Image by Peter H. Seeberger
Malaria-infected cell bursting
Progress is being made in the battle against malaria. From engineering a mosquito-killing fungus to discovering new anti-malaria targets, scientists are making advances on multiple malaria fronts.
And US aid to combat malaria is having a positive impact on reducing childhood mortality in 19 sub-Saharan countries. A few of the recent developments are described here.
Genetic engineering
Scientists developed a genetic technique that disrupts the heme synthesis pathway in Plasmodium berghei parasites, which could be an effective way to target Plasmodium parasites in the liver.
Heme synthesis is essential for P berghei development in mosquitoes that transmit the parasite between rodent hosts. However, the pathway is not essential during a later stage of the parasite’s development in the bloodstream.
So researchers produced P berghei parasites capable of expressing the FC gene. The FC (ferrochelatase) gene allows P berghei to produce heme. The parasites could develop properly in mosquitoes, but produced some FC-deficient parasites once they infected mouse liver cells.
FC-deficient parasites were unable to complete their liver development phase.
The team says this approach would be prophylactic, since malaria symptoms aren't apparent until the parasite leaves the liver and begins its bloodstream phase.
The team published its findings in PLOS Pathogens.
Mosquito-killing fungi
In a report that sounds almost like a science fiction story, researchers genetically engineered a fungus to kill mosquitoes by producing spider and scorpion toxins.
They suggest this method could serve as a highly effective biological control mechanism to fight malaria-carrying mosquitoes.
The researchers isolated genes that express neurotoxins from the venom of scorpions and spiders. They then engineered the genes into the fungus's DNA.
The researchers used the fungus Metarhizium pingshaensei, which is a natural killer of mosquitoes.
The fungus was originally isolated from a mosquito and previous evidence suggests it is specific to disease-carrying mosquito species, including Anopheles gambiae and Aedes aegypti.
When spores of the fungus contact a mosquito's body, the spores germinate and penetrate the insect's exoskeleton, eventually killing the insect host from the inside out.
And the most potent fungal strains, Brian Lovett, a graduate student at the University of Maryland in College Park, explained, “are able to kill mosquitoes with a single spore."
He added that the fungi also stop mosquitoes from blood feeding. Taken together, this means “that our fungal strains are capable of preventing transmission of disease by more than 90 percent of mosquitoes after just 5 days."
The fungus is specific to mosquitoes and does not pose a risk to humans. The study results also suggest the fungus is safe for honeybees and other insects.
The researchers plan to expand on-the-ground testing in Burkina Faso.
For more on this mosquito-killing approach, see their study published in Scientific Reports.
Potential new target
Researchers have described a new protein, the transcription factor PfAP2-I, which they say may turn out to be an effective target to combat drug-resistant malaria parasites.
PfAP2-I regulates genes involved with the parasite's invasion of red blood cells. This is a critical part of the parasite's 3-stage life cycle that could be targeted by new anti-malarial drugs.
“Most multi-celled organisms have hundreds of these regulators,” said lead author Manuel Llinás, PhD, of Penn State University in State College, Pennsylvania, “but it turns out, so far as we can recognize, the [Plasmodium] parasite has a single family of transcription factors called Apicomplexan AP2 proteins. One of these transcription factors is PfAP2-I."
PfAP2-I is the first known regulator of invasion genes in Plasmodium falciparum.
The new study also indicates that PfAP2-I likely recruits another protein, Bromodomain Protein 1 (PfBDP1), which was previously shown to be involved in the invasion of red blood cells.
The two proteins may work together to regulate gene transcription during this critical stage of infection.
For more on this potential new target, see their study published in Cell Host & Microbe.
Parasite diversity
Not all malaria infections result in life-threatening anemia and organ failure, and so a research team led by Matthew B. B. McCall, MD, PhD, of Erasmus Medical Center in Rotterdam, the Netherlands, set out to determine why.
They exposed 23 healthy human volunteers to sets of 5 mosquitoes carrying the NF54, NF135.C10, or NF166.C8 isolates of P falciparum.
All volunteers developed parasitemia, were treated with anti-malarial drugs, and recovered, although some strains caused more severe symptoms.
The investigators found that 3 geographic and genetically diverse forms of the parasite each demonstrated a distinct ability to infect liver cells.
They also observed the degree of infection in human liver cells growing in culture was closely correlated with parasite loads in the bloodstream.
The investigators believe the variability among parasite types suggests that malaria vaccines should use multiple strains.
In addition, the infectivity of different parasite strains could vary in populations previously exposed to malaria.
For more details on parasite diversity, see the team’s findings in Science Translational Medicine.
Malaria test
A new malaria test can diagnose malaria faster and more reliably than current methods, according to a report in the NL Times.
The new test uses an algorithm that can diagnose malaria at a rate of 120 blood tests per hour. It is 97% accurate.
Rather than search for the parasite itself in blood samples, the new test analyzes the effect the infection has on the blood, such as shape and density of red blood cells, hemoglobin level, and 27 other parameters simultaneously.
The developers won the European Inventor Award for the rapid malaria test, which will be further developed by Siemens.
Aid to combat malaria
The US malaria initiative in 19 sub-Saharan African countries has contributed to a 16% reduction in the annual risk of mortality for children under 5 years, according to a new study published in PLOS Medicine.
Thirteen sub-Saharan countries did not receive funding from the initiative, which allowed researchers to compare and analyze the impact of the intervention.
Because the study may have had confounding variables that were not measured, however, the results could not be definitively interpreted as causal evidence of the reduction in child mortality rates.
However, they do indicate an association between the receipt of funding and mortality.
The funding went to support malaria prevention technologies, such as insecticide-treated nets and indoor residual spraying.
The authors believe further investment in these interventions “may translate to additional lives saved, reduced household financial burdens associated with caring for ill household members and lost wages, and less strain on health systems associated with treating malaria cases.”
Countries that received funding included: Angola, Benin, Congo DRC, Ethiopia, Ghana, Guinea, Kenya, Liberia, Madagascar, Malawi, Mali, Mozambique, Nigeria, Rwanda, Senegal, Tanzania, Uganda, Zambia, and Zimbabwe.
Comparison countries include: Burkina Faso, Burundi, Cameroon, Chad, Congo, Cote d’Ivoire, Gabon, Namibia, Niger, Sierra Leone, Swaziland, The Gambia, and Togo.
