New part of cell death process could play a key role in infection control strategy

Researchers have unmasked a part of the cell death process that could play a critical role in a better infection-fighting strategy.

Scientists at the Duke University School of Medicine teamed up with the University of North Carolina at Chapel Hill and the University of Virginia to identify the function behind caspase-7, an enzyme that’s part of a cell’s self-destruct program. Although researchers knew that the enzyme is involved in the process, its exact function is unclear.

The findings were published June 15 in the journal Nature.

The researchers found that caspase-7 is the start of a Rube Goldberg series of events that allow the cell to die in an orderly manner, said the study’s corresponding author, Edward Miao, MD, Ph.D., a professor of the study. Departments of Immunology and Molecular Genetics and Microbiology at Duke University School of Medicine.

Orderly cell death is essential for the immune response. However, without the enzyme, the dying cell can explode violently and cause collateral damage.

Miao said this research lays the groundwork for exploring exciting possibilities for therapeutic applications, especially if caspase-7 can be stimulated or blocked.

There is still so much we need to understand about the basic components of our cells, what they do and why. If we can uncover this blueprint, it could become a map to understanding how disease moves in the body, helping scientists devise a more accurate plan of action. With the discovery of the role of caspase-7 in the cell, we are one step closer to a complete scheme.”

Edward Miao, MD, Ph.D., professor, Duke University School of Medicine

In the study, the researchers found that caspase-7 serves as a timing device in cell death. It activates a protein called acidic sphingomyelinase, or ASM, which triggers a cell membrane repair mechanism, which in turn gives the cell enough time to get its affairs in order before it dies.

To identify the function of the caspase-7 enzyme, the team studied several infection models in genetically altered mice and cultured gut tissue. They looked at the role of caspase-7 in two types of ordered cell death: extrusion and apoptosis.

The role of Caspase-7 was different in the context of different pathogens – Salmonella, Listeria and a rare pathogen called Chromobacterium.

With Salmonella, cells undergo an orderly way of cell death called extrusion. In this context, researchers found that the absence of caspase-7 caused the unnecessary death of healthy cells, which was the collateral damage of nearby infected cells that were unable to detach or extrude from their neighbors.

With Chromobacterium and Listeria, dying cells normally undergo a process called apoptosis or programmed cell death. The lack of caspase-7 allowed the bacteria to survive an immune system attack, presumably because their infected cell host failed to complete an apoptotic task before exploding.

If caspase-7 can be manipulated, Miao said one possible application is exploring the possibility of targeting the enzyme as an igniter of cell death to evade antibiotic resistance.

Antibiotics are a standard and broad approach to fighting infections, but pathogens have devised strategies to adapt and resist.

“Antibiotics don’t take into account that each pathogen has its own strategy — some live outside cells, some live inside cells. If a pathogen is inside the cell,” he said, “you could be stimulating caspase-7 to enter the infected cell.” die in the right way. If you know the strategy the pathogen uses, you can help the immune system by adjusting it in the right direction.”

“On the other hand, if you have a pathogen outside the cell, and cells explode inappropriately, maybe we can stimulate caspase-7 to keep them alive, preventing excessive damage,” Miao said, pointing out that this approach may be effective against sepsis.

Miao said this enzyme may also play an important role in activating the immune system to fight cancer.

“Cancer cells probably run the entire Rube Goldberg machine and die in an orderly fashion,” Miao said. “If the immune system comes and looks around, it sees that everything seems to be fine and then it goes away.

“If you could turn off the Rube Goldberg device, instead of putting itself away neat and tidy, the tumor cell would just lie dead on the floor,” Miao said. “This could cause the immune system to become alarmed and activated. Theoretically, that could cause the immune system to attack a tumor that it would otherwise ignore.”


Reference magazine:

Nozaki, K., et al. (2022) Caspase-7 activates ASM to repair the pores of gasdermin and perforin. Nature.

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