# Pseudorabies Virus Infection Triggers PANoptosis to Enhance Inflammatory Responses Both In Vitro and In Vivo

## TL;DR

This study shows that pseudorabies virus infection triggers PANoptosis, a type of inflammatory cell death, which worsens inflammation in both lab cells and mice lungs.

## Contribution

The study is the first to demonstrate that PRV induces PANoptosis and that inhibiting it reduces inflammation.

## Key findings

- PRV replicates in THP-1-derived macrophages and induces PANoptosis with Gasdermin D, caspase-3, and MLKL activation.
- PANoptosis inhibition reduces inflammatory cytokine production in vitro and lung inflammation in mice.
- PRV infection in mice causes productive lung infection with PANoptosis molecular and histopathological features.

## Abstract

Pseudorabies virus (PRV), an alphaherpesvirus, causes severe neurological and respiratory diseases in multiple mammalian species and poses an emerging threat to public health. Increasing evidence suggests that virus-induced inflammatory cell death plays a pivotal role in shaping host immune responses and disease outcomes. PANoptosis, a newly defined inflammatory programmed cell death pathway integrating pyroptosis, apoptosis, and necroptosis, has been implicated in host defense against diverse pathogens. However, whether PRV infection induces PANoptosis and contributes to inflammatory pathology remains largely unexplored. In this study, we demonstrate that PRV efficiently replicates in Human Acute Monocytic Leukemia Cells (THP-1)-derived macrophages and robustly induces PANoptosis, characterized by the concurrent activation of Gasdermin D, caspase-3, and Mixed Lineage Kinase Domain-Like (MLKL). Pharmacological inhibition of PANoptosis markedly attenuated PRV-induced inflammatory cytokine production in vitro. Furthermore, intranasal inoculation of PRV in Balb/c mice resulted in productive lung infection accompanied by pronounced pulmonary inflammation. Lung tissues from PRV-challenged mice exhibited molecular and histopathological hallmarks of PANoptosis. Importantly, drug-mediated suppression of PANoptosis significantly reduced lung inflammation and inflammatory cytokine expression in vivo. Collectively, our findings identify PANoptosis as a critical mechanism underlying PRV-induced inflammatory responses and suggest that targeting PANoptosis may represent a promising therapeutic strategy for PRV-associated inflammatory diseases.