# Defining the role of microbiota-derived cyclic dinucleotides in priming antiviral immune defenses.

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $405,730

## Abstract

Enteric pathogens represent a major group of disease-causing agents, and must overcome the physical and
immunological barrier of the gastrointestinal tract. The resident microbiota presents with a large array of ligands
and pathogen-associated molecular patterns (PAMPs) which can prime immune defenses, through pattern
recognition receptors (PRRs), both on enterocytes and immune resident cells. Indeed, microbial-derived TLR
ligands are necessary for the development and maintenance of the intestinal barrier and immune homeostasis.
Moreover, the microbiota is not static and imbalanced bacterial communities, termed dysbiosis, impact immunity,
in particular during aging. Aging is associated with increased susceptibility to enteric pathogens, and how the
dysbiotic microbiota alters susceptibility is largely unknown. The complement of microbial-derived ligands that
are sensed and that can prime antiviral immunity is incomplete. A better understanding of the molecular
mechanisms by which immunity is maintained, how the microbiota and epithelia interact, and how this impacts
infection and pathogenesis has the potential to reveal novel strategies to treat enteric viral infections. Studies
exploring the role of the microbiota and host genes in the context of aging in enteric infections are challenging
in small animal models due to costs and technical hurdles. To overcome our gap in knowledge of the molecular
mechanisms that control enteric viral infection, we developed an oral model of infection using the powerful
genetic model organism, Drosophila. We found that the gut presents a high barrier to infection: young wild type
flies are refractory to oral challenge with human viruses, while inoculation into the body cavity, which bypasses
the gut, results in robust infection. The spectrum of antiviral pathways engaged in the gut, and how the microbiota
shapes immunity in the intestine is incompletely understood. Preliminarily, we found that Drosophila STING
controls infection in the intestine; dSTING mutants are more susceptible to enteric viral infection. STING is known
to be activated by cyclic dinucleotides (CDNs). While cGAS can produce CDNs endogenously, STING can also
be activated by bacterially derived CDNs. This led us to explore the possibility that commensal bacteria-derived
CDNs may impact innate defenses in the gut through STING, as it is known that microbiota-derived CDNs are
present in the gut. Our new data identifies a role for microbiota-derived CDNs in antiviral defense. Ablation of
the microbiota in young animals leads to increased infection, and feeding these microbiota-deficient flies CDNs
was protective. In Aim 1 we will define the role of dSTING in antiviral defense and in Aim 2 we will define the role
of commensal-derived CDNs in antiviral defense in young and old animals.

## Key facts

- **NIH application ID:** 10102202
- **Project number:** 5R01AI152362-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Sara Cherry
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,730
- **Award type:** 5
- **Project period:** 2020-02-10 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10102202

## Citation

> US National Institutes of Health, RePORTER application 10102202, Defining the role of microbiota-derived cyclic dinucleotides in priming antiviral immune defenses. (5R01AI152362-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10102202. Licensed CC0.

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