Pathogenicity and virulence of PRRSV: From regulated cell death reprogramming landscape and immune subversion to precision vaccinology

Figure 1.. Multilayered PRRSV immune evasion mechanisms. (A) Schematic overview of major innate antiviral pathways in uninfected porcine alveolar macrophages. These pathways include RIG‑I-like receptor signaling, the cGAS–STING axis, and interferon‑dependent JAK–STAT signaling. (B) PRRSV‑infected cells show extensive disruption of host antiviral defense by viral proteins. Nsp5, Nsp4, Nsp1β, Nsp11, and GP2a target distinct but interconnected signaling nodes to weaken innate immune responses. (C) At the molecular level, Nsp5 promotes FAM134B‑dependent reticulophagy and drives degradation of RIG‑I-like receptor signaling components. Nsp4 cleaves MAVS and targets DHCR24. Nsp1β induces degradation of karyopherin α1 and prevents STAT1 nuclear translocation. Nsp11 targets IRF9 and promotes cleavage of MAVS mRNA. GP2a enhances RIG‑I ubiquitination and redirects the TRIM25–RIG‑I complex through ZCCHC3. (D) These immune evasion events are temporally coordinated. Early infection is characterized by suppression of viral sensing, whereas later stages are dominated by blockade of downstream interferon signaling.

Figure 2.. PRRSV reprograms apoptosis over time and induces RTC–dTGN NLRP3‑dependent pyroptosis in porcine alveolar macrophages. (A) During early infection, IFI30 restrains caspase activation and supports a replication‑permissive state. Loss of IFI30 increases apoptosis and promotes viral replication. During late or persistent infection, apoptosis shifts toward full execution and may facilitate viral release and spread. Soluble Fas reflects this temporal transition and is reduced in vaccinated piglets. (B) PRRSV induces pyroptosis through an RTC‑linked pathway. The viral replication–transcription complex forms on endoplasmic reticulum‑derived membranes with TMEM41B and intermediate filaments and promotes trans‑Golgi network fragmentation into dispersed vesicles that support NLRP3 clustering. PRRSV nsp2 enhances inflammasome assembly, leading to Caspase 1 activation, GSDMD cleavage, inflammatory mediator release, and lytic cell death. In vivo findings support this pathway, and disruption of TMEM41B or intermediate filaments suppresses these responses.

Figure 3.. PRRSV coordinates ferroptosis, autophagic rewiring, and PANoptosis‑related cell death convergence in porcine alveolar macrophages. (A) PRRSV promotes ferroptotic vulnerability by suppressing the Nrf2–GPX4 antioxidant axis and increasing Keap1 and ACSL4, which drives reactive oxygen species accumulation, lipid peroxidation, and ferrous iron overload. In parallel, YY1 reshapes lipid metabolism through FASN suppression and PPARγ activation, leading to lipid droplet accumulation that restricts viral replication. Resveratrol partly reverses these changes and modulates the autophagy–ferroptosis axis through PI3K–Akt signaling. (B) PRRSV initiates autophagy but blocks its completion. Nsp4 promotes TRIM28‑dependent stabilization of the Vps34–Beclin1 complex and supports phagophore formation. Endoplasmic reticulum stress induces FAM134B and drives formation of double‑membrane vesicles that support viral RNA replication. Nsp10 and SNX1 then disrupt RAB7‑dependent trafficking, inhibit autophagosome–lysosome fusion, and protect viral particles from degradation. (C) PRRSV induces features of pyroptosis, apoptosis, and necroptosis, suggesting convergence into a PANoptosis‑related death…

Figure 4.. PRRSV-mediated immune dysregulation and viral persistence through macrophage subversion, innate signaling suppression, and adaptive immune hyporesponsiveness. (A) PRRSV reshapes alveolar macrophage polarization in a context-dependent manner and consistently weakens antiviral competence. Although some experimental systems show an M1-like inflammatory profile, broader evidence supports immunoregulatory dysfunction linked to IL‑10, TGF‑β, β, and Arg‑1 and associated with viral persistence. (B) PRRSV antibody immune complexes engage Fcγ receptors and suppress RIG‑I and MDA5-dependent sensing, weakening MAVS, TBK1, and IRF3 signaling, reducing type I interferon production, and promoting viral persistence. (C) PRRSV is associated with adaptive immune hyporesponsiveness with regulatory bias. Effector T cells show reduced functional activity, whereas regulatory signatures become more prominent.

Figure 5.. Molecular mechanisms of PRRSV vaccine failure and principles of precision vaccinology. (A) Modified live virus vaccines rarely induce sterilizing immunity against heterologous PRRSV strains. Residual replication, viremia, and shedding sustain viral circulation, favor co‑infection with field strains, and create conditions for recombination that can generate pathogenic mosaic variants such as GM2 and FJWQ16. Protection is weakened by antigenic mismatch with prevalent lineages, especially lineages 1.8 and 3, together with variation in nsp1α, GP2, GP3, and GP5 and increased glycan shielding of GP5. Antibody-dependent enhancement may suppress RIG‑I-driven antiviral signaling in porcine alveolar macrophages through FcγRI-linked pathways and reduce TBK1, IRF3, STAT1, STAT2, and downstream interferon-stimulated effectors. (B) Rational attenuation targets viral determinants that suppress innate immunity and amplify immunopathology, including nsp1, nsp2, nsp4, and nsp11. Editing these regions may restore interferon induction, preserve MAVS-dependent signaling, relieve JAK–STAT inhibition, and limit excessive regulated cell death while retaining immunogenicity. (C) Precision vaccine design…