A new experimental study led by the Francis Crick Institute in London has suggested the potential for new treatments to reduce reliance on antibiotics for intracellular infections like tuberculosis (TB).
The researchers reported that their study demonstrated "strong evidence" for the role of autophagy, the body's process for eradicating old and damaged cell parts when they are under stress or infected, in controlling intracellular infections naturally. They said: "If this pathway can be boosted or strengthened, it could be a new avenue for tackling antibiotic resistance, by making existing antibiotic drugs more effective or presenting an alternative to drugs in cases where bacteria have evolved resistance."
Their study published in Nature Microbiology ahead of World TB Day on 24 March, involved developing a human macrophage cell model by taking induced human pluripotent stem cells, which have the ability to become any cell type in the body, and using them to engineer macrophages, known to be the main host cell in humans for Mycobacterium tuberculosis. However previously it remained "unresolved" quite how autophagy might function to control the infection within cells.
Without Autophagy Bacterial Replication is Enhanced
So the team used CRISPR–Cas9 genome-editing tools to manipulate the macrophages’ ability to perform autophagy. They found that removing the key genes for autophagy, ATG7 and ATG14, and then infecting the macrophages with wild-type M tuberculosis, resulted in increased replication and enabled the bacterial infection to take hold, replicating more within the engineered cells and causing mass host cell death.
The team concluded that both genes were required to restricting M tuberculosis replication in human macrophages. They also validated their results using macrophages isolated from blood samples, confirming the importance of autophagy in human defences.
"Using a combination of genetic and imaging approaches we show that autophagy-deficient human macrophages have crucial defects in M tuberculosis control," they said. "These results are evidence for a strong role of autophagy in controlling intracellular infections like TB."
They added: "Understanding how autophagy acts to control the infection of intracellular pathogens in humans will enable the development of host-directed therapies."
'Valuable New Tool' In the Fight Against Infections
Corresponding author Maximiliano (Max) Gutierrez, head of the Host-Pathogen Interactions in Tuberculosis Laboratory at the Crick, said: "I first studied the role of autophagy in infection during my PhD, so it's incredible to see renewed interest in this field. Using the latest technologies, we've been able to show a key role for this pathway in controlling infection.
"As immunotherapies have harnessed the immune system to fight cancer, [so] boosting this immune defence with a host-directed therapy could be a valuable new tool in the fight against infections, particularly those becoming resistant to antibiotics."
The team are now planning further experiments to screen for drug compounds that might be used to boost autophagy in a targeted way that affects only macrophages.
Dr Gutierrez explained: "Boosting the autophagy pathway isn't as simple as it might seem. This is because all parts of the body use autophagy as a way to recycle old and damaged cells. In order safely to increase autophagy in the location of infections, we need to target the pathway in macrophages alone."
Beren Aylan, a PhD student at the Crick and joint first author, said: "Antibiotic resistance is a huge threat to our health so it's incredibly important to understand how our bodies fight infection and where there might be room for improvement.
"TB is a great example of where targeting our own immune defences could be really effective, because it takes a very long course of different antibiotic treatments to effectively remove the infection. Anything that can be done more effectively to remove bacteria could also make a huge difference to the cost and accessibility of treatments."
This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme. The authors declared no competing interests.
