# Human GBPs in cell-autonomous immunity to intracellular bacterial pathogens

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $458,935

## Abstract

SUMMARY - Human GBPs as regulators of immunity to intracellular bacterial pathogens
 Guanylate binding proteins (GBPs) are host defense proteins that play diverse and critical roles in
cell-autonomous immunity to intracellular bacterial pathogens. These proteins are major regulators of
fundamental host defense modules and involved in processes such as inflammasome activation and the
execution of direct bactericidal activities. However, almost all of this work has been performed in mouse
models and antimicrobial functions of human GBPs (hGBPs) are still poorly characterized. In our
recent studies we identified divergent host defense functions of the human GBPs and linked specific human
GBPs to novel resistance mechanisms that protect against an important class of bacterial pathogens.
Specifically, we found that human GBP1 (hGBP1) underpins two novel host defense mechanisms against
cytosolic Gram-negative bacterial pathogens: 1) hGBP1 protein associates with cytosolic Gram-
negative bacteria such as Shigella flexneri or Burkholderia thailandensis in the host cell cytosol.
Once bound to bacteria, hGBP1 directly interferes with the actin-based intracellular motility of bacteria
and thereby blocks bacterial dissemination; and 2) hGBP1 mediates activation of chemokine production
by infected epithelial cells. Thus, hGBP1 activation appears to serve as a central node for two distinct but
synergistic immune functions: a cell-intrinsic defense program prevents cell-to-cell spread of the
pathogen while the production of paracrine immune signals promotes the activation and recruitment of
immune cells to the site of infection. In this work, we will define the molecular mechanisms underlying these
two important roles for hGBP1 that we have uncovered. In Aim1 we will combine cell culture and
biochemical approaches to define the mechanism by which hGBP1 specifically detects Gram-negative
bacteria in the host cell cytosol, a process critical for the inhibition of actin-based motility. In Aim2 we will
characterize the mechanism by which hGBP1 bound to bacteria blocks actin-based motility. In Aim3 we will
explore a second, independent function of hGBP1 as a novel regulator of an immune sensing pathway
leading to the production of immune-modulatory chemokines using bacterial genetics, host genetics and cell
biological approaches. In all of these studies we will take advantage of our recent discovery that the
S. flexneri effector protein IpaH9.8 antagonizes hGBP1 function. Therefore, the use of IpaH9.8-
deficient S. flexneri strains will enable us to monitor and functionally dissect an operational hGBP1-driven
host response. Overall, the work proposed here will provide a fundamental understanding of the role of
hGBP1 and other human GBPs in cell-autonomous immunity to intracellular bacterial pathogens.
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## Key facts

- **NIH application ID:** 10241505
- **Project number:** 5R01AI139425-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Joern Coers
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $458,935
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241505

## Citation

> US National Institutes of Health, RePORTER application 10241505, Human GBPs in cell-autonomous immunity to intracellular bacterial pathogens (5R01AI139425-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241505. Licensed CC0.

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