Entamoeba histolytica is a tiny pathogen that takes a terrible toll. The single-celled parasite—an amoeba about a tenth the size of a dust mite—infects 50 million people worldwide and kills as many as 100,000 each year. Now, a new report reveals how the microbe does its deadly damage: by eating cells alive, piece by piece. The finding offers a potential target for new drugs to treat E. histolytica infections, and it transforms researchers’ understanding of how the parasite works.
“This process of nibbling of cells went unrecognized by everyone in this field, including me, for over a hundred years,” says infectious disease specialist William Petri of the University of Virginia in Charlottesville, a co-author of the report who has studied E. histolytica for more than 2 decades.
Although scientists have studied E. histolytica for more than a century, much about the parasite remains a mystery. Part of the problem is that it behaves unpredictably. Many of those infected show no symptoms at all—the amoeba lives quietly in their gut, feeding on bacteria without causing trouble. But in others, the parasite attacks the gut itself and can cause potentially fatal diarrhea, intestinal ulcers, and liver abscesses. This illness, called amebiasis, is a leading cause of parasitic death among humans. Common in parts of the developing world, including Africa, Latin America, and South Asia, it is transmitted via contaminated food and water. But researchers knew only bits and pieces of how the disease plays out in the gut. They knew, for example, that the amoeba killed only cells with which it had direct contact, and that it bound itself to those cells using specific sugars, called lectins.
“We thought they somehow caused the cells to die, and then the parasites would eat the dead cells,” says microbiologist Katherine Ralston of the University of Virginia. Because amoebae are known to feed by phagocytosis—a process in which one cell engulfs and “eats” another—researchers assumed the amoebae ingested the dead cells whole.
But Ralston wondered if new live microscopy techniques, which enable scientists to capture video of cells in action, might reveal more. Working with Petri and colleagues from the University of Virginia and Jawaharlal Nehru University in New Delhi, Ralston put the parasitic amoebae and human cells that were made fluorescent so they would be easier to spot in a dish and examined their interaction. What the team saw surprised them.
“It was remarkable to see the amoebae were taking bites,” Ralston says. Within one minute of contact, the parasites were ripping off and ingesting fragments of the human cells, which were visible as bits of fluorescent material within the amoebae. The biting resembled trogocytosis, a process in which immune cells extract bits of other immune cells, but was unique in that it occurred between a parasite and its host and ultimately caused cell death. Once an amoeba took its first bite, it continued to consume more and more of the cell until the cell died about 10 minutes later.
“A little bit of nibbling caused more nibbling,” Ralston says, “and this was happening while the human cells were alive.”
When the cells were dead, the amoebae stopped nibbling, detached from the cells, and moved on. Human red blood cells faced the same gruesome end. (See video—the human cell appears in pink, the amoeba in green.) The team then repeated the experiment with live intestinal tissue from mice engineered to have fluorescent intestinal cells and found the parasites invaded this tissue and caused damage similar to that seen in samples of E. histolytica-infected human colon tissue.
The researchers couldn’t be sure that the nibbling was actually causing the cell deaths, however, so they used a drug that interferes with the amoeba’s ability to reshape itself for biting to observe its impact on cell death. The drug-hampered amoebae nibbled less and did not kill the cells. Neither did amoebae the team genetically modified, so they could not produce the proteins and lectins often found where the parasites make contact with human cells.
Together, the results suggest that this piecemeal nibbling drives the cell death and damage sometimes seen in E. histolytica’s wake, and that the lectins may induce or regulate the biting behavior, the team reports online today in Nature. If additional studies confirm that E. histolytica actually kills cells this way in people suffering from amebiasis, Ralston says, they could point the way to new treatments for the illness. “If we could understand how the amoeba takes a bite, that would be a good target for therapeutic drugs.”
The team’s discovery could change the game for E. histolytica research, says Upi Singh, a physician and infectious disease researcher at Stanford University in California who was not involved in the study. “It’s really fantastic for the field to have a study of this caliber come along,” she says. “This changes the paradigm.”