Researchers at the
Johns Hopkins Bloomberg School of Public Health have
for the first time
identified a molecular pathway that triggers an immune
response in multiple mosquito species that is
capable of stopping the development of Plasmodium
falciparum, the parasite that causes malaria in
humans.
By silencing the gene, caspar, the researchers were
able to block the development of the
malaria-causing parasite in Anopheles gambiae, A. stephensi
and A. albimanus mosquitoes, three
species that spread malaria in Africa, Asia and the
Americas. Their findings were published March 13
in PLoS Pathogens.
According to the study, the transcription factor Rel 2
is a key molecule involved in regulating
several potent anti-Plasmodium defense genes that attack
the parasite in the mosquito gut. Rel 2 is
activated by the immune deficiency pathway that, in turn,
is negatively regulated by the caspar gene;
when caspar is silenced, the Rel 2 is activated. The
researchers found that silencing of the caspar
gene through the manipulation of gene expression resulted
in mosquitoes that successfully blocked the
development of Plasmodium falciparum in the gut tissue.
Silencing the gene known as cactus, which is
part of another pathway called Toll, was shown to have
similar effect in controlling the development of
Plasmodium berghei, which causes malaria in rodents.
"When a mosquito is feeding on malaria-infected blood,
the parasite will be recognized by the
mosquito's immune system through receptors that then start
the immune response. In the wild, this
response is believed to occur too late to mount an
efficient immune defense that would kill all
parasites. At least a few Plasmodia will successfully
develop inside the mosquito and enable
transmission of malaria," said George Dimopoulos, senior
author of the study and associate professor
at the Johns Hopkins
Malaria Research Institute. "In the lab we activated
this immune response in
advance of infection, giving the mosquito a head start in
defeating the invading parasite."
Dimopoulos and his colleagues Lindsey Garver and
Yuemei Dong also found that Rel 2 activation
did not affect the survival and egg-laying fitness of the
modified mosquitoes.
"This came as a pleasant surprise since it essentially
means that we one day could spread this
trait in natural mosquito populations using genetic
modification. Furthermore, by activating Rel 2, the
genetically modified mosquitoes will attack the malaria
parasite with several independent immune
factors, and this will make it very difficult for
Plasmodium to develop resistance," Dimopoulos said.
Malaria kills more than 1 million people worldwide
each year.
The study was written by Garver, Dong and Dimopoulos.
Funding was provided by National
Institutes of Health, National Science Foundation and Johns
Hopkins Malaria Research Institute.