Mosquito Protein Quality Control System Offers New Antimalarial Target

A molecular quality-control system in Anopheles mosquitoes—the species responsible for most of the world’s malaria cases—is a promising target for future malaria-control strategies, according to a study led by researchers at the Johns Hopkins Bloomberg School of Public Health.

The researchers found that the protein quality-control system called the prefoldin chaperonin system in Anopheles mosquitoes is needed for malaria parasites to move efficiently through their life cycle within mosquitoes. Disrupting the prefoldin chaperonin system both reduced mosquitoes’ ability to host and transmit malaria parasites and killed about 60% of mosquitoes in laboratory experiments.

The researchers also found that the prefoldin chaperonin system is consistent across Anopheles mosquitoes, suggesting that their strategy could work in all the major malaria-endemic areas of the world.

The findings indicate that a vaccine that induces the human immune system to produce anti-prefoldin antibodies may one day be an effective way to achieve this disruption, the researchers say, although they note that this is many years away as a new vaccine would have to be developed. In the interim, a strategy using antibody-containing mosquito baits that mosquitoes can feed on might prove effective. 

The study was published online in Nature Microbiology on March 6.

“This study showcases a unique malaria-control strategy that should be very difficult for mosquitoes to develop resistance against and could be effective against all the mosquito and malaria parasite species that cause malaria in humans,” says study senior author George Dimopoulos, PhD, deputy director of the Johns Hopkins Malaria Research Institute at the Bloomberg School’s Department of Molecular Microbiology and Immunology.

There were about 263 million malaria cases and 597,000 malaria deaths in 2023, most of them children under age 5 in sub–Saharan Africa, according to the World Health Organization. Researchers are seeking additional anti-malaria strategies, as no single approach can eliminate the disease. While insecticides are generally effective, mosquitoes have developed resistance to these chemicals in recent decades. And while malaria vaccines are in use in Africa, their effectiveness is limited. 

Dimopoulos and his team uncovered the importance of the Anopheles prefoldin system using a screening technique in which they blocked the activities of different genes, one by one, in the main African malaria-transmitting mosquito, Anopheles gambiae. They found that silencing a gene called Pfdn6 or other genes encoding subunit proteins of the Anopheles prefoldin complex strongly reduced the mosquitoes’ ability to host malaria parasites, and also made the mosquitoes so sick that about 60% did not survive. Similar results were found for other Anopheles species including Anopheles stephensi, the main malaria-transmitting mosquito in Asia.

The team’s experiments revealed that disrupting the Anopheles prefoldin system led to a “leaky gut” condition in the insects. “In affected mosquitoes, microbes from the gut leak out into the circulatory system, leading to a systemic infection as well as a large inflammatory response, which in turn disrupts the malaria-parasite life cycle,” Dimopoulos says. “This systemic infection also killed about 60% of mosquitoes in our experiments.”

The researchers also showed that a vaccine strategy could be effective in disrupting the mosquito gut and blocking malaria parasite transmission: When they vaccinated mice with an Anopheles prefoldin protein, Anopheles mosquitoes that fed on the mice—taking up the anti-prefoldin antibodies—lost much of their ability to host and transmit P. falciparum parasites.

Disrupting Anopheles prefoldin proteins worked against multiple malaria-parasite species, including the main human-infecting African malaria parasite, Plasmodium falciparum, and the most prevalent human-infecting malaria parasite outside Africa, Plasmodium vivax. The researchers found that their strategy was effective even against the evolutionarily distant Plasmodium berghei, a mouse-infecting malaria parasite commonly used as a laboratory model.

The researchers now are pursuing further development of their vaccine strategy. One necessary element of its success, Dimopoulos says, will be to precisely select for mosquito prefoldin proteins, so that the vaccine doesn’t disrupt human proteins as well. If that selectivity can be achieved, the new strategy will have the great advantage that it can target—for example in a polyvalent vaccine—multiple prefoldin subunits, which should virtually eliminate the mosquito’s ability to evolve resistance.

Reference: Dong Y, Kang S, Sandiford SL, et al. Targeting the mosquito prefoldin–chaperonin complex blocks Plasmodium transmission. Nat Microbiol. 2025. doi: 10.1038/s41564-025-01947-3

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