# Research Supplements to Promote Diversity in Health-Related Research (Admin Supp - Clinical Trial Not Allowed)

> **NIH NIH DP2** · UNIVERSITY OF COLORADO · 2024 · $91,505

## Abstract

PROJECT SUMMARY
 This is a proposed supplement to Dr. Aaron Whiteley’s NIH Director’s New Innovator Award
(DP2AT012346) titled “Deciphering the crosstalk between bacteria and their mammalian hosts”. Bacteria must
defend themselves against the constant threat of bacteriophages (phages) and mobile genetic elements that
seek to parasitize bacterial hosts for their selfish replication and spread. The conflict between bacteria and their
threats has driven the evolution of genes that cooperate to form sophisticated signaling pathways to protect
bacteria; these pathways collectively form the bacterial immune system. Interestingly, a subset of proteins found
in the bacterial immune system are homologous to proteins in the human immune system, which provides a
basis for cross-kingdom signaling, from bacteria to humans. The focus of this supplement is on understanding
the bacterial immune system to improve our understanding and design of probiotic bacteria that might better
survive in the human gut or influence human immune signaling pathways.
 The proposed goals for this supplement are to investigate the prevalence and function of known bacterial
immune pathways in the microbiome and to uncover novel immune pathways that restrict horizontal gene
transfer. In the first Aim, we will investigate the antiphage system CBASS (Cyclic Oligonucleotide Based
Antiphage Signaling Systems) in the context of the human microbiome. CBASS is a potent antiphage system
that is evolutionarily related to the human cGAS-STING antiviral pathway. A defining feature of CBASS systems
is a CD-NTase (cGAS/DncV-like nucleotidyltransferase) protein, which is homologous to cGAS. Both cGAS and
CD-NTases synthesize cyclic nucleotides that elicit potent immune signaling. In the parent grant, we investigate
how cyclic nucleotides produced by bacteria in the gut may impact mammalian host immune signaling. This aim
synergizes with that work by investigating the abundance of CBASS systems in metagenomes derived from
healthy and disease-related mammalian microbiomes and interrogating their function in heterologous systems.
In the second Aim, we will discover novel aspects of the bacterial immune system that restrict horizontal gene
transfer by screening diverse bacteria using a functional assay. We will then assess the role of these systems in
bacteria from the mammalian microbiome, including estimating their prevalence and disease association in
metagenomes.
 The supplemental aims proposed will illuminate cryptic aspects of antiphage systems, interdomain
signaling, and how bacteria control mobile genetic elements. Further, findings from this work will contribute to
the ultimate development of novel pre- and probiotic complementary therapies that can durably remain within
the human gut microbiome and even promote appropriate immune responses.

## Key facts

- **NIH application ID:** 11071838
- **Project number:** 3DP2AT012346-01S1
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Aaron Thomas Whiteley
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $91,505
- **Award type:** 3
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11071838

## Citation

> US National Institutes of Health, RePORTER application 11071838, Research Supplements to Promote Diversity in Health-Related Research (Admin Supp - Clinical Trial Not Allowed) (3DP2AT012346-01S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11071838. Licensed CC0.

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