Parasite Shreds Its Own mRNA to Evade Immune Detection

For 40 years, nobody could explain how the African trypanosome parasite survived in the human bloodstream — fully exposed to the immune system — by wearing a "cloak" of proteins. A team at the University of York has now solved that cold case. In a paper published in Nature Microbiology, they identify a protein called ESB2 — short for Expression Site Body — that operates as a "molecular shredder." As the genetic instructions for the VSG protective cloak are being transcribed, ESB2 sits inside the parasite's protein factory and surgically destroys the helper gene mRNA while leaving the cloak mRNA intact. The parasite is not just printing what it needs; it is redacting what it doesn't.

"When we first saw the molecular shredder localised in the microscope, we knew we had found something special," said Lianne Lansink, the paper's first author. The senior author, Dr. Joana Correia Faria, put it this way: "The parasite's secret to staying invisible isn't just what it prints, but what it chooses to redact."

The VSG gene produces mRNA at levels 140-fold higher than the helper genes also encoded on the same genetic sequence, yet the parasite somehow keeps those helpers scarce enough to avoid immune detection. That mystery is now answered. But the finding is a basic science advance — nobody has shown that blocking ESB2 kills the parasite in a living animal or a human. Drug discovery based on this mechanism is a path that now exists; how long that path takes is an entirely separate question.

Understanding the redaction mechanism matters because VSG cloaking is precisely what makes sleeping sickness so difficult to eliminate. The parasite switches between more than 1,000 VSG variants, each time presenting the immune system with a different surface coat. Antibodies against one variant do not protect against the next. A vaccine based on VSG has never worked. Every treatment that has gotten this far — fexinidazole, acoziborole — targets something else in the parasite's biology.

Which is where the acoziborole story becomes relevant. Acoziborole, developed by DNDi and Sanofi, is a single-dose oral therapy effective against both early and late-stage disease. It received a positive opinion from the European Medicines Agency (EMA) and represents one of the most significant advances against sleeping sickness in decades. But a paper published in March 2026 in PLOS Pathogens by Ridgway and colleagues shows that resistance to acoziborole is already emerging — via mutations in CPSF3, a different trypanosome nuclease that acoziborole targets. The researchers engineered a triple-mutant strain more than 40-fold resistant to the drug, showing that while acoziborole's selectivity is remarkable, it is not invulnerable. The drug works because trypanosome CPSF3 is different enough from the human version that the compound hits the parasite while sparing patients. The resistance mutations are precisely the changes that close that gap.

The context that other coverage of the ESB2 discovery has largely omitted is this: the molecular shredder finding is basic science, not a near-term drug target. The York team demonstrated ESB2's function in vitro — in cultured cells, using RNAi to deplete the protein and observe what accumulated. The research was funded by a Sir Henry Dale Fellowship, a joint Wellcome Trust and Royal Society program, and brought together collaborators from the United Kingdom, Portugal, the Netherlands, Germany, Singapore, and Brazil.

The elimination goal for 2030 is real. Fewer than 1,000 cases of sleeping sickness were reported in Africa last year, down from nearly 40,000 in 1998 — a 97.5 percent reduction. The WHO has set a goal of interrupting transmission entirely by 2030, which would make sleeping sickness the first fatal human disease eliminated without a vaccine. The progress is genuine, and it was hard-won. The last 1,000 cases are, in a biological sense, the hardest to find. The people most affected live in some of the most remote parts of sub-Saharan Africa. Diagnosis requires blood tests and, for late-stage disease, a lumbar puncture to confirm the parasite has reached the central nervous system. The tsetse fly vector remains in the environment.

In 2004, Dr. Wilfried Mutombo Kalonji finished medical school in the Democratic Republic of Congo and moved to Kasansa, a village of 11,000 people where he was the only physician. Of all the diseases he faced, sleeping sickness was the one he dreaded most — not because it kills nearly everyone who gets it, but because the only drug he had was nearly as terrifying. Melarsoprol, an arsenic-based compound first developed in 1949, required ten days of injections that patients described as "fire in their veins." Between 5 and 10 percent of patients died during treatment. Two of Mutombo's young male patients were among them. "I could imagine what their parents were telling themselves," he told Nature: "This doctor has killed our son." He joined DNDi in 2006 and has spent the years since watching the case numbers fall.

What ESB2 opens is a new window into the parasite's RNA processing biology. Whether that window leads to a drug in time for the 2030 elimination target is, at this point, a question nobody can answer. The cold case is solved. The harder story — what you do with that answer — is just beginning.