ORLANDO – Stopping the cycle by which the Plasmodium parasite spreads from people to mosquitoes and back to people could be the key to controlling malaria, according to scientists who have developed what may be a strategy for doing just that.
Dr. John G. Quigley and his coinvestigators are targeting a protein called FLVCR that mosquitoes express after feasting on blood. FLVCR protects cells from the toxicity of excess heme, or iron, a part of hemoglobin that binds and transports oxygen in red blood cells.
The ongoing study aims to induce oxidative stress in the midgut of malaria-transmitting mosquitoes by inhibiting the heme-exporting function of FLVCR. As a consequence, the midgut should become inhospitable to the blood-borne parasite, causing it to die instead of reproducing, Dr. Quigley explained in a plenary presentation at the annual meeting of the American Society of Hematology.
Ultimately, the goal is to create an FLVCR-suppressing vaccine for use in humans in areas where malaria is widespread, he said. The vaccine would not protect the person who is already infected, but it would break the cycle of transmission if that person is bitten by a mosquito.
"It’s called the altruistic vaccine because it’s not actually protecting you, but it is preventing the mosquito from infecting the next person," Dr. Quigley of the University of Illinois at Chicago said in an interview.
FLVCR – an abbreviation for feline leukemia virus subgroup C receptor – was initially isolated as a cause of severe anemia in cats, he said. Working with two common malaria-transmitting mosquitoes (Anopheles gambiae and A. stephensi), the Chicago-based group of scientists at the University of Illinois and Loyola University isolated the gene encoding mosquito FLVCR proteins.
The researchers conducted a series of studies, verifying that the proteins export heme and could protect cells from the oxidative stress that results when too much free heme overloads cells with reactive oxygen species (ROS). They also showed that anopheline FLVCR is highly expressed after a mosquito gorges on blood.
If the mosquito bites an infected person, this blood will contain anywhere from 10,000 to 100,000 parasites, most of which are unable to reproduce, according to Dr. Quigley. Only 20-100 will be fertilized successfully and invade the midgut, but their fertilized eggs develop into Plasmodium cysts (or oocysts) that release thousands of parasites after maturing for 1-3 weeks in the mosquito gut. These offspring then travel to the mosquito’s salivary gland from which they are transmitted via the insect’s next bite.
"You are trying to kill the parasite ... the idea is to interfere with the invasion of the gut epithelium," Dr. Quigley said, characterizing the blood drinking as "a major bottleneck" and "the weakest point" in the process.
The researchers so far have developed an antibody "that appears to bind (and likely inhibit) FLVCR in vivo." They also have used gene-silencing techniques to "knock down" FLVCR gene expression. The next step will be to analyze the effects on parasite transmission, and if those show FLVCR is required, develop a vaccine to block transmission. If this is successful, the mosquito would no longer be a womb but a tomb for Plasmodium.
"Disruption of FLVCR function may be an ‘Achilles heel’ of blood-eating disease vectors," Dr. Quigley said.
Dr. Alexis Thompson
Such a vaccine could have a major impact on public health globally, commented Dr. Alexis Thompson, who moderated a press briefing on the research. Malaria infects 250 million people, causing 1 million deaths annually, noted Dr. Thompson, director of hematology services at Children’s Memorial Hospital, Chicago.
"This is a global problem that the United States really has an opportunity to contribute to solving," she said. Even in the United States, she added, despite widespread belief that draining swamps in Florida and Louisiana eliminated malaria, a small number of cases are seen each year.
The authors said they had no relevant conflicts to disclose.