Researchers engaged in the global effort to reduce or even eliminate malaria watched their major gains of the prior decade level off in 2017. During this span, the world saw malaria cases reduced from about two million to one million cases annually. But additional gains have proved elusive.
“Malaria control has hit an asymptote,” says EPI researcher Rhoel Dinglasan, Ph.D., a UF preeminence faculty scholar. “We can’t seem to get more reductions in malaria prevalence, because all our tools have reached the limit of their efficacy.”
Over time, mosquitoes acquire resistance to the various insecticides designed to kill them; and the Plasmodium parasites that cause malaria acquire resistance to the drugs invented to eliminate them. Which explains why Dinglasan, a professor of infectious diseases shared by the EPI and UF’s College of Veterinary Medicine, is taking a different and unusual approach: repurposing known antimalarials to treat mosquito vectors.
“We are very human centric in our interventions, and rightly so,” Dinglasan notes. “But all our interventions tend to focus on areas where mosquitoes enter houses to blood feed, which does not consider the mosquitoes that feed on people outside, and when infected, transmit the parasites outside of homes, which fuels the malaria cycle.”
From this perspective, Dinglasan considered that all mosquitoes that take a blood meal, whether from a person or an animal, later need a sugar meal to support host-seeking and egg-laying behaviors. If an antimalarial that works effectively in mosquitoes could be identified, he thought, then perhaps lacing attractive sugar traps with the drug could clear the parasites from infected mosquitoes, interrupting the parasite transmission cycle between mosquitoes, and mammals — including people.
With this in mind, Dinglasan and his team tested a compound derived from primaquine, known as NPC1161B, which has a better therapeutic profile than its parent compound. Primaquine belongs to a class of drugs approved by the Food and Drug Administration and known as 8–aminoquinolines, or 8AQs. Drugs in this class interested Dinglasan because they have potent antimalarial activity: they can clear dormant parasites from someone’s liver, kill blood stage parasites and block transmission of parasites from an infected person.
However, these drugs can also be lethally toxic to people with certain genetic profiles, and these profiles tend to make up a high proportion of populations in some malaria endemic areas. Which means they can’t be widely deployed in areas that most need them.
Dinglasan wondered about switching the drug’s intended recipient. What if 8AQs worked in mosquitoes?
To test this idea, his team fed NPC1161B-laced sugar to Anopheles stephensi mosquitoes infected with Plasmodium falciparum parasites. Fifty or more Anopheles species are common vectors for malaria, and P. falciparum is one of the deadliest species of malaria in people.
Once malaria parasites are taken up by a mosquito during a blood meal, the sexual stages penetrate the mosquito gut to form oocysts; within each oocyst, up to 1,500 sporozoites can be produced. These then migrate to the mosquito’s salivary glands where they hitch an injectable ride into a new host the next time the insect probes a mammal for a blood meal.
The team found that infected mosquitoes treated with NPC1161B showed little effect on the number of oocysts that formed, but that no sporozoites ever emerged from these oocysts. The parasite’s reproductive process was fully disrupted.
In essence, the compound short-circuited the parasite’s sporogonic cycle; and although infected, treated mosquitos were no longer infectious to humans.
Prior to this work, the prevailing thought was that in order for an 8AQ to work against malaria parasites, it had to first be metabolized by a vertebrate host
“It was thought that these drugs could be used to widely block transmission in infected people, but then it turned out lots of people can’t use these drugs because of toxicity issues,” Dinglasan says. “But we’ve shown that you don’t need a mammal to metabolize a compound derived from this class of drugs. You can feed it directly to a mosquito, and it blocks transmission within the vector instead.”
While outside the scope of the current study, Dinglasan posits that the detoxification system used by mosquitos must break the parent compound down into daughter metabolites in a process analogous to how a human liver processes 8AQs. Although his team found evidence of compound metabolites, the study did not confirm the structure of these metabolites or how mosquitoes actually break down NPC1161B.
Their work, the first to report NPC1161B successfully curing mosquitoes of an on-going infection, was published in Frontiers in Pharmacology in October. Other UF researchers involved in the study include lead author Timothy Hamerly, Ph.D., and Vincent Nyasembe, Ph.D., both postdoctoral researchers in the Dinglasan Lab; and Rebecca Tweedell, Ph.D., a former lab member who was a doctoral student at the time of the study.
“Consider the millions of dollars that went into developing and identifying some of these compounds with antimalarial activities,” Dinglasan says. “Even if they missed the drug makers’ targets for use in humans, maybe we can still take advantage of their mode of action if we just think differently about how to use them.”
His next step will be to test delivery of the compound to mosquitoes in natural settings. If the compound proves safe for other sugar feeders, such as butterflies, bees, and ants, then Dinglasan envisions networks of drug-laced sugar traps inside and outside homes, businesses, and mosquito breeding areas in malaria-endemic areas. Because it’s not an insecticide, the compound isn’t predicted to have cascading effects by removing or poisoning a food source for animals that eat mosquitoes, such as bats, birds, fish, frogs and turtles.
When used in conjunction with existing vaccines, human antimalarials and insecticides, treating mosquitoes could be the next breakthrough needed to pull malaria prevalence back toward a downward decline.
“We’ve been thinking too narrowly in the past,” Dinglasan says. “If we remove that human-centric lens and think more broadly about treating all mosquitoes, we could potentially get rid of these parasites.”
By: DeLene Beeland