# Neisseria gonorrhoeae exploits host interferon epsilon to establish infection in the female urogenital tract

> **NIH NIH R01** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2021 · $813,011

## Abstract

PROJECT ABSTRACT
Neisseria gonorrhoeae (Ng) is a sexually-transmitted gram-negative bacterium that causes inflammation and
pelvic inflammatory disease (PID). In the U.S., the incidence of Ng is rising dramatically. Alarmingly, Ng has
become increasingly resistant to all approved antibiotics.
Interferon-epsilon (IFN-e) is a type I IFN that is highly expressed by epithelial cells of the female urogenital tract
(both in mice and humans) but not in leukocytes. IFN-e, unlike the other type I IFNs, is not induced by bacterial
“pathogen-associated molecular patterns,” such as lipopolysaccharides (LPS) or nucleic acids. Rather, IFN-e is
regulated by sex hormones in the urogenital tract. We discovered that estrogen contributes to Ng infection by
inducing the expression of IFN-e. Estrogen treatment dramatically prolongs Ng infection of the female genital
tract. Type I IFNs, including IFN-e, share a common receptor, the IFN-alpha/beta receptor (IFNAR). Our data
using IFNAR and IFN-e knockout (KO) animals, as well as blocking mAbs to IFNAR, strongly support the
hypothesis that estrogen-induced type I IFNs contribute to Ng immune evasion. In the absence of IFNAR
signaling, Ng is virtually incapable of maintaining colonization of the female urogenital tract. Furthermore, local
administration of recombinant IFN-e (rIFN-e) protein completely reverted the phenotype to resemble the wild-
type mice. Preliminary studies suggest that this may be related to regulation of cationic antimicrobial peptides
(CAMP), such as CRAMP, as well as the sialylation of Ng lipooligosaccharide (LOS). We hypothesize that
estrogen-induced IFN-e is required for productive Ng infection because it regulates the availability of sialic acid
precursors to Ng sialyltransferase, thus, allowing Ng to evade AMP killing.
In Aim 1, we will assess the impact of estrogen and IFN-e on gene expression in epithelial cells in the female
genital tract during infection using both mouse and human models of Ng infection. We will use proteomics and
gene expression approaches to determine if IFN-e regulates the expression of CAMPs and complement proteins
in the genital tract. In Aim 2, we will determine how IFNAR-expressing cell types promote Ng survival. We will
also assess the impact of type I IFN on the intrinsic bactericidal activity of phagocytes and their recruitment to
the genital tract. In Aim 3, we will assess the impact of IFN-e on Ng genes, particularly genes that regulate
CAMP evasion, and their impact on killing of Ng in the absence of IFN-e. We will also determine if IFN-e reduces
the sensitivity of Ng to complement and/or CRAMP-mediated killing by regulating LOS sialyation.
The ability to modulate IFN responses during sexually-transmitted infections is a valid and potentially
transformative strategy to ameliorate or prevent the damaging sequelae of Ng infection and PID.

## Key facts

- **NIH application ID:** 10317367
- **Project number:** 1R01AI164727-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Douglas T Golenbock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $813,011
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317367

## Citation

> US National Institutes of Health, RePORTER application 10317367, Neisseria gonorrhoeae exploits host interferon epsilon to establish infection in the female urogenital tract (1R01AI164727-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10317367. Licensed CC0.

---

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