# The Macrophage Reverse Transsulfuration Pathway: A Novel Mediator of Helicobacter pylori Immunopathogenesis

> **NIH NIH R21** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $212,500

## Abstract

SUMMARY:
Half of the global human population harbors the gastric bacterial pathogen Helicobacter pylori. Despite a
vigorous mucosal immune response, H. pylori survives in its ecological niche. The failure of the host response to
the pathogen is the key issue: the persistence of the bacterium leads to gastric inflammation. This chronic
gastritis can progress through a histologic cascade that can ultimately result in gastric carcinoma in 1-3% of all
those infected. Our laboratory has directly implicated gastric macrophages as major orchestrators of the mucosal
innate immune response that also mediate development of adaptive immunity. Efforts are needed to understand
more precisely the interaction of the bacterium and the host macrophage response. Our project seeks to further
elucidate a new mechanism of gastric inflammation induced by H. pylori. Our novel data show that cystathionine
γ-lyase (CTH), an enzyme involved in the mammalian reverse transsulfuration pathway, is induced in cultured
macrophages and in gastric macrophages of mice and humans infected with H. pylori. Our data indicate that
compared to wild-type animals, mice with deletion of the Cth gene exhibit reduced gastritis, and less macrophage
and T cell activation, associated with increased colonization by H. pylori. These findings suggest that CTH is an
unrecognized mediator of inflammation. Moreover, we have found that increased CTH activity in infected
macrophages regulates polyamine concentrations through the depletion of decarboxylated S-
adenosylmethionine (dcSAM), which is required for the conversion of putrescine to spermidine and of spermidine
to spermine. Further, we show that decreased putrescine and increased spermidine levels are observed in the
gastric tissues of Cth-deficient mice. Importantly, we have reported that both putrescine and spermidine play a
critical role in H. pylori gastritis. In this context, we hypothesize that CTH induction in macrophages contributes to
innate immune cell activation in response to H. pylori, dysregulating immunometabolism and thus increasing
inflammatory response and pathogenesis. This new concept for H. pylori interaction with macrophages will be
studied in two Specific Aims. 1) To determine the role of H. pylori-induced CTH in the immunopathogenesis of
gastritis; for this, we will determine colonization, gastritis, mucosal immune response, and the metabolomic
signature of gastric macrophages and T cells in wild-type and Cth-deficient mice. 2) To determine if dysregulation
of polyamine metabolism by CTH causes gastritis through effects on the polyamines putrescine and/or
spermidine. Thus, we will A) analyze methionine flux in the reverse transsulfuration pathway and in polyamine
metabolism in vivo in WT and Cth–/– mice; then, we will determine whether changes in response to H. pylori in
Cth-deficient or WT mice are modulated by i) a putrescine or spermidine supplementation, or ii) an inhibitor of
adenosylmethionine decarboxylase 1, the e...

## Key facts

- **NIH application ID:** 9968034
- **Project number:** 5R21AI142042-02
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Keith T. Wilson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $212,500
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968034

## Citation

> US National Institutes of Health, RePORTER application 9968034, The Macrophage Reverse Transsulfuration Pathway: A Novel Mediator of Helicobacter pylori Immunopathogenesis (5R21AI142042-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9968034. Licensed CC0.

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