# Neisseria gonorrhoeae metal transporters that subvert nutritional immunity

> **NIH NIH R01** · GEORGIA STATE UNIVERSITY · 2020 · $608,587

## Abstract

The human-specific bacterial pathogen Neisseria gonorrhoeae (Ngo) causes the sexually-transmitted infection
gonorrhea. Ngo expresses outer membrane transporters to acquire iron and other metals in a TonB-dependent
manner. In order to prevent microbial growth and infectivity, humans use high affinity metal-binding proteins to
sequester essential metals, a phenomenon known as “nutritional immunity.” Ngo subverts nutritional immunity
by using dedicated transporters that bind to and remove the metals from human metal-binding proteins such as
transferrin and lactoferrin. Our preliminary data indicates that two poorly-characterized Ngo outer membrane
transporters, TdfH and TdfJ, enable Ngo to internalize zinc (Zn). Furthermore, we show that TdfH affords Ngo
the ability to overcome Zn sequestration imposed by the innate immunity protein, calprotectin (CP), which is
produced in abundance by neutrophils and macrophages and accumulates to high concentrations at sites of
inflammation. We hypothesize that TdfH and TdfJ are Zn transporters that enable Ngo to overcome the growth
inhibitory effects of the innate immunity proteins produced during inflammation. These studies are significant
because knowing how Ngo acquires essential metals like Zn from the human host opens new opportunities for
developing new therapeutics against `superbug' strains, whether they be targets for a protective vaccine or small
molecule inhibitors of crucial transporters. The overarching hypothesis to be tested in the proposed study
is that Ngo subverts nutritional immunity imposed by S100 proteins produced by neutrophils and macrophages
by the deployment of outer-membrane transporters that bind to and relieve these proteins of their sequestered
transition metal cargo. The specific aims are as follows: Aim 1 will define the characteristics of ligand interactions
with TdfH and TdfJ using crystallography, biophysical approaches to protein-protein interactions and
mutagenesis to confirm interactions. We will also ascertain if ligand interactions are specific to human proteins,
given that humans are the only natural host for Ngo. Aim 2 will define the nutritional and metal environment
sensed by Ngo upon exposure to human immune cells and secretions, employing mass spectrometry and
imaging techniques alongside bacterial gene expression. Aim 3 will explore how Zn uptake systems impact
survival of Ngo after exposure to human immune cells and secretions that contain S100 proteins. These studies
will utilize Ngo survival assays with macrophages and neutrophils, combined with real-time confocal visualization
and S100 inhibition studies. Overall these innovative studies will provide an in-depth analysis of two new outer
membrane transport proteins involved in Zn acquisition and will provide novel insights into the human
environmental niches in which Ngo normally resides.

## Key facts

- **NIH application ID:** 9983559
- **Project number:** 5R01AI127793-05
- **Recipient organization:** GEORGIA STATE UNIVERSITY
- **Principal Investigator:** CYNTHIA N CORNELISSEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $608,587
- **Award type:** 5
- **Project period:** 2019-03-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983559

## Citation

> US National Institutes of Health, RePORTER application 9983559, Neisseria gonorrhoeae metal transporters that subvert nutritional immunity (5R01AI127793-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9983559. Licensed CC0.

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