# Investigating the Antiviral Role of STING During Enteric RNA Virus Infection in Drosophila

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $15,548

## Abstract

Project Summary:
The intestine serves as a physical and immune barrier to protect against infection by enteric
pathogens. The Cherry lab uses Drosophila as an in vivo model of human and mosquito enteric
infection to understand the intestinal innate immune response and how it is influenced by the
composition of the microbiota. Sindbis virus is a mosquito-borne virus that is transmitted to
mosquito vectors orally during a blood meal. Our preliminary data suggest the Drosophila
homologue of Stimulator of Interferon Genes (STING) is antiviral against Sindbis virus within the
intestine. Mammalian STING is activated by binding cyclic dinucleotides produced endogenously
by cyclic GMP-AMP synthase (cGAS) or exogenously by bacteria. Mammalian cGAS produces a
cyclic dinucleotide after binding cytosolic DNA from bacteria or DNA viruses but is not activated
by binding RNA. Our preliminary data shows that the closest cGAS ortholog is antiviral against
enteric Sindbis infection. Sequence analysis of this Drosophila cGAS candidate reveals it lacks
the DNA binding domain found in mammalian cGAS, suggesting that d-cGAS senses a non-DNA
ligand, perhaps viral RNA. Metagenomic data reveals that Drosophila commensal bacteria
encode CDN synthases indicating that the microbiota could provide an exogenous CDN pool to
prime basal STING activity from subsequent viral infection. Indeed, our preliminary data suggests
exogenous feeding of CDNs to flies lacking their microbiota protects against enteric Sindbis virus
infection. Moreover, we found that STING may be antiviral through the activation of autophagy
and inflammatory NF-kB activation.
We hypothesize that both d-cGAS and the microbiome produce CDNs that activate dSTING to
protect from RNA virus infection through infection-dependent autophagy within the intestine. To
expand on this hypothesis in Aim 1 we propose to determine the role of d-cGAS and CDNs in
STING-dependent antiviral defense. Additionally, in Aim 2 we propose to define the mechanism
by which STING is antiviral in enterocytes. This work sheds light on evolution of the ancient cGAS-
STING defense pathway and defines how additional microbiota-derived products, such as CDNs,
may influence intestinal immunity.

## Key facts

- **NIH application ID:** 10219056
- **Project number:** 5F31AI147415-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Elisha Segrist
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $15,548
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-12-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219056

## Citation

> US National Institutes of Health, RePORTER application 10219056, Investigating the Antiviral Role of STING During Enteric RNA Virus Infection in Drosophila (5F31AI147415-03). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10219056. Licensed CC0.

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