A nitisinone-treated tsetse fly surrounded by untreated healthy flies. Photo by Lee Haines
As they buzz through the grasses of the African savannah and forested riverbanks, tsetse flies hunt for one thing: blood.
Tsetse flies carry the human and animal parasite, African trypanosomes, which cause sleeping sickness in humans and a related wasting disease in animals. The flies transmit the deadly parasites to their hosts when they bite them and drink their blood.
Sleeping sickness in humans has been nearly eliminated due to careful disease monitoring and targeted therapeutic interventions. However, “Animal trypanosomiasis will continue to be a problem in sub-Saharan Africa. There is a huge problem with drug resistance, [and] there are no vaccines to treat it,” said Álvaro Acosta-Serrano, a vector biologist at Liverpool School of Tropical Medicine in the UK.
“It affects, obviously, humans indirectly. Cattle production really drops, not only in terms of dairy and meat production, but also on the cattle that is used for traction in some of these regions. It really causes several billions of US dollars in losses per year,” he continued.
But what if you could turn tsetse flies’ need for blood against them?
In a new study published in PLoS Biology, senior author Acosta-Serrano and his team report that the drug nitisinone specifically kills blood-feeding insects, while leaving non-blood-feeding insect pollinators unharmed (1). This FDA-approved drug has the potential to halt not only the transmission of trypanosomes by tsetse flies, but also the transmission of deadly parasites by other blood-feeding bugs like fleas, ticks, and mosquitos.
“Any blood-sucking insect is in trouble,” said Lee Haines, a vector biologist from the Liverpool School of Tropical Medicine and co-first author of the study.
Originally developed as a weed killer, nitisinone inhibits the second enzyme in the tyrosine degradation pathway, which breaks down the amino acid tyrosine into molecules that can be used by the body. In the late 1980s, clinical chemists wondered if nitisinone could help treat children with the rare genetic disorder, tyrosinaemia type 1. Children with this disorder lack the final enzyme in the tyrosine metabolism pathway, leading to toxic metabolite build up in the liver and potential liver failure in early childhood. In a small 1992 clinical trial, scientists found that nitisinone successfully treated these children (2).
During his postdoctoral studies in Pedro Olivera’s lab, Marcos Sterkel, a vector biologist at the Universidad Nacional de La Plata in Argentina and a co-first author of the study, discovered that if he fed mosquitos or kissing bugs—both blood-feeding insect vectors—blood infected with nitisinone, they died. But non-blood-feeders fed the same drug were completely fine.
“This is because blood-feeders ingest a huge quantity of blood every time they feed,” Sterkel explained. “The blood contains huge quantities of proteins.”
These proteins, which are made up of amino acids including tyrosine, must be broken down and digested. Blood-feeding insects only feed every few days, but when they do, they tend to overdo it.
“When it takes a big blood meal, it’s something like taking a five gallon smoothie mostly made up of hamburger,” explained Brian Foy, a vector biologist at Colorado State University who was not involved in the study.
Blood-feeders digest their giant protein shakes at different rates, and compared to other blood-feeders, tsetse flies digest their bloodmeals pretty quickly. Sterkel thought that perhaps blocking their digestion of tyrosine with nitisinone might kill the flies before they transmit the parasites they carry to more people or animals.
The researchers found that if they knocked down expression of either of the first two enzymes in the tyrosine metabolism pathway, tsetse flies died once they fed on blood.
Additionally, either feeding tsetse flies blood treated with nitisinone or allowing them to feed on mice given nitisinone, killed the flies as well.
And that death? It was pretty grisly.
“[Flies] get paralyzed, and then they can't get rid of their excrement, so they stay fat and bloated,” Haines explained. “They turn really dark black, like they've been burned, and the insides are completely liquefied. It's like some sort of horror story,” she said.
Surprisingly, it did not matter whether the flies ingested nitisinone or brushed their cuticle against it, it still killed them when they took their next bloodmeal.
“Ingestion with the blood, you would think, ‘okay, now it has a chance to work,’ but going and absorbing through the skin was pretty cool and kind of scary,” Haines said.
Nitisinone’s environmental stability and potency in blood makes it an attractive candidate for use in the field against tsetse flies.
When the researchers fed bumblebees sugar water supplemented with nitisinone, the bees survived just as long as untreated bees. While these results are promising, the researchers want to test whether nitisinone has any effect on the reproductive capacity of the bees as well.
Nitisinone has not yet been tested in people or animals in regions where tsetse flies live, but Acosta-Serrano hopes to do those studies soon. The results of their modeling suggest that giving people and animals in tsetse fly endemic regions monthly doses of nitisinone could significantly reduce transmission of the parasite.
While nitisinone is very effective at killing tsetse flies in the lab, it will be important to determine that the dose they ingest from animal or human-treated blood is enough to kill them in the field, Acosta-Serrano said.
But what’s most exciting about these results is nitisinone’s potential to target other disease-carrying blood-feeders like mosquitos.
Adding nitisinone to bed nets might target mosquitos that are insecticide resistant. “If they touched a bed net, picked up some nitisinone, and then took a blood meal, you're blocking the chain of transmission,” Haines said.
Spraying the drug onto the underbellies of herd animals like cows would protect the drug from the rain. And “You could target other blood feeders that are stuck to the cow like ticks and flies maybe, and mosquitoes,” Haines added.
Overall, Foy thinks this strategy of targeting blood-feeders by poisoning their bloodmeals is very clever, especially in terms of overcoming the problem of blood-feeders that have developed resistance to current insecticides.
“It's really novel that they're focusing on a new pathway that they can target vectors via the blood meal,” said Foy.
“There's more than just this pathway that is support for blood digestion,” he added. “This might open up a whole range of potential targets in vectors that people haven't thought about too much before.”
1. Sterkel, M. et al. Repurposing the orphan drug nitisinone to control the transmission of African trypanosomiasis. PLoS Biol 19, e3000796 (2021).
2. Lindstedt, S. et al. Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. The Lancet 340, 813-817 (1992).