Uncovering TB’s Survival Strategy in Lipid-Rich Environments

At a recent IDM seminar, Dr Tiago Beites shared new insights into how Mycobacterium tuberculosis, adapts to one of the body’s more unusual defence environments: lipid-rich infection sites.

When TB infects the body, it often forms infection foci, which are localised pockets of infection where bacteria cluster and the immune system responds. These sites, commonly known as granulomas, are rich in lipids (fat-like molecules). While this may seem beneficial for the bacteria, it creates a paradox: lipids can serve as food, but they can also be toxic.

M. tuberculosis has evolved to use the host lipids, especially long-chain fatty acids and cholesterol as key energy sources. However, these same fatty acids can act as natural antimicrobial agents. This raises an important question: how does TB survive in an environment that is both nourishing and potentially harmful?

Dr Beites’ research shows that the bacterium doesn’t rely on a single trick, but rather a network of survival strategies. Using a technique called transposon sequencing, a method that helps scientists identify which genes are important for survival under specific conditions, his team identified 38 genes that help TB resist the harmful effects of fatty acids.

Interestingly, these genes are involved in a wide range of processes. Some help build and maintain the bacterial cell wall, while others are linked to metabolism and cell signalling, including cyclic AMP signalling, which is a communication system that allows cells to sense changes in their environment and respond accordingly.

One of the standout discoveries is the role of a protein called TB15.3, known as a “universal stress protein.” This protein helps the bacterium carefully control how it takes in and breaks down fatty acids, preventing toxic overload. It also plays a critical role in helping TB survive during the chronic phase of infection, when the disease persists in the body over long periods.

These findings offer more than just insight into TB biology, they point to new possibilities for treatment. If scientists can disrupt the bacterium’s ability to manage and use lipids, they may be able to turn a preferred food source into a weakness, opening the door to novel therapeutic strategies.

Dr Beites, who leads a research group at the Institute for Research and Innovation in Health (i3S) at the University of Porto, focuses on understanding how bacterial pathogens adapt to the human body, with the goal of identifying new drug targets.

Join us every Wednesday at 13h00 for the IDM Seminar Series.