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Modified Mosquitos May Help Curb Malaria

Anopheles stephensi mosquito larvae (left), pupa (center), and adults expressing the malaria parasite-blocking SM1 gene (indicated by the green fluorescent marker) introduced by researchers. (Photos courtesy of Marcelo Jacobs-Lorena, Case Western Reserve University.)

Imagine this: a swarm of mosquitoes is released near a village in an area where malaria has been endemic for decades. Instinctively seeking out blood meals to nourish their eggs, some of these insects zero in on the villagers’ exposed limbs. As they dine here and there, several hungry mosquitoes pick up the dreaded malaria parasites. But they don’t pass the protozoa on to people they subsequently bite. Rather, the parasites languish, arrested in the mosquitoes’ bodies. As the newcomers and their offspring mate with native insects, the area’s mosquito population gradually loses its competence to transmit malaria. The disease disappears.

Sound like science fiction? It is for now, but a team of scientists has brought such a scenario closer to reality with the creation of genetically engineered mosquitoes that successfully thwart the malaria parasite’s escape from the midgut and entry into the salivary glands. The research was presented by Marcelo Jacobs-Lorena of Case Western Reserve University, Cleveland, Ohio, at the 10th annual meeting of the International Centers for Tropical Disease Research Network on 7-9 May.

The key to this technology is a peptide dubbed SM1 that binds to receptors on the inner lining of the midgut and outer lining of the salivary glands. SM1 works like numerous molecular pieces of gum jammed into the specific keyholes the protozoa need to unlock in order to cross these tissues. " It’s not at all harmful to the parasite,’’ Jacobs-Lorena explains. "It doesn’t kill the parasites. It acts by blocking invasion of the host tissues.’’

Twice during the parasites’ life cycle in their insect vector, they must pass through host tissues, first when in the form of ookinetes they traverse the midgut epithelium to enter the hemolymph and later when as sporozoites they enter the salivary glands to position themselves for transmission through the insect’s bite. Blocking the parasites at either stage would prevent spread of the disease, the researchers reasoned. So they injected millions of phages, each displaying a unique peptide on its surface, into mosquitoes and selected those molecules that bound specifically to the insects’ salivary glands or midgut lumen. SM1 bound tightly and specifically to both tissue linings.

That SM1 binds so strongly to these two different epithelial surfaces—and not to any other organs—came as a bit of a surprise. "There must be a specific receptor on these surfaces, but we don’t know what it is,’’ Jacobs-Lorena says.

The team inserted a gene for SM1 into germline cells of Anopheles stephensi embryos. A gut-specific carboxypeptidase promoter joined to the SM1 gene ensured targeted expression of the peptide in the midgut. A separate construct with a vitellogenin promoter targeted expression of the SM1 gene to the body cavity of the mosquito, enabling binding to the salivary glands. Examination of the resultant adult mosquitoes’ midguts and salivary glands showed that SM1 had bound across the entire targeted surfaces.

When the researchers tested the transgenic mosquitoes’ ability to spread Plasmodium burghei to mice, they achieved an average of 85% blockage of the protozoa in the midgut and between 85 and 97% blockage in the salivary glands.

Whether the technology would work as effectively in blocking transmission of the principal human malaria pests, P. falciparum and P. vivax, remains to be seen. However, Jacobs-Lorena notes that these parasites are carried by Anopheles gambiae, which the team initially used to screen the phage display library, switching to A. stephensi because the mouse parasite, P. berghei, grows better in that species. "Since SM1 binds as effectively to gambiae surfaces, we assume that it would work as well in blocking falciparum and vivax,’’ he says, assuming that these species rely on the same key receptors to pass through their host’s tissues.

A bigger concern facing the team is figuring out how to drive the new genes into wild mosquito populations in the field. "The idea would be to come into a target area and wipe out as much of the mosquito population as possible with insecticide spraying,’’ Jacobs-Lorena says. "Then you would release mosquitoes with the SM1 gene,’’ he explains. Ideally, the transgenic mosquitoes would mate with any remaining wild-type mosquitoes, passing on the transgene to all offspring. He and his colleagues are also exploring methods to spread the genes through natural populations, such as linking the SM1 gene to a transposon that would boost its multiplication in hosts.

But skeptics object that there would always be at least some untransformed insects left that could spread malaria. Moreover, it is not yet known how well the transgenic mosquitoes can compete with their wild-type cousins. "A high priority now is determining whether this gene puts any fitness burden on mosquitoes,’’ Jacobs-Lorena says. "From initial observations, my guess is that there will be little or no load.’’

Although the prospect of genetically engineered mosquitoes buzzing about might still seem a far-fetched notion, Jacobs-Lorena notes the consensus opinion that multiple approaches will be needed to combat malaria. "Even if we found a great drug or vaccine, we’ll need to attack the problem from many sides because malaria transmission is so effective.’’ As he points out, the disease has stubbornly frustrated efforts to develop new treatments and vaccines and steadily increasing resistance to the available arsenal of drugs and insecticides demands the pursuit of innovative solutions.

Christine Stencel