A new front in the fight against malaria

Key Takeaways:

• HHMI Investigator Flaminia Catteruccia is developing new ways to stop the transmission of malaria — a deadly disease that kills more than 600,000 people annually — by disrupting the growth of malaria parasites in mosquitoes.
• Catteruccia and her team engineered two compounds that target mitochondrial proteins in malaria parasites during their critical growth phase inside the mosquito. The insects absorb the compounds through contact with a treated bed net, disrupting parasite development before it can be transmitted to humans.
• This fall, volunteers in Ethiopia will sleep under the treated nets during peak malaria season — an important real-world test of whether the approach holds up outside the lab.

Body Text:

HHMI Investigator Flaminia Catteruccia is not a mosquito lover; she won’t hesitate to kill one if it lands on her arm. But she does respect their adaptiveness and resiliency.

“They’ve been on the planet for 400 million years — much longer than humans,” Catteruccia points out. “Trying to eradicate them is probably impossible. Even if it were feasible, it would have huge repercussions for our food chain and our environment.”

Efforts to reduce the spread of malaria — which kills more than 600,000 people each year — have focused on killing mosquitoes using bed nets laced with insecticide. But mosquitoes develop resistance to these chemicals, and the nets gradually lose efficacy. And despite their bad reputation, the mosquitoes are not directly responsible for deadly illnesses like malaria; they just act as conduits for parasites and pathogens.

That’s why Catteruccia’s lab at the Harvard T.H. Chan School of Public Health is taking a different approach: attacking the parasites themselves.  

Targeting the Parasite’s Power Supply

Plasmodium falciparum — the deadliest of the parasites responsible for malaria — multiply from a handful of cells into several thousand over a span of about two weeks inside a mosquito host. The parasite’s mitochondria fuels that explosive growth — it provides the energy that the parasite needs to develop, replicate, and ultimately transmit itself to humans. Disrupt that engine, and — they hoped — the parasite would stall for good.

Catteruccia and her team set about finding the right drug to target these structures in parasite-infected mosquitoes. Like all insects, mosquitoes have a cuticle — a tough exoskeleton that blocks most chemical compounds from entering the body. Their solution needed to be potent enough to both penetrate the mosquito’s defenses and disable the parasite’s mitochondria.

So Catteruccia turned to a drug that is already used to treat and prevent malaria infections in people: atovaquone. It was known to block mitochondrial function in the parasite. It is also oily, which they hoped might allow it to penetrate the mosquito’s cuticle.

To test the idea, the team coated a glass plate with atovaquone and then allowed mosquitoes to rest on the plate for a few minutes before giving them blood containing the parasite. Catteruccia was in Burkina Faso with her field team when the results came in — the mosquitoes exposed to atovaquone were parasite-free. “It was a moment of pure joy,” she recalls. “Until then, there was no prior evidence that parasites could be killed with drugs within the mosquito. It was our first demonstration that this idea was a good one.”

Attacking From Multiple Fronts

Finding the parasite’s weak spots was one thing; acting on them was another. “You can’t take mosquitoes to a pharmacy to drug them,” she jokes. The answer was to incorporate the compounds directly into bed nets — the same delivery mechanism already used for insecticides.

Although atovaquone worked to kill the parasite, it was not optimized for absorption through a bed net. Working with collaborators at Oregon Health & Science University, the lab identified and optimized two new compounds — endochin-like quinolones, or ELQs — that could work on bed nets, penetrate the mosquito’s cuticle, and cripple the parasite. In fact, these compounds hit two separate targets on an essential mitochondrial protein. Targeting multiple sites means that even if the parasite develops resistance to one compound, it won’t necessarily become resistant to the other, making it significantly harder for the parasite to escape both.

The team designed an experiment where mosquitoes briefly landed on compound-coated surfaces that mimicked a bed net. They found that even brief exposure to these compounds effectively abolished parasite growth.

From Bench to Bed Net

Working with the Southwest Research Institute, Catteruccia’s team developed a method to directly coat full-scale bed nets with the mitochondria-targeting compounds . They then went to Adama, Ethiopia, where they worked with local health partners to test the treated nets. First, mosquitoes were exposed to the treated nets; then, they were fed blood drawn from malaria patients at local clinics. Those mosquitoes showed no parasite development — confirming that the lab results held up against real, genetically diverse parasites circulating in the field.

Larger-scale experiments are scheduled for September and October — Ethiopia’s peak malaria season — to test whether the treated nets can protect people from contracting malaria. Volunteers will sleep in experimental huts under the treated nets, confirming that the nets work under realistic exposure conditions. If those go well, Catteruccia hopes that large-scale epidemiological trials will follow, comparing these new nets to the existing standard ones.

Catteruccia and her colleagues are also searching for other potential drug targets. They recently discovered that the parasites’ growth also depends on PfApiAT2 — a transporter that shuttles amino acids into the parasite cell — another weakness they hope to harness in future compounds.

“Just like mosquitoes themselves, parasites are capable of developing resistance,” she says. “The more ways we can simultaneously attack, the harder that will be.”