# Genital Chlamydia spreading to the gastrointestinal tract promotes chlamydial pathogenicity in the upper genital tract

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2021 · $188,929

## Abstract

Genital Chlamydia spreading to the gastrointestinal tract promotes chlamydial pathogenicity in the upper genital tract
Chlamydia trachomatis (CT) causes long-lasting tubal fibrosis/hydrosalpinx/infertility and is also frequently
detected in human gastrointestinal (GI) tract. Most research efforts are focused on CT interactions with the
genital but not GI tracts because CT is not associated with any significant pathology in the GI tract. However, it
is not clear whether GI CT can impact pathogenicity of CT in the genital tract. Addressing this question directly
in humans may require large-scale human studies with therapeutic interventions. Alternatively, we are
proposing to use a C. muridarum (CM) mouse model for proof of concept studies. The CM mouse model has
been used extensively for investigating chlamydial pathogenic mechanisms because CM can induce long-
lasting tubal fibrosis/hydrosalpinx/infertility in mice. CM can also colonize the mouse GI tracts for long periods
of time. Our in vivo imaging studies revealed CM spreading from the mouse genital to GI tracts via a
hematogenous route. CM spreading to the GI tract may promote CM pathogenicity in the genital tract. First, our
series of CM mutants are attenuated in both inducing hydrosalpinx and spreading to the GI tract although still
maintaining robust infectivity in the genital tract. Second, co-inoculating a wild type CM into GI tract rescued a
CM mutant to induce hydrosalpinx. GI CM does not autoinoculate or spread to the genital tract tissues even
after oviduct surgery, indicating that the GI CM organisms must promote hydrosalpinx via an indirect
mechanism. CD8+ T cell depletion significantly reduced hydrosalpinx induced with CM that is able to spread to
the GI tract, suggesting that GI CM may promote hydrosalpinx by inducing the “pathogenic” CD8+ T cells.
Thus, we propose a 2-hit model for chlamydial pathogenicity in the upper genital tract: CM ascends to the
upper genital tract to cause the 1st hit that may be insufficient for driving long-term tubal fibrosis/hydrosalpinx in
the absence of a 2nd hit. The 2nd hit is caused by recruiting pathogenic CD8+ T cells (induced by GI CM) to the
oviduct to convert the 1st hit-induced tubal repairing response into long-lasting tubal fibrosis/hydrosalpinx. We
will test the 2-hit hypothesis using 2 specific Aims by determining whether CM spreading to and colonizing the
GI tract is both necessary and sufficient for promoting hydrosalpinx and whether the GI CM-induced CD8+ T
cells are responsible for promoting hydrosalpinx. These proposed studies will lay a foundation for both future
mechanistic and clinic investigations.

## Key facts

- **NIH application ID:** 10105289
- **Project number:** 5R21AI151724-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** GUANGMING ZHONG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $188,929
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10105289

## Citation

> US National Institutes of Health, RePORTER application 10105289, Genital Chlamydia spreading to the gastrointestinal tract promotes chlamydial pathogenicity in the upper genital tract (5R21AI151724-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10105289. Licensed CC0.

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