# Z-DNA binding protein 1 mediates necroptotic cell death in primary murine microglia following herpes simplex virus-1 infection

## TL;DR

This study shows that ZBP1 helps microglia fight HSV-1 infection by causing cell death, but the effect depends on the virus strain and may worsen brain damage.

## Contribution

The study reveals ZBP1's role in HSV-1-induced necroptosis in microglia and highlights strain-specific differences in cell death pathways.

## Key findings

- ZBP1 acts as a restriction factor for HSV-1 in primary murine microglia.
- HSV-1 isolates induce necroptosis in microglia via ZBP1-dependent and independent mechanisms.
- Apoptosis in microglia occurs only with a lab-adapted HSV-1 strain and is ZBP1-independent.

## Abstract

The mechanisms by which microglia respond to viral central nervous system (CNS) pathogens are now becoming apparent with the demonstration that they express an array of pattern recognition receptors that include cytosolic sensors for exogenous nucleic acids. We have previously shown that microglia express Z-DNA binding protein 1 (ZBP1) and found that this sensor contributes to their inflammatory responses to the clinically relevant DNA virus, herpes simplex virus-1 (HSV-1). More recently, we showed that ZBP1 serves as a restriction factor for HSV-1 in murine astrocytes and is associated with the induction of both necroptotic and apoptotic cell death pathways in these cells. Here, we demonstrate that this cytosolic DNA sensor similarly functions as a HSV-1 restriction factor in primary murine microglia. However, unlike astrocytes, we have determined that a neuroinvasive clinically-derived HSV-1 isolate induces necroptosis, but not apoptosis, in these myeloid cells in a ZBP1-dependent as well as a ZBP1-independent manner. Interestingly, we found that a laboratory adapted HSV-1 strain elicits microglial apoptosis in a ZBP-1-independent manner, in addition to both ZBP1-dependent and independent necroptosis, indicating that viral strain-specific differences may exist. However, it remains to be seen whether ZBP1-mediated cell death in microglia contributes significantly to host protection or, rather, exacerbates DNA virus-associated CNS pathology in mice.

The online version contains supplementary material available at 10.1007/s13365-025-01304-4.