# Novel roles for lipopolysaccharide modifications in immune evasion

> **NIH NIH R21** · DUKE UNIVERSITY · 2024 · $231,231

## Abstract

The outer membrane of Gram-negative bacteria forms a permeability barrier blocking antimicrobials from
efficiently reaching their molecular targets residing within the bacterial cell wall or inside the bacterial cytosol.
This barrier function is dependent on one of the outer membrane’s central building blocks, lipopolysaccharide
(LPS). The LPS molecule is anchored in the outer bacterial membrane by its lipid A moiety. Lipid A, an
acylated disaccharide, is sensed by the pattern recognition receptor TLR4 of the human immune system. To
avoid TLR4 sensing, bacteria evolved mechanisms to modify their lipid A structure, for example by changing
the number or lengths of its fatty acid side chains, or adding or removing terminal phosphate moieties.
However, not all LPS modifications are important for TLR4 avoidance and the biological function of many LPS
modifications is only poorly characterized.
This proposal will test the novel hypothesis that specific lipid A modifications enable bacteria to escape from
host immunity exerted by human guanylate binding protein 1 (GBP1). We recently showed that GBP1 is an
additional bona fide LPS-binding protein. Intracellular GBP1 executes at least two functions: i) it accelerates
the kinetics of LPS-mediated inflammasome activation and ii) it binds directly to the surface of cytosolic Gram-
negative bacteria, where it acts as a surfactant operating synergistically with antimicrobials that need to
penetrate the bacterial outer membrane. In Aim1 we will identify specific lipid A modifications that block the
binding of GBP1 to the surface of two important human pathogens: the intracellular enteric pathogen
Salmonella enterica Typhimurium and the extracellular pathogen Pseudomonas aeruginosa.
GBP1 resides in the host cell cytosol but GBP1 is also secreted into the extracellular milieu. Secreted GBP1
can be found at high concentrations in plasma and cerebrospinal fluids of bacterial meningitis patients.
However, the biological function of secreted GBP1 is unknown. Because we found that GBP1 binds to the
extracellular bacterial pathogen Pseudomonas aeruginosa, we will test whether and how secreted GBP1 can
exert host defense to extracellular bacteria in Aim2. Specifically, we will test the hypothesis that secreted
GBP1 works synergistically with extracellular antimicrobial peptides. Conceptually related, Aim2 will also
identify extant antibiotics that operate synergistically with GBP1. Together, Aims 1 and 2 provide a roadmap
towards novel strategies for the treatment of many Gram-negative infections: targeting LPS-modifying
enzymes involved in GBP1 evasion combined with the use of antibiotics that operate synergistically with
GBP1.

## Key facts

- **NIH application ID:** 10889028
- **Project number:** 5R21AI169122-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Joern Coers
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $231,231
- **Award type:** 5
- **Project period:** 2023-07-17 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10889028

## Citation

> US National Institutes of Health, RePORTER application 10889028, Novel roles for lipopolysaccharide modifications in immune evasion (5R21AI169122-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10889028. Licensed CC0.

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