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Published on: August 7, 2018
Z-DNA binding protein 1 mediates necroptotic cell death in primary murine microglia following herpes simplex virus-1
Alexander J Suptela1, Ian Marriott2
1University of North Carolina at Charlotte, 9201 University City Blvd, Charlotte, NC, 28223, USA.
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.
Insights
Microglia utilize Z-DNA binding protein 1 (ZBP1) to restrict herpes simplex virus-1 (HSV-1) infection, influencing cell death pathways. Viral strain impacts ZBP1
Area of Science:
- Neuroimmunology
- Virology
- Cellular Biology
Background:
- Microglia, the immune cells of the central nervous system (CNS), possess pattern recognition receptors, including cytosolic sensors for nucleic acids.
- Z-DNA binding protein 1 (ZBP1) is a cytosolic sensor previously implicated in microglial inflammatory responses to herpes simplex virus-1 (HSV-1).
- ZBP1 acts as a restriction factor in murine astrocytes, inducing necroptosis and apoptosis in response to HSV-1.
Purpose of the Study:
- To investigate the role of ZBP1 as a restriction factor for HSV-1 in primary murine microglia.
- To determine the cell death pathways (necroptosis and apoptosis) induced by HSV-1 in microglia.
- To explore potential differences in ZBP1-mediated cell death induction based on HSV-1 viral strains.
Main Methods:
- Primary murine microglia cultures were infected with clinically-derived and laboratory-adapted HSV-1 strains.
- ZBP1 expression and its role in cell death pathways were assessed.
- Analysis of necroptosis and apoptosis induction in response to different viral isolates.
Main Results:
- ZBP1 functions as an HSV-1 restriction factor in primary murine microglia, similar to its role in astrocytes.
- A clinically-derived HSV-1 isolate induced ZBP1-dependent and independent necroptosis, but not apoptosis, in microglia.
- A laboratory-adapted HSV-1 strain induced ZBP1-independent apoptosis and both ZBP1-dependent and independent necroptosis in microglia.
Conclusions:
- ZBP1 plays a role in restricting HSV-1 in microglia, influencing distinct cell death pathways.
- Viral strain-specific differences exist in ZBP1-mediated cell death induction in microglia.
- Further research is needed to ascertain whether ZBP1-mediated microglial cell death contributes to host protection or exacerbates CNS pathology.
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