It was the killer T cells, on the cell surface, with granzyme B
It is well known in the scientific community that immune cells called cytotoxic lymphocytes, or killer T cells, target bacteria invading the body’s cells — but how do they get away with it? For the first time ever, US researchers have caught killer T cells red-handed in the act of microbial murder.
Bacteria can quickly evolve resistance against antibiotics, yet they have not so readily been able to evade killer cells. And although killer T cells can trigger bacterial death by inflicting oxidative damage, it has not yet been understood how killer cells destroy bacteria in environments without oxygen.
Now, researchers from Boston Children’s Hospital, the Wistar Institute and the University of Michigan have discovered that killer T cells act methodically, shooting deadly enzymes into bacteria to ‘program’ a complete internal breakdown and cell death. The process inflicts bacterial cell death regardless of whether the environment contains oxygen or not.
As explained by Judy Lieberman, co-senior author on the study from the Boston Children’s Program in Cellular and Molecular Medicine, the scientists tested killer T cells against three very different types of bacteria: Escherichia coli, Listeria monocytogenes and Mycobacteria tuberculosis. Using a combination of proteomics and computer modelling, the researchers were able to see how the multipronged attack targeted multiple processes. The results were published in the journal Cell.
“To see which proteins were destroyed by killer cells, we measured their protein levels before, during and after they were attacked,” Lieberman said. Proteins are critical to life because they direct the use of nutrients and production of cellular machinery that bacteria need to survive.
“Each strain of bacteria has about 3000 proteins, and we saw that — in all three bacterial species — about 5–10% of those proteins were slashed by the killer cells’ death-inducing enzyme, called granzyme B,” Lieberman explained. “If you made a list of the proteins that bacteria absolutely needed to survive, it would be a small list — interestingly, this seems to be identical to granzyme B’s hit list.”
To deliver granzyme B, killer T cells seek out surface markers on the body’s cell surfaces that might indicate a bacterial invader has taken up residence inside the cell. The killer T cells then latch onto the infected cell and use an enzyme to create a small pore in the cell’s surface, through which they inject granzyme B.
Once granzyme B gets into the cell, it passes into the invading bacterium and essentially destroys critical proteins for cell survival as well as its ribosomes, the pieces of bacteria’s cellular machinery that actually make proteins. It’s almost as if the bacteria’s internal factory of life not only loses the blueprints for the parts it needs to make, but also suffers a catastrophic mechanical failure of its assembly line.
“This enzyme breaks down multiple proteins that are essential for the bacteria to survive,” said Sriram Chandrasekaran, co-senior author from the University of Michigan. “It’s essentially killing several birds with one stone.”
Importantly, no matter how many times the researchers exposed the bacteria to granzyme B, the bacteria did not develop resistance to its fatal attack. The researchers theorise that the only way bacteria can survive is to camouflage themselves so that the killer T cells cannot ‘see’ them or shoot granzyme B into them.
The research comes in the midst of the antibiotic resistance crisis, with Chandrasekaran noting that most drugs that treat diseases like tuberculosis or listeria, or pathogens like E.coli, are no longer effective. The scientists are therefore hopeful that their work may lead to a new class of antimicrobial drugs that fight infections by mimicking granzyme B, going after bacteria in a similar way. They are also searching for the specific mechanisms by which bacteria might evade killer cells and investigating how similar ‘death pathways’ take effect in fungi and parasites, such as those that cause malaria.
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