Glucose and glutamine transport: novel targets in cystic fibrosis immune responses

The National Institute of Allergy and Infectious Diseases awarded National Jewish Health $164,350 on July 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to investigate glucose and glutamine transport as novel targets in cystic fibrosis immune responses.

The research examines solute carrier proteins SLC2A4RG and SLC38A9, which show significant expression changes in CD3+ T cells following triple combination CFTR modulator therapy (elexacaftor-tezacaftor-ivacaftor). Preliminary data correlate these changes to improved lung function and reduced hospitalizations. The study will utilize gene-editing technologies, bioenergetic analyses, and clinically relevant patient samples to identify the roles of these two transporters in baseline health and disease states, with the objective of reducing cystic fibrosis inflammation beyond what current modulator therapy achieves. This work addresses patients who continue to experience pulmonary exacerbations despite modulator treatment or who are ineligible for CFTR modulators based on genotype.

National Jewish Health, a Denver-based nonprofit hospital and research center, is the recipient. The award funds research activities performed in Denver, Colorado 80206. The period of performance runs from July 1, 2026 through June 30, 2027.

Abstract

Triple combination cftr (cystic fibrosis transmembrane conductance regulator) modulator therapy reduces pulmonary exacerbation episodes (PEX), but does not eradicate these events, which are a primary driver of disease progression. The inability to clear chronic infections limits CF patients from realizing the full benefit of modulator therapy, in the over 5,000 patients in the US CF registry who continue to experience PEX or are ineligible for cftr modulators based upon their genotype. In single cell sequencing studies of CD3+ t cell populations in CF before and after elexacaftor-tezacaftor-ivacaftor (ETI), we have identified that 2 understudied solute carrier proteins, SLC2A4RG and SLC38A9, changes significantly in expression after ETI, with correlations to improved FEV1 and reduced hospitalizations following treatment. We have identified that t cell metabolic reprogramming occurs in adults with CF (awcf) taking ETI, which is likely due to myriad benefits of cftr rescue, but also includes primary effects of cftr protein in human lymphocyte metabolism. Cftr affects metabolic sensing by lymphocytes and the transport of nutrients essential to producing cellular energy. Glucose and amino acids are principal metabolites utilized by t cells to drive activation, proliferation, memory development, and ATP generation required for response to pathogens. Building upon our preliminary data, we propose that both cftr-dependent membrane transporters, known to drive cellular energy processes through master regulators such as mtor, are potential targets in the effort to further reduce CF inflammation, particularly since expression and metabolism is not normalized after ETI. In the proposed study, we will utilize gene-editing technologies, bioenergetic analyses, and clinically relevant patient samples in order to identify the roles of these 2 transporters in baseline health and during PEX. We will identify the relative contribution and importance of those transporters in the response to CF pulmonary infections, measuring their expression real time during acute PEX. Finally, having identified the roles of these transporters in CF immunity, we will evaluate the role of small molecular compounds in regulating those transporters, assessing their effects on t cell activation, proliferation and bioenergetics. The knowledge and data produced from these studies will be pivotal in addressing novel approaches to mitigate the destructive consequences of PEX. Findings will be utilized in applying for funding and carrying out future studies addressing the treatment of excessive inflammation in CF based upon abnormalities in SLC2A4RG and SLC38A9.