Of the various ways for a cell to die — necrosis, autophagy, etc. — apoptosis is probably the most orderly and contained. Also called programmed cell death (or, colloquially, “cellular suicide”), apoptosis is an effective way for diseased or damaged cells to remove themselves from a population before they can cause problems such as tumor formation.
“Apoptosis has special features,” says Judy Lieberman, MD, PhD, an investigator in Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “It’s not inflammatory, and it activates death pathways within the cell itself.”
Conventional wisdom holds that apoptosis is exclusive to multicellular organisms. Lieberman disagrees. She thinks that microbial cells — such as those of bacteria and parasites — can die in apoptotic fashion as well. In a recent Nature Medicine paper, she and her team make the case for the existence of what they’ve dubbed “microptosis.” And they think it could be harnessed to treat parasitic and other infections.
Over the last couple of years, Lieberman’s lab has uncovered evidence for what could be an evolutionarily ancient form of immune defense directed against intracellular pathogens. In a 2014 Cell paper, her lab revealed that the immune system’s T-cells can kill intracellular bacteria directly by pummeling infected cells with three proteins:
- perforin, which opens a hole in the membrane of the infected cell
- granulysin, which enters the cell and pierces the bacterium’s surface
- granzymes, which enter the bacterium and trigger a molecular cascade that kills it.
At the time, Lieberman’s team noted that granzymes disrupt metabolism in the mitochondria of both the infected cell and the infecting microbe, triggering both to release toxic reactive oxygen species (ROS). ROS, in turn, killed both the cell and the microbe.
A lethal blow to parasites
This time around, the lab has found that T-cells can release the same 1-2-3 punch against intracellular parasites like Trypanosoma cruzi, Toxoplasma gondii and Leishmania major, all major pathogens of concern in developing countries. But looking more closely, they noted that parasites react to granzymes in ways that look remarkably similar to apoptosis:
- Shortly after ROS levels rose, the parasite’s DNA started to condense.
- Their nuclei started to fragment.
- Their membranes start to bulge or bleb.
“Basically, the parasite is triggered to kill itself, as opposed to dying from just having things leak out of its damaged membrane,” Lieberman says. “It’s a very controlled kind of death.
“There’s a little bit of literature suggesting that parasites treated with cytotoxic drugs or radiation undergo a kind of programmed cell death, but there’s not a lot about it,” she adds. “This really is a new kind of death in microorganisms.”
Lieberman thinks that there are enough enzymatic differences between parasites’ and mammalian cells’ microptotic and apoptotic pathways that it should be possible to trigger microptosis without pushing host cells over the brink into apoptosis. For instance, apoptosis in mammalian cells relies in part on enzymes called caspases. Parasitic microptosis takes place without caspases being involved, however.
“It should be relatively easy to develop drugs that target them and leave a patient’s cells alone,” she says. “I think these findings potentially open up whole new kinds of therapies.”
Learn more about Lieberman’s portfolio of research.