Entamoeba histolytica infects almost 50 million folks every year and kills round 70,000. It’s a shape-shifting parasite that invades the human intestine, usually inflicting delicate signs like diarrhea. However in some circumstances, it turns into lethal. It might probably chew ulcers into the colon, liquefy elements of the liver, and even unfold to the mind and lungs.
This single-celled killer is tough to review, despite the fact that it causes main sickness and demise, particularly in creating international locations. Scientists have lengthy struggled to know the way it causes injury and evades the immune system. However because of years of cautious work, they’re lastly starting to construct the instruments wanted to unlock its secrets and techniques.
A parasite that eats its victims alive
As soon as contained in the physique, Entamoeba histolytica heads straight for the colon. It often spreads by means of meals or water contaminated with feces. Poor sanitation makes the an infection frequent in lots of elements of the world. Within the U.S., it principally seems in individuals who’ve lately traveled overseas or immigrated.
The species title “histolytica” means tissue-dissolving. And that’s precisely what it does. It doesn’t digest cells neatly. As a substitute, it tears off chunks of residing tissue, leaving open wounds and liquefied tissue behind. These pockets of broken tissue, referred to as abscesses, are painful and typically deadly.
Again in 2011, Katherine Ralston started finding out the parasite throughout her postdoctoral work on the University of Virginia. Most consultants then thought the amoeba killed by injecting toxins. However when Ralston noticed it underneath a microscope, she noticed one thing else solely.
The parasite was biting human cells, not poisoning them.
“You might see little elements of the human cell being damaged off,” mentioned Ralston, now an affiliate professor at UC Davis. Fluorescent dyes made the bitten cell fragments glow inexperienced underneath her microscope. These glowing items piled up contained in the parasite, proving it had taken them in.
This course of, referred to as trogocytosis, was described in her 2014 paper in Nature. The invention was a significant breakthrough. “To plot new therapies or vaccines, you actually need to understand how E. histolytica damages tissue,” Ralston mentioned.
How the parasite hides in plain sight
In 2022, Ralston and her workforce found one other trick the parasite makes use of to outlive. After biting human cells, it turns into immune to the immune system. In a paper shared on bioRxiv in October 2024, Ralston and graduate college students Maura Ruyechan and Wesley Huang defined how.
They discovered that the amoeba swipes proteins from the outer layer of human cells and places them by itself floor. These stolen proteins, CD46 and CD55, cease the immune system’s “complement proteins” from attacking. In impact, the parasite kills human cells after which wears their protein coats as a disguise.
“It might probably kill something you throw at it, any sort of human cell,” Ralston mentioned. Even white blood cells meant to combat it will probably fall sufferer.
Any such stealth assault explains why the parasite might be so lethal. It not solely assaults tissue straight, but in addition hides from the very system that ought to be stopping it.
A posh and cussed genome
One cause why this parasite remained so mysterious for therefore lengthy is that its genome is extraordinarily complicated. It was first sequenced in 2005 utilizing a shotgun sequencing technique. The pressure used, HM-1:IMSS, was taken from a affected person with dysentery and remains to be probably the most extensively studied.
The genome is about 23.8 million base pairs in dimension, with almost 10,000 predicted genes. Many of those genes—about 25%—have introns, and 6% have multiple intron. Roughly 75% of the genome is made up of adenine and thymine. It has between 31 to 35 linear chromosomes over 300,000 base pairs lengthy, and about 200 round DNA molecules that include rRNA genes.
Regardless of being tetraploid—having 4 copies of every chromosome—its gene expression doesn’t observe the same old guidelines. Extra copies of a gene don’t essentially imply extra of its protein. That’s as a result of the parasite makes use of RNA interference, or RNAi, to regulate gene expression. This acts like a quantity knob that may flip genes up or down.
The genome is stuffed with repeated sequences, making it troublesome to assemble. The primary revealed model had 888 contigs—way over the precise variety of chromosomes—indicating it was incomplete. Even so, scientists discovered indicators of lateral gene switch from micro organism and a large enlargement of sure gene households. These included genes for cysteine proteases, Rab and Arf proteins for vesicle transport, and regulators of the actin cytoskeleton.
The genome additionally lacks genes to make thymidylate, purines, pyrimidines, and fatty acids from scratch. It has no mitochondrial DNA, and the organelles referred to as mitosomes don’t include DNA, which inserts with its uncommon biology.
Turning genetic instruments into weapons
Progress has been sluggish, nevertheless it’s beginning to repay. In 2013, scientists confirmed that E. histolytica makes use of RNAi to handle gene expression. That gave researchers an thought: what if they may flip this pure course of right into a lab device?
In 2021, Ralston and her workforce revealed a paper demonstrating a brand new RNAi library. This highly effective device lets scientists block every of the parasite’s 8,734 identified genes one after the other. By silencing particular person genes, they will check which of them are important for the parasite to contaminate cells, steal proteins, or keep away from immune assaults.
Of their newest paper, revealed in Trends in Parasitology, Ralston, Huang and Ruyechan clarify the right way to use this device to search out the parasite’s weak spots. They recommend pairing RNAi with CRISPR/Cas9 gene modifying. By doing this, they may label proteins with fluorescent tags to observe them in real-time or minimize out small sections of DNA to see what’s essential.
“We now see a lightweight on the finish of the tunnel,” mentioned Huang. “And we expect this could possibly be achievable.”
The thought is to construct on every step. Uncover which genes matter most. See how they assist the parasite chunk cells or dodge the immune system. Then discover medicine that may block these steps.
How fundamental science paves the highway to cures
The lengthy journey to know this parasite exhibits how fundamental analysis results in actual progress. Rising E. histolytica within the lab wasn’t simple. Sequencing its genome took years. Discovering that it bites human cells and steals their proteins took extra.
However now, armed with a working RNAi system and near utilizing CRISPR, researchers are positioned to find the parasite’s most vital genes and proteins. These discoveries could level the best way to vaccines or new medicines that might save hundreds of lives.
“Science is a strategy of constructing,” Ralston mentioned. “You must construct one device upon one other, till you’re lastly prepared to find new therapies.”
This work is already laying the inspiration for that future. And for one of many world’s most missed parasites, that might imply the distinction between lethal silence and eventually being heard.
