Amoebas don’t usually make headlines. But Entamoeba histolytica, a single-celled killer with a taste for human cells, may deserve the spotlight.

This microscopic parasite infects up to 50 million people annually, mostly in the Global South, and kills nearly 70,000. For many, it causes only mild diarrhea. But in others, it leaves a trail of biological destruction: ulcers in the colon, liquefied livers, even invasion into the brain and lungs. Its name, histolytica, means “tissue-dissolving,” and it lives up to the label.

“It can kill anything you throw at it, any kind of human cell,” said Katherine Ralston, a microbiologist at UC Davis.

Now, in a new review published in Trends in Parasitology, Ralston and her colleagues Maura Ruyechan and Wesley Huang are revealing how E. histolytica might be pulling off its deadliest tricks — and it’s almost too wild to be true.

A Parasite in Disguise

Scientists used to think that E. histolytica harmed people by injecting toxins into cells. But in 2011, Ralston began to suspect otherwise. Watching the amoeba through a microscope, she saw something bizarre: it was biting human cells.

“You could see little parts of the human cell being broken off,” she said. Those glowing fragments, tagged with a fluorescent dye, were visible inside the amoeba’s body.

In a 2014 Nature paper, Ralston described this awkward process — trogocytosis, or “cell nibbling.” It was a revelation at the time. The parasite wasn’t just poisoning human cells. It was feeding on them, piece by piece.

Even more alarming, Ralston’s team discovered in 2022 that the amoeba wasn’t just eating.

When E. histolytica ingests fragments of human cells, it absorbs proteins from the cell’s outer membrane. Two of those proteins, CD46 and CD55, are normally used by human cells to block “complement proteins” — immune molecules that tag invaders for destruction. After ingesting them, the amoeba places those same proteins on its own surface, donning a kind of molecular disguise.

“It’s dressing up in the proteins of the cells it just killed,” said Ralston. That cloak helps it slip past the immune system undetected.

An Enigmatic Genome

Understanding how the amoeba performs these feats has been slow work. Unlike more familiar pathogens like HIV or Salmonella, E. histolytica has been notoriously difficult to study. Its genome, first sequenced in 2005, is sprawling — over five times larger than Salmonella’s, and with a chaotic structure.

The parasite has 31 to 35 linear chromosomes and about 200 circular DNA segments, known as episomes. Its DNA is ~75% adenine and thymine — a composition that makes genetic manipulation difficult. On top of that, the genome is aneuploid: some chromosomes occur in irregular numbers, and gene expression doesn’t necessarily match the number of gene copies.

“We still don’t know how it regulates gene expression so tightly despite that chaos,” Ralston said.

In a breakthrough, her lab discovered that the parasite uses RNA interference (RNAi) — a gene-silencing mechanism — to tune the activity of its genes. That insight allowed the team to create a comprehensive “RNAi library” in 2021. With it, they could silence any of the parasite’s ~8,700 genes and observe the consequences.

Their latest paper outlines a plan to scale this up, combining RNAi with CRISPR gene editing to map the amoeba’s functional genome — and identify which genes are essential for trogocytosis, immune evasion, or virulence.

“We now see a light at the end of the tunnel, and we think this could be achievable,” said Huang.

A Path to Therapies

Yet technical hurdles remain. While stable transfection of the amoeba with plasmids is routine, scientists still can’t directly edit its endogenous genome. So far, CRISPR/Cas9 has only been used to edit plasmids — a proof-of-concept, not yet a breakthrough.

Ralston’s team is pushing for wider adoption of modern molecular tools. They hope to tag proteins with fluorescent markers to watch them in action, or use CRISPRi — a gene-silencing variant of CRISPR — to improve on the sometimes messy results of RNAi.

But progress has been hard-won.

“Science is a process of building,” Ralston said. “You have to build one tool upon another, until you’re finally ready to discover new treatments.”

For all its scientific obscurity, E. histolytica causes real suffering. It is a leading cause of death from diarrheal disease in children. It spreads through contaminated food or water, often in places lacking access to clean sanitation. In a recent study, it was the pathogen most strongly associated with death among infected children.

Despite this, it remains dramatically understudied. There is no vaccine, and the treatment options are decades old. The complexity of the parasite — and its genome — has stymied researchers for years.

Ralston’s work could change that. By uncovering how the amoeba feeds, how it hides, and which genes control these behaviors, her lab is charting a new path forward.