DDX3X to enhance ferroptosis, enhancing viral replication and pathogenesis (Jun et al., 2021; Wen et al., 2025). 3.3 Immune evasion mechanisms PRRSV has evolved various mechanisms to evade the host innate immunity and cause persistent infection. PRRSV suppresses type I IFN production and signaling through the actions of the nonstructural proteins Nsp1, Nsp2, and Nsp5 that interfere with key steps in the IFN pathway, such as the activation of IRF3 and NF-κB, and protein degradation in the RIG-I-like receptor (RLR) signaling pathway through FAM134B-induced ER-phagy. PRRSV also inhibits host miRNAs besides miR-218 to induce SOCS3, a JAK-STAT signaling negative regulator, to suppress IFN responses and enhance viral replication. Other mechanisms include the interference with LGP2 and MDA5-mediated signaling, inhibition of PKR expression, and modulation of cytokine profiles to inhibit pro-inflammatory responses and induce anti-inflammatory cytokines such as IL-13. Such mechanisms of immune evasion cause poor and delayed adaptive immune responses, chronic infection, and increased susceptibility to secondary pathogens (He et al., 2022). 3.4 Molecular basis of pathological changes and clinical manifestations The molecular pathogenesis of PRRSV is manifested in its interference with innate immunity, induction of apoptosis, and induction of chronic inflammation. PRRSV infection results in sow reproductive loss and respiratory disease in piglets with secondary infection complication. The virus's ability to retard and inhibit innate and adaptive immunity results in chronic infection, chronic inflammation, and susceptibility to future pathogens. PRRSV activates the NLRP3 inflammasome through induction of mitochondrial injury and cytosolic mitochondrial DNA stress, leading to IL-1β secretion and inflammation. Immune evasion and induction of characteristic pathological lesions, including interstitial pneumonia, alveolar septal thickness, and most severely necrotizing and proliferative pneumonia, are achieved by the nucleocapsid protein and other viral factors. Severity and pattern of pulmonary damage depend on viral strain virulence and host immune reaction, with increased virulence leading to increased tissue damage and immune dysregulation (Zhang et al., 2023; Ruedas-Torres et al., 2024; Zheng et al., 2024).
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