# PRRSV NSP5 orchestrates dual immune disruption by targeting NLRP3 and STING

## TL;DR

PRRSV uses its NSP5 protein to disrupt two key immune defenses, causing high inflammation and low interferon during infection.

## Contribution

PRRSV NSP5 is shown to simultaneously activate NLRP3 and inhibit STING, revealing a novel dual immune evasion strategy.

## Key findings

- NSP5 recruits NLRP3 to the ER-mitochondrial interface, inducing ER stress and activating the NLRP3 inflammasome.
- NSP5 retains STING in the ER, blocking its trafficking and type I interferon production.
- A G30A mutation in NSP5 suppresses NLRP3 activation and IL-1β release.

## 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.

The online version contains supplementary material available at 10.1186/s13567-025-01636-3.