# Mechanisms regulating peptidoglycan fragment production

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2020 · $242,750

## Abstract

In symptomatic Neisseria gonorrhoeae infections, the inflammatory response to bacterial products results in
tissue damage and pain in the human host. Peptidoglycan fragments released by the bacteria during growth
represent a major pro-inflammatory factor in these infections. In particular, the peptidoglycan monomers are
known to cause the death and sloughing of ciliated cells in human Fallopian tubes, and one of the
peptidoglycan monomers is an agonist for the intracellular pattern-recognition receptor NOD1.
Peptidoglycan dimers, also released by the bacteria, are processed by host lysozyme to create
peptidoglycan fragments that are agonists for another peptidoglycan sensing receptor, NOD2.
Peptidoglycan monomers and dimers are created by enzymes called lytic transglycosylases that function to
degrade strands of peptidoglycan in the cell wall so that additional strands can be inserted to facilitate
growth. The lytic transglycosylase LtgA produces nearly half of the peptidoglycan monomers released by
gonococci and a vast majority of the peptidoglycan fragments that are recycled. LtgD produces the rest of
the peptidoglycan monomers released by N. gonorrhoeae. Published transcriptomic studies indicate that
ltgA is subject to transcriptional regulation, and this regulation may therefore affect gonococcal cell wall
metabolism and release of pro-inflammatory peptidoglycan fragments.
 To understand how N. gonorrhoeae might control peptidoglycan fragment metabolism or release, we
previously performed a proteomics analysis of five different mutants that have distinct defects in
peptidoglycan fragment recycling. This analysis identified a putative transcriptional regulator, NGO1982, as
significantly increased in three of the mutants. Deletion of ngo1982 resulted in 8-9 fold increased transcript
levels for ltgA, suggesting that NGO1982 is a repressor of ltgA. Since published studies had identified MtrR
as an activator of ltgA and the antisense RNA NgncR_246 as an additional regulator of ltgA expression, ltgA
appears to be regulated by three distinct factors.
 To understand the consequences of this regulation for infection, we will: 1) Determine how growth in
human tissues affect ltgA and ltgD regulation, and how this regulation affects cell wall-related phenotypes in
infection, and 2) Use biochemical and genetic methods to determine the molecular mechanisms used by
these regulators. Preliminary results demonstrate that ltgA is strongly regulated, and that regulatory factors
can greatly increase or decrease peptidoglycan fragment release. In cervical infection, LtgA and LtgD levels
decreased even as colony forming units increased. Significantly reducing or greatly increasing
peptidoglycan fragment release may allow gonococci to cause asymptomatic infection in some tissues and
highly inflammatory infections other tissues.

## Key facts

- **NIH application ID:** 9896150
- **Project number:** 1R21AI145201-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Joseph P Dillard
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $242,750
- **Award type:** 1
- **Project period:** 2020-02-18 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896150

## Citation

> US National Institutes of Health, RePORTER application 9896150, Mechanisms regulating peptidoglycan fragment production (1R21AI145201-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896150. Licensed CC0.

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