Urinary tract infections (UTIs) are one of the most common bacterial infections worldwide, with around 150 million cases each year. Nearly half of all women will contract a UTI at least once in their lifetime, which apart from being painful in their own right, can lead to very serious conditions such as kidney infection and sepsis.

Given the large burden of this disease around the globe, the increasing resistance of uropathogenic Escherichia coli (UPEC) – the bacteria that cause the majority of UTIs - to multiple types of antibiotics is very concerning. There is an urgent need to develop new strategies to combat these infections.

However, any new antibiotic holds the likely prospect of bacteria becoming resistant to it, too. So, a UQ team is seeking to understand how antibiotic-resistant UPEC cause UTI and develop new, immune-based treatment strategies to treat these infections.

To do this, they first need to better understand our own immune system, and the tactics it uses to fight off foreign invaders, such as UPEC.

The researchers, comprising members of the IMB – Professor Matt Sweet, Dr Ronan Kapetanovic, Claudia Stocks and Dr Nick Condon, and members of UQ’s School of Chemistry and Molecular Biosciences – including Professor Mark Schembri and Dr Minh-Duy Phan, joined forces to examine how our immune system uses zinc in the fight against bacterial infections.

A two-pronged method of attack

The team’s particular focus is on a type of cell known as a macrophage, which literally means ‘big eater’. You can think of macrophages as the body’s ‘Pac-Man’.

“Macrophages are key immune cells in the body. They digest and destroy a variety of different pathogens and have many strategies to do this, some of which are very well known and some that we’re really only discovering now,” Miss Stocks said.

“One such recently discovered macrophage antimicrobial response uses zinc poisoning to kill bacteria, so we investigated how macrophages deploy zinc against UPEC.”

Macrophages (blue nucleus and red membranes) harnessing zinc (green) to fight off infection. Credit: Claudia Stocks & Dr Nick Condon.

The team developed new systems to track and assess the delivery of zinc in macrophages, with this work just published in Proceedings of the National Academy of Sciences USA (PNAS USA).

They found that, compared to non-pathogenic E. coli, UPEC has a two-pronged strategy to survive the body’s immune response.

Firstly, it can evade the delivery of zinc by hiding within the macrophage itself.

“We knew that UPEC can escape from the normal digestion pathway of the macrophage,” Dr Kapetanovic said.

“Our latest results show that UPEC can also avoid the delivery of zinc by hiding in different niches in these cells,” Dr Kapetanovic said.

“It’s now clear that UPEC’s ability to occupy these specific compartments is an important factor in allowing it to spread through the body to cause severe disease.”

But evasion isn’t UPEC’s only trick. The team also found that UPEC has an enhanced ability to resist zinc toxicity.

“When we looked at UPEC, we found that they can also resist the toxic effects of zinc better than other bacteria,” Dr Kapetanovic said.

“Taken together, these results may provide some potential avenues to develop treatments to combat UPEC and the diseases it causes, such as UTIs and sepsis. For example, blocking UPEC’s escape from zinc to make it more sensitive to this metal could help the body fight back.”

Professor Schembri and Dr Phan used technology called TraDIS to identify the full suite of UPEC genes involved in zinc resistance. Some of these genes had previously been identified, however a large number of others had not been explored for their involvement in defending against zinc stress.

Dr Phan said the TraDIS analysis had given the researchers a map of which genes they could potentially target to make them more sensitive to zinc.

Reprogramming our immune system to avoid resistance

Though the possibility of new treatments is exciting, Dr Kapetanovic stressed that any clinical treatment is some way off.

For him and his colleagues, the real excitement lies in the fundamental knowledge gained by such experiments. Nonetheless, this knowledge can ultimately help in the development of new, non-antibiotic treatments that are less likely to lead to resistance to these treatments.

“Our team are looking to develop treatment strategies that don’t rely on antibiotics,” he said.

“While antibiotics are life-saving and a cornerstone of modern medicine, widespread antibiotic resistance in UPEC and other bacterial pathogens means that alternative treatments are now urgently needed.

“If we can reprogram our immune cells to make them stronger, or change the way they respond to bacteria, then we would be better equipped to fight superbugs.

“This is a long-term project, but that’s our ultimate goal.”

Want to kill bacteria? Think zinc!

Zinc and its role in our immune system has been a focus for Miss Stocks since she began her PhD in 2015.

“Zinc is interesting because there’s a range of supplements that people recommend taking when you’re sick, but it’s one of the very few ones actually recommended by the World Health Organization, particularly in diarrhoeal disease,” she said.

Miss Stocks was a finalist in the Judge's Choice Award for the QLD Women in STEM 2018 competition for her zinc research.

The new research doesn’t just have implications for UPEC and the UTIs they cause. The team developed zinc sensors that could be used to study a variety of disease-causing bacteria.

“Macrophages deploy zinc against persistent bacteria that aren’t necessarily being cleared by normal mechanisms, for example, Mycobacterium tuberculosis, Salmonella and Streptococcus; all bacteria that can cause chronic infections,” Miss Stocks said.

“In creating this tool, we’ve not just found out more about E. coli, but have also created a model to study different types of bacteria, bringing us closer to not only understanding our immune system better, but also to creating therapies for a range of infectious diseases.”