# The role of CFTR during macrophage-mediated killing of bacteria

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2021 · $387,928

## Abstract

PROJECT SUMMARY
Why patients with cystic fibrosis (CF) continue to suffer from chronic bacterial infections despite
new medications that improve CF transmembrane conductance regulator (CFTR) function is not
known. The long-term goal is to develop therapeutics that modulate host immune responses
in CF patients to mitigate chronic infection and inflammation. The objective of this proposal is to
define how CFTR regulates macrophage function. The rationale underlying this proposal is that
our prior work demonstrates that CF macrophages are integral to the inability of patients with
CF to clear bacterial infections through failed NADPH oxidase (NOX) assembly and reduced
autophagy. The central hypothesis is that loss of functional CFTR in human MΦs inhibits NOX
assembly and subsequent ROS-mediated autophagy, independent of CFTR mutation class, but
worsened by specific opportunistic bacteria. Further, we expect that a critical threshold of CFTR
function is needed to reverse the NOX assembly/autophagy deficits and can be re-established
by CFTR modulators combined with alternative CFTR restoration agents such as cysteamine or
our novel autophagy stimulator, AR-13. The central hypothesis will be tested by pursuing
three specific aims: 1) Define the mechanism by which CFTR regulates MΦ NOX assembly; 2)
Determine how CF specific pathogens differentially regulate MΦ ROS production; 3) Determine
the extent to which novel therapeutic approaches alter the MΦ NOX/autophagy axis. We will
pursue these aims using an innovative combination of genetic and pharmacologic techniques in
human macrophages. The proposed research is significant because a precise understanding
of how CF macrophage function is regulated would allow novel antibiotic- and CFTR mutation-
agnostic treatment approaches to infection. It is also significant because it will determine if
specific pathogens independently contribute to deficits in macrophage-mediated bacterial killing.
The expected outcome of this work will establish a mechanistic framework to enable us to
target and correct defective CF MΦ-mediated bacterial killing. Ultimately, we will translate this
new knowledge into a new treatment paradigm that uses innovative host-directed therapies to
combat bacterial infections.

## Key facts

- **NIH application ID:** 10133136
- **Project number:** 5R01HL148171-02
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** Benjamin T Kopp
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $387,928
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133136

## Citation

> US National Institutes of Health, RePORTER application 10133136, The role of CFTR during macrophage-mediated killing of bacteria (5R01HL148171-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133136. Licensed CC0.

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