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 M?s 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 M? NOX assembly; 2) Determine how CF specific pathogens differentially regulate M? ROS production; 3) Determine the extent to which novel therapeutic approaches alter the M? 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 M?-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.

Public Health Relevance

Cystic fibrosis (CF) remains one of the most common, life-limiting genetic disorders due to chronic bacterial lung infections that do not respond to traditional antibiotic therapy. The proposed research will achieve a thorough understanding of how the immune system fails to respond to bacterial infections in CF in order to develop targeted therapies to prevent life- limiting bacterial lung infections. The proposal is relevant to public health and the NIH's mission as the findings will impact the treatment and understanding of immunodeficiencies and lung diseases associated with chronic bacterial infections.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
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Lachowicz-Scroggins, Marrah Elizabeth
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Nationwide Children's Hospital
United States
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