# Mechanisms of type I IFN enhanced gonococcal infection

> **NIH NIH R21** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2020 · $251,250

## Abstract

Project Abstract
Infection with Neisseria gonorrhoeae (Ng) remains a major public health issue. Ng gonococci are sexually
transmitted between individuals causing inflammation and pelvic inflammatory disease (PID). The emergence of
antibiotic-resistant Ng is cause for concern, and Ng strains with antibiotic-resistance to nearly all of the approved
therapeutics have developed with cephalosporins being the last remaining effective antibiotic. Understanding
the mechanisms that underlie Ng susceptibility will be crucial for the development of new and effective
therapeutic options for treating gonococcal disease.
 We discovered that Ng bacteria trigger innate cytokine gene expression through two separate pathways, the
Toll-like receptor 4 (TLR4) pathway and via a recently discovered intracellular DNA sensing pathway. DNA
released into the cytosol during infection or introduced by transfection binds to an enzyme cyclic-GMP-AMP
synthase (cGAS). DNA-activated cGAS produces a cyclic di-nucleotide (cdN), 2’3’-cGAMP, which acts as a
second messenger and triggers a protein stimulator of interferon genes (STING). STING, in turn, activates
TANK-binding kinase 1 (TBK-1) leading to interferon regulatory factor 3 (IRF3) activation and type I interferon
(IFN) gene expression. Bacteria cdNs can also activate STING and type I IFN expression, another example of
immune evasion. Based on our preliminary studies, where we found that type I IFNs greatly enhanced
gonococcal infection, we hypothesize that Ng-induced type I IFN is a method of immune evasion that enhances
the replication and survival of Ng in host phagocytes.
 Recently, an estrogen-induced type I IFN (IFN-epsilon) was identified in mice and humans. IFN-epsilon is
expressed in the genital tract of both men and women and binds the same receptor as other type I IFNs. Estrogen
is also known to promote gonococcal infection of vaginal tissues in humans and in mouse models of Ng infection.
The goal of this project is to assess the role of estrogen-induced and immune receptor-induced type I IFN in
enhancing Ng infection. We will identify and characterize the molecular pathways that are responsible for
controlling Ng infection. In Aim 1, we will!elucidate the role of type I IFNs in enhancing Ng infection. These studies
will be performed using several knockout mouse models that our labs have generated and examine the role of
type I IFN receptor (IFNAR) signaling in promoting Ng infection. In Aim 2, we will look at the molecular
mechanism(s) of immune receptor-driven type I IFN production, particularly the cGAS and STING receptor
pathways and the role of outer membrane vesicles, during Ng infection. The goal of these studies is to develop
novel strategies for therapeutic interventions that may ameliorate or prevent the damaging sequelae of Ng
infection and PID.

## Key facts

- **NIH application ID:** 9979327
- **Project number:** 1R21AI142249-01A1
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Douglas T Golenbock
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $251,250
- **Award type:** 1
- **Project period:** 2020-01-10 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979327

## Citation

> US National Institutes of Health, RePORTER application 9979327, Mechanisms of type I IFN enhanced gonococcal infection (1R21AI142249-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979327. Licensed CC0.

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