Think “ZINC”: Improving bacterial killing and reducing inflammation through restoring immune function in people with Cystic Fibrosis

Project Duration – 1 Year

Professor Matt Sweet, Dr Divya Ramnath and Professor Chenzhong (Michael) Yu from the University of Queensland are working with Professors Peter Sly and Paul Robinson to understand why immune cells in people with Cystic Fibrosis (CF) cannot fight infections. The Brisbane-based team discovered that people with CF have difficulties with one of the important white blood cells that fights infections in our lungs.  The cells are called macrophages, which literally means “big eaters”.  In people with CF, these big eaters do not work in the same way as in people who do not have CF.  

When the macrophages fail to eat bacteria and then kill the bacteria, there is ongoing infection and inflammation which causes damage to lung tissue. Zinc is an important nutrient used by macrophages to kill bacteria and control inflammation. Professor Sweet’s team has shown macrophages from people with CF have reduced levels of a protein called SLC301A needed to transport the zinc within the macrophages to kill bacteria. They will now undertake experiments in human cells in their laboratory (in vitro) to explore this further. 

With Cure4CF funding, Professor Sweet’s team will:

• Determine if they can deliver SLC30A1 to healthy and CFTR inhibited macrophages in vitro.
• Determine if delivering SLC30A1 can restore normal, bacteria-killing, macrophage activity in vitro.

Infection in CF

Bacterial infections remain a significant challenge for people with CF, even in those whose health has been improved by modulator therapy.  Repeated infections along with significant antibiotic resistance often mean long-term treatment, many side effects and low success rates.  In recent research from the UK, intravenous antibiotic therapy for more than a year could not resolve Pseudomonas aeruginosa infections in around half of the people studied.  This highlights the urgent need for new strategies to better combat infections.

Why macrophages?

While many research projects focus on ways to kill bacteria by targeting the bacteria, the team in Brisbane are taking a new approach.  Another way to combat infection is to support our bodies’ natural immune function.  Macrophages are a specialised type of white blood cell that is specially formed to be able to engulf (eat) and kill bacteria and other foreign material in our bodies.  They are part of the innate immune system, the system that senses and responds quickly when threats are detected. 

Research has shown that in people with CF, macrophages do not work properly, and they cannot kill bacteria efficiently.  By helping to restore macrophage functions, the team hope to be able to help reduce both bacterial infection and destructive inflammation. This would ultimately reduce lung tissue damage which can become permanent.

Why Think Zinc?

Zinc is a metal found in some foods such as oysters, fish, red meat and dairy products.  It plays a role in many cellular functions and is very important in immunity.  Even if we have enough zinc in our diet, we also need to have the proteins in our body that can move zinc to where it needs to act. A special transporter protein is needed to deliver zinc to the bacteria within the macrophage to enable bacterial killing.  This protein is reduced in macrophages from people with CF and so the zinc cannot be transferred within the macrophage properly and at the right concentration. If the team can deliver the transporter protein to macrophages in people with CF, then zinc may be able to return to the levels needed for macrophages to achieve their normal bacteria-killing capacity.

What will be the pathway to moving this therapy into the clinic?

This is an exciting early project that will begin to understand if changing the levels of the transporter protein in macrophages can improve bacteria killing. Following this project, the team hope to obtain more funding to develop a system to deliver the transporter using a nanoparticle.  A nanoparticle delivery system that could be delivered through the nose could then be carefully tested in pre-clinical models to check both safety and effectiveness.  If those experiments prove to be successful, the next steps would be to optimise the delivery system and test this in humans.

About Professor Sweet

Professor Matt Sweet is an NHMRC Leadership Fellow, Group Leader, and Director of Higher Degree Research (DHDR) at the Institute for Molecular Bioscience (IMB) at The University of Queensland, Brisbane, Australia. He was the founding Director of the IMB Centre for Inflammation and Disease Research (2014-2018), also serving as Deputy Head of the IMB Division of Cell Biology and Molecular Medicine during this period. Matt studies innate immunity, the body’s danger sensing system that responds to infection, injury and dysregulated homeostasis, and the role of this system in health and disease. Matt’s research team focuses on manipulating the innate immune system for the development of anti-infective and anti-inflammatory strategies. To do so, his lab characterizes the roles of specific innate immune pattern recognition receptors and their downstream signalling pathways/gene products in inflammatory disease processes, as well as in host responses to bacterial pathogens.