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Going Molecular on Mosquitoes

By Marie-Claire Gwayi-Chore

Complementing current efforts deployed against malaria—drugs, bed nets, insecticides and others—two new pieces of the malaria puzzle have been discovered by researchers at the Johns Hopkins Malaria Research Institute (JHMRI). The discoveries target two key events in the transmission cycle, one that occurs in the mosquito’s midgut, and one that takes place in the mosquito’s salivary glands.

As part of the transmission cycle, Plasmodium, the malaria parasite, reproduces in and on the mosquito’s midgut. Typically, the mosquito’s immune system attacks Plasmodium, but does so too late to kill all of the parasites. But what if the mosquito were better at killing the parasite in its gut? George Dimopoulos, PhD, associate professor in the W. Harry Feinstone Department of Molecular Microbiology and Immunology (MMI), and colleagues have discovered how to make the mosquito mount a better defense. Their study shows that the mosquito’s defense against Plasmodium is activated by the protein known as Rel 2, which is ultimately regulated by the caspar gene. When caspar is expressed, Rel 2 is suppressed; likewise, when caspar is silenced, Rel 2 is activated, and the mosquito launches a successful defense against the parasite. Dimopoulos and colleagues used a method known as RNAi (RNA interference) to silence the caspar gene, and the results were good—the mosquito’s immune defense prevailed against Plasmodium. Even better news is that by activating Rel 2, not just one, but several, immune defenses are launched: “This will make it very difficult for Plasmodium to develop resistance,” says Dimopoulos.

Another discovery, by Marcelo Jacobs-Lorena, PhD, and Nirbhay Kumar, PhD, both professors in MMI and JHMRI, targets the disease later in the transmission cycle, after the parasites have traveled from the mosquito’s gut to the salivary glands. While scientists have known for some time about the parasite’s infection of the salivary glands, little has been known about the specific molecular activity that takes place during the infection. Jacobs-Lorena, Kumar and colleagues identified for the first time a mosquito salivary protein known as saglin, which acts as a receptor for a protein produced by the parasite. In binding, the two proteins make the salivary gland vulnerable to invasion by the parasite. As part of the study, the researchers were able to switch off the expression of saglin, which reduced salivary gland invasion. By targeting saglin and turning it off, scientists may be able to reduce or even halt the transmission of malaria when the mosquito takes its bloodmeal from humans.

Having identified new molecular targets, both discoveries provide incentive to do further research on transgenic mosquitoes—and how they could be introduced into wild populations.

A multifaceted attack on malaria is required, says Jacobs-Lorena: “We need to implement a concerted effort in using all the weapons we have available: drugs, bed nets, insecticides, transgenics, vaccines—if we use it all, there is hope of eliminating malaria one day.”