# A Novel CDN Sensor-Adaptor System for Host Defense Against Infection

> **NIH NIH R01** · YALE UNIVERSITY · 2021 · $418,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Mammals defend against infection by detecting foreign and/or danger signals to mount both cell-autonomous
as well as paracrine immune responses. Among the microbial signatures sensed by mammalian hosts are a
new class of signaling intermediates termed cyclic di-nucleotides (CDNs). CDNs are recognized by the host
protein, STING (STimulator of INterferon Genes), to elicit type I IFN production. In this application we will
characterize a new CDN recognition system that mobilizes protective immunity independently of STING or type
I IFN release. This new circuit enlists four members of an immune GTPase family – the 65-73kDa Guanylate
Binding Proteins (GBPs) – to activate distinct host defense programs in both humans and mice. Preliminary
evidence implicates GBP1 as the proximal CDN sensor which recruits GBP2, GBP3 and GBP5 as adaptors
that link the antimicrobial machinery further downstream. In Aim 1, we will test the importance of GBP1 to act
as a broad-spectrum CDN sensor capable of binding c-diGMP, c-diAMP and cGAMPs under physiological
conditions to elicit either inflammasome assembly, pyroptosis or autophagy in a STING-independent manner.
This will be examined using a powerful host-pathogen genetic strategy where mice and cells lacking GBP1 or
expressing GBP1 CDN-binding mutants will be infected with important bacterial pathogens (M. tuberculosis, S.
typhimurium and L. monocytogenes) engineered to secrete a specific CDN moiety to define this relationship in
vitro and in vivo. In Aim 2, we expand this CDN sensor circuit to include GBP2, GBP3 and GBP5 as
heterotypic partners that direct core components of the inflammasome, pyroptotic or autophagy cascade to
restrict bacterial replication. This aim will enlist newly-created Gbp2-/-, Gbp3-/- and Gbp5-/- mice as well as
mixed sensor-adaptor chimeras as a novel binary approach to dissect how the GBP relay mobilizes different
types of CDN-dependent immunity to bacterial pathogens. Collectively, our proposal examines a new set of
host proteins that define a novel CDN sensor-adaptor circuit with important implications for developing host-
directed therapies as an adjunct to standard antibiotic treatment.

## Key facts

- **NIH application ID:** 10165463
- **Project number:** 5R01AI068041-15
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** John David MacMicking
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2006-07-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165463

## Citation

> US National Institutes of Health, RePORTER application 10165463, A Novel CDN Sensor-Adaptor System for Host Defense Against Infection (5R01AI068041-15). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165463. Licensed CC0.

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