# Abortive and productive infection of CNS cell types following in vivo delivery of VSV

## TL;DR

This study explores how different brain cells respond to a virus, revealing that neurons are highly infected while glial cells show varied responses.

## Contribution

The paper introduces a dual-labeling virus to distinguish abortive and productive infections in vivo, enabling detailed analysis of virus-host interactions in the CNS.

## Key findings

- Neurons exhibit high levels of viral gene expression, while glial cells show varied infection outcomes.
- Astrocytes are predominantly productively infected, whereas oligodendrocytes are largely abortively infected.
- Microglia are the main producers of IFNb early after infection, but IFN signaling does not significantly alter primary infection outcomes.

## Abstract

Virus–host interactions can vary widely, with some host cell types resisting virus entry or replication, and others supporting a full viral replication cycle. Such interactions have not been easy to characterize in vivo, particularly for infections of the central nervous system (CNS). We developed a dual-labeling virus with the capability of distinguishing abortive or productive viral replication in vivo. We used this virus to examine the response of different CNS cell types to infection with vesicular stomatitis virus. Additionally, we were able to uncover early host responses and assess their impact on primary infection. Investigation of other virus–host interactions can use this dual labeling strategy to better track the dynamics and specificity of virus–host interactions.

Viral infection is frequently assayed by ongoing expression of viral genes. These assays fail to identify cells that have been exposed to the virus but limit or inhibit viral replication. To address this limitation, we used a dual-labeling vesicular stomatitis virus (DL-VSV), which has a deletion of the viral glycoprotein gene, to allow evaluation of primary infection outcomes. This virus encodes Cre, which can stably mark any cell with even a minimal level of viral gene expression. Additionally, the virus encodes GFP, which distinguishes cells with higher levels of viral gene expression, typically due to genome replication. Stereotactic injections of DL-VSV into the murine brain showed that different cell types had very different responses to the virus. Almost all neurons hosted high levels of viral gene expression, while glial cells varied in their responses. Astrocytes (Sox9+) were predominantly productively infected, while oligodendrocytes (Sox10+) were largely abortively infected. Microglial cells (Iba1+) were primarily uninfected. Furthermore, we monitored the early innate immune response to viral infection and identified unique patterns of interferon (IFN) induction. Shortly after infection, microglia were the main producers of IFNb, whereas later, oligodendrocytes were the main producers. IFNb+ cells were primarily abortively infected regardless of cell type. Last, we investigated whether IFN signaling had any impact on the outcome of primary infection and did not observe significant changes, suggesting that intrinsic factors are likely responsible for determining the outcome of primary infection.