Molecular Medicine Israel

CFTR is required for zinc-mediated antibacterial defense in human macrophages


Mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) cause CF, a disease characterized by aberrant lung function, dysregulated innate immunity, and susceptibility to infections. Combination drugs such as elexacaftor–tezacaftor–ivacaftor (ETI) restore lung function in most people with CF (pwCF), but there is little evidence that they correct innate immune defense. We show that CFTR is required for the macrophage zinc toxicity antibacterial response and that manipulating zinc availability can restore bacterial killing in CFTR-defective macrophages. Significance lies in identification of a link between CFTR and the macrophage zinc toxicity response and of approaches that could be used to restore innate immune antimicrobial defense in pwCF. Our findings may lead to strategies to reduce infections in pwCF.


Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with CFTR mutations leading to the autosomal recessive genetic disease CF. Apart from excessive mucus accumulation and dysregulated inflammation in the airways, people with CF (pwCF) exhibit defective innate immune responses and are susceptible to bacterial respiratory pathogens such as Pseudomonas aeruginosa. Here, we investigated the role of CFTR in macrophage antimicrobial responses, including the zinc toxicity response that is used by these innate immune cells against intracellular bacteria. Using both pharmacological approaches, as well as cells derived from pwCF, we show that CFTR is required for uptake and clearance of pathogenic Escherichia coli by CSF-1-derived primary human macrophages. CFTR was also required for E. coli-induced zinc accumulation and zinc vesicle formation in these cells, and Ecoli residing in macrophages exhibited reduced zinc stress in the absence of CFTR function. Accordingly, CFTR was essential for reducing the intramacrophage survival of a zinc-sensitive E. coli mutant compared to wild-type E. coli. Ectopic expression of the zinc transporter SLC30A1 or treatment with exogenous zinc was sufficient to restore antimicrobial responses against Ecoli in human macrophages. Zinc supplementation also restored bacterial killing in GM-CSF-derived primary human macrophages responding to P. aeruginosa, used as an in vitro macrophage model relevant to CF. Thus, restoration of the zinc toxicity response could be pursued as a therapeutic strategy to restore innate immune function and effective host defense in pwCF.

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