# Pathologic Role of Bacterial Cyclic Dinucleotides in Sepsis

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $283,500

## Abstract

Abstract
 Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, is a major
public health concern with limited therapeutic options. Despite extensive studies on inflammatory signal
transduction, the pathophysiology of sepsis is still poorly understood. We recently provided evidence to support
a novel role for the anaplastic lymphoma kinase (ALK), a tumor-associated receptor tyrosine kinase, in the
regulation of bacterial cyclic dinucleotide (CDN)-induced innate immunity during lethal sepsis. The genetic
disruption of ALK expression diminishes the stimulator of interferon genes (STING)-mediated host immune
response to CDNs in monocytes and macrophages. Mechanistically, ALK directly interacts with the epidermal
growth factor receptor (EGFR) to trigger AKT phosphorylation and activate interferon regulatory factor 3 (IRF3)
and nuclear factor κB (NF-κB) signaling pathways, enabling STING-dependent rigorous inflammatory responses.
Notably, pharmacological or genetic inhibition of the ALK-STING pathway confers protection against lethal sepsis
in younger mice. These exciting findings raise several important questions regarding the previously unidentified
pathologic role of bacterial CDN signaling in sepsis. Our central hypothesis is that the ALK-STING pathway is a
prospective new and key therapeutic target for lethal inflammation and coagulation in sepsis. To test this
hypothesis, we will exploit complementary molecular, cellular, and animal models to pursue the following aims.
Aim 1: Define the molecular mechanism of ALK-mediated STING activation in host responses to CDNs. Aim 2.
Define the molecular mechanism of ALK-mediated STING release in host responses to CDNs. Aim 3. Evaluate
the efficacy of targeting the ALK-STING pathway in protecting against sepsis in aged mice. The completion of
these exciting studies will not only identify a potential strategy for sepsis therapy, but also provide new
perspectives on the pathologic role of bacterial CDNs in lethal inflammation.

## Key facts

- **NIH application ID:** 10019400
- **Project number:** 5R01GM127791-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Daolin Tang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $283,500
- **Award type:** 5
- **Project period:** 2018-08-10 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10019400

## Citation

> US National Institutes of Health, RePORTER application 10019400, Pathologic Role of Bacterial Cyclic Dinucleotides in Sepsis (5R01GM127791-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10019400. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*