Q&A: Zinc transport protein may help decrease bacterial infections in cystic fibrosis

Key takeaways:

• Patients with cystic fibrosis may be more susceptible to infections due to a defect in their immune cells.
• Elevated levels of a zinc transport protein may help prevent infections in this population.

Patients with cystic fibrosis frequently experience bacterial infections, but a zinc transport protein may be able to lower infection incidence, according to findings published in Proceedings of the National Academy of Sciences.

In this study, Matthew J. Sweet, PhD, group leader at the Institute for Molecular Bioscience at The University of Queensland, and colleagues found a defect in immune cells called macrophages in patients with CF. According to a university press release, this defect was observed in a zinc pathway where bacteria are supposed to be killed.

Building onto this finding, researchers noted that higher levels of a zinc transport protein can benefit macrophages in their fight against bacteria and potentially reduce infections.

Healio spoke with Sweet to learn more about these findings and future research.

Healio: Why are patients with CF more susceptible to infections? Does this outcome occur across all CF variants?

Sweet: People with CF (pwCF) have a build-up of thick, sticky mucus in their airways, because the gene that is defective (CFTR) has important functions in regulating water and salt balance. This mucus build-up provides an environment that supports bacterial colonization, survival and growth. CFTR also has important functions in the immune system, including in macrophages — cells that provide frontline defense against infection. So defective macrophage functions also likely contribute to pwCF being susceptible to recurring bacterial infections and an inability to clear them.

As far as I am aware, increased susceptibility to infections is common in all pwCF, irrespective of what mutation(s) cause the defect in CFTR function. While most mutations knock out all CFTR function, some rare milder mutations do leave some residual CFTR function. PwCF with these milder mutations may have less severe lung disease and lower infection risk.

Healio: What fault did you find in the immune cells of patients with CF? What does this mean in the context of infections?

Sweet: We found that macrophages are defective in a particular antimicrobial response in which the metal ion zinc is used to poison bacteria. It was already known that macrophages from pwCF are defective in taking up bacteria — we found that once the bacteria are taken up, macrophages are also defective in killing bacteria through the zinc pathway.

Healio: In addition to the fault found in immune cells, you observed a zinc transport protein in this study. What is this protein capable of?

Sweet: We previously found that this protein has an important function in antibacterial defense in macrophages. This protein (SLC30A1, also known as ZnT1) exports zinc across biological membranes. In most cells, it transports zinc out of cells — thus, protecting cells from excess zinc that could be toxic to cells. It serves this function in macrophages too, but we previously found that it can also help macrophages toxify intracellular bacteria with zinc — by transporting zinc into cellular compartments that contain intracellular bacteria. In this study, we found that if we increase levels of SLC30A1 in macrophages, it can help macrophages without a functional CFTR to kill bacteria.

Healio: Why is the immune system important to consider when caring for patients with CF?

Sweet: A major issue affecting pwCF is recurrent bacterial infections. Thus, pwCF often need to be treated with antibiotics, so there is the threat of antibiotic-resistant bacteria emerging, which reduces treatment options. If we can restore or improve immune functions in pwCF, this may in the future lead to new treatment options that reduce the reliance on antibiotics.

Healio: How will knowledge from this study impact future studies on this patient population?

Sweet: We hope that our work will generate enough interest in the CF field, such that other researchers consider this particular zinc pathway, as well as other approaches to manipulate immune functions, in devising new treatment strategies for pwCF.

Immunologists sometimes refer to this approach of reawakening the immune system as “host-directed therapies.” The development of effective host-directed therapies may ultimately enable us to reduce our reliance on antibiotics to treat bacterial infections — although these will still be very important for treating bacterial infections into the future.

Healio: What do you have planned next?

Sweet: We are using mRNA technology (similar to that used in COVID-19 vaccines) to boost SLC30A1 levels in macrophages. In the long-term, this may have potential as a therapeutic strategy to treat bacterial infections in pwCF.

We continue to collaborate with Peter Sly, MBBS, MD, FRACP, DSc, NHMRC leadership fellow and director of the children’s health and environment program at The University of Queensland, on this work.

Our discovery of this defect in macrophages from pwCF would not have been possible without fundamental discovery research, which underlies all medical and other scientific discoveries. It can be difficult to find Australian funding for this type of research, despite its importance. Indeed, much of Sly’s CF research has been funded by the Cystic Fibrosis Foundation, U.S. We encourage the government to lift funding for this vital research to match our Organization for Economic Co-operation and Development counterparts, an investment that would have both economic and health benefits.

References:

• Das Gupta K, et al. Proc Natl Acad Sci. 2024;doi:10.1073/pnas.2315190121.
• Zinc discovery holds promise for people with cystic fibrosis. https://www.uq.edu.au/news/article/2024/02/zinc-discovery-holds-promise-people-cystic-fibrosis. Published Feb. 23, 2024. Accessed March 4, 2024.