PRRSV NSP5 orchestrates dual immune disruption by targeting NLRP3 and STING

Vet Res. 2025 Oct 16;56(1):199. doi: 10.1186/s13567-025-01636-3.

Abstract

Inflammasomes and interferons are two critical defense mechanisms of innate immunity, and their imbalance is a key strategy employed by viruses to evade host immune surveillance. During porcine reproductive and respiratory syndrome virus (PRRSV) infection, an arteritis virus, a characteristic "high inflammation, low interferon" immune imbalance is observed. This study identifies PRRSV non-structural protein NSP5 as a central mediator of this immune imbalance. We demonstrate that NSP5 recruits NLRP3 to the endoplasmic reticulum (ER)-mitochondrial interface, triggering ER stress and Ca2+ leakage, which subsequently activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome. Notably, a specific NSP5 mutation (G30A) abolishes its ability to activate NLRP3. PRRSV carrying this mutation exhibits suppressed NLRP3 activation and IL-1β release. Concurrently, NSP5 retains STING in the ER, preventing its trafficking and inhibiting type I interferon induction. This dual mechanism ultimately drives the high inflammation and low interferon phenotype observed during PRRSV infection. Importantly, our findings reveal that a single viral protein can orchestrate immune imbalance, suggesting a potentially widespread strategy for viral evasion of host immune surveillance.

Keywords: IFN-I; NLRP3 inflammasome; NSP5; PRRSV; STING.

MeSH terms

  • Animals
  • Immunity, Innate
  • Inflammasomes
  • Membrane Proteins* / genetics
  • Membrane Proteins* / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein* / genetics
  • NLR Family, Pyrin Domain-Containing 3 Protein* / immunology
  • NLR Family, Pyrin Domain-Containing 3 Protein* / metabolism
  • Porcine Reproductive and Respiratory Syndrome* / immunology
  • Porcine Reproductive and Respiratory Syndrome* / virology
  • Porcine respiratory and reproductive syndrome virus* / genetics
  • Porcine respiratory and reproductive syndrome virus* / immunology
  • Porcine respiratory and reproductive syndrome virus* / physiology
  • Swine
  • Viral Nonstructural Proteins* / genetics
  • Viral Nonstructural Proteins* / immunology
  • Viral Nonstructural Proteins* / metabolism

Substances

  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Viral Nonstructural Proteins
  • Inflammasomes
  • Membrane Proteins