# Interferon and TLR genes, but not endogenous bornavirus-like elements, limit BoDV1 replication after intracerebral infection

## TL;DR

The study found that conventional immune pathways, not EBLN-derived piRNAs, are key to controlling Borna disease virus 1 in newborn mouse brains.

## Contribution

The study provides new evidence that EBLN-derived piRNAs are not the main defense against BoDV1 in neonatal brain infections.

## Key findings

- Interferon gamma and TLR7 are critical for controlling BoDV1 replication in the brain.
- EBLN knockout mice did not show increased susceptibility to BoDV1 compared to wild-type mice.
- Conventional immune pathways are more important than EBLN-derived piRNAs in this infection model.

## Abstract

Borna disease virus 1 (BoDV1) is a disease-causing agent in some livestock and, as has recently been shown, in humans. What constitutes a protective immune response to BoDV1 is unclear. Previous studies found that endogenous bornavirus-like nucleoprotein elements (EBLNs) present in mammalian genomes produce piRNAs antisense to BoDV1 nucleoprotein mRNAs. As a known function of piRNAs is to restrict transposons via RNA interference, it has been hypothesized that EBLN-derived piRNAs may restrict BoDV1. Here we used EBLN knockout (KO) and other KO mice to test genetic factors potentially involved in antiviral immunity to BoDV1. In previous reports, BoDV1 replication was higher in mice deficient in interferon gamma, and we confirmed a role for this cytokine in BoDV1 restriction at 12 weeks post infection using mice lacking its receptor. We show that BoDV1 replicates to higher levels in the brain of mice without Toll-like receptor 7 (TLR7), suggesting a role for this innate immune receptor in BoDV1 immunity. In contrast, mice lacking piRNA-producing EBLNs were no more susceptible to BoDV1 infection than wild-type under the infection conditions used here. We thus expand the genetic evidence implicating specific conventional immune pathways in BoDV1 control and conclude that EBLN-derived piRNA-guided antiviral silencing, if it occurs, is relatively less impactful in intracerebral infection of neonates.

The study examined the immune response to Borna disease virus 1 (BoDV1), which infects both animals and humans. Previous studies suggest that endogenous bornavirus-like nucleoprotein elements (EBLNs) within mammalian genomes might contribute to antiviral immunity against BoDV1 through a novel mechanism involving piRNA silencing. To dissect the potential role of EBLNs in BoDV1 immunity at a genetic level, we engineered EBLN knockout (KO) mice lacking all three piRNA-producing EBLNs. These mice, along with other KO mice lacking specific immune factors, were injected intracerebrally with BoDV1. The study confirmed that conventional immune pathways involving interferon gamma and Toll-like receptor 7 (TLR7) are more critical for controlling BoDV1 infection compared to the proposed mechanism involving EBLN-derived piRNAs, at least in the context of brain infections in newborn mice. These findings suggest that, while EBLNs might play a role in different scenarios, conventional immune pathways are likely the primary defense against BoDV1 infection, particularly in newborn mouse brains. Further research is needed to determine the significance of EBLNs in antiviral immunity.