Turning the tables on tuberculosis: boosting our own immune forces
Tuberculosis bacteria survive by hiding in our immune cells. In her PhD research, biologist Salomé Muñoz Sánchez explores how boosting the body’s own defenses might outsmart this deadly pathogen. Her work reveals two key proteins that help immune cells destroy the bacteria.
Imagine an enemy that does not hide in the shadows, but right at the heart of your defense system. Tuberculosis bacteria do exactly that. When they are engulfed by our immune cells, protective vesicles keep them from being broken down, allowing the bacteria to feed on nutrients from the cells and quietly multiply. This ability makes tuberculosis one of the deadliest infectious diseases worldwide.
‘How can bacteria survive inside the very cells meant to kill them?’
That is why scientists are eager to understand more about this ability. ‘We want to understand how these bacteria can survive and kill the very cells that are meant to kill them,’ says Muñoz Sánchez. ‘If we understand the enemy better, we can also fight it more effectively.’
Watching the immune system in action
To study the earliest stages of infection, Muñoz Sánchez used zebrafish as a model. ‘Zebrafish larvae are transparent, allowing researchers to observe infections in real time under the microscope,’ explains Muñoz Sánchez. ‘This offers a unique view of how the host’s immune system responds.’
Muñoz Sánchez focused on autophagy, the process by which immune cells capture and break down invading bacteria. ‘In tuberculosis, the “breaking down” part doesn’t work properly,’ she explains. ‘We had strong hints that two proteins -PIKfyve and Rubicon- play a key role.’
To uncover their function, Muñoz Sánchez studied infected cells in which PIKfyve or Rubicon was switched off, either genetically or chemically. Muñoz Sánchez : ‘We studied how the cells without PIKfyve or Rubicon responded upon infection with Mycobacterium marinum, a close relative of Mycobacterium tuberculosis, the bacteria that causes tuberculosis. From that, deduced the role of each protein in the autophagy process.’
How do you disable a protein in a cell?
Chemical inhibition: Some proteins, like PIKfyve, are enzymes with an active site. Researchers can use small chemical compounds to block this site, stopping the protein from working without removing it from the cell.
Genetic inactivation: Rubicon is not an enzyme, so chemical inhibitors won’t work. Therefore, Muñoz Sanchez used a genetic tool called CRISPR-Cas9 to disrupt the gene, preventing the protein from being formed.
Why PIKfyve and Rubicon matter
Both PIKfyve and Rubicon proved essential for immune cells to properly process and degrade the bacteria. Muñoz Sánchez: ‘ When these proteins do not function properly, bacteria survive longer and multiply faster.’
PIKfyve helps immune cells process the vesicles that capture and break down bacteria. When PIKfyve doesn’t work properly, these vesicles fail to develop correctly, immune cells die more easily and bacteria survive longer. Rubicon acts like a guide, ensuring the captured bacteria reach the right pathway for destruction. Without it, this process is less efficient, allowing bacteria to multiply more easily.
Strengthening the body instead of the bacteria
Rather than attacking the bacteria head-on, Muñoz Sánchez’s work explores ways to strengthen the body’s own defenses – giving our defense system a better chance to outsmarts the enemy from within. ‘With host-directed therapy, we focus on boosting the immune system itself,’ she says. ‘Think of chemical compounds to block the (working) of proteins, or genetic therapy to prevent them from forming.
This shift in focus is especially important today, as antibiotic resistance is increasing rapidly worldwide. By strengthening the body’s own defenses instead of directly attacking bacteria with antibiotics, we reduce the risk of creating even stronger, drug-resistant pathogens—giving our immune system the upper hand without arming the enemy.’
Thesis and promotion
Salomé Muñoz Sánchez will defend her PhD thesis, titled Illuminating Host Defence against Mycobacterial Infection: Interactions with Autophagy and LC3-Associated Phagocytosis, on 3 February at the Academy Building. Her supervisors are Prof. Annemarie Meijer and Dr. Michiel van der Vaart.