The authors of two separate studies have expressed their concern about increasing malaria transmission potential, pointing to recent mutations against an antimalarial drug and how the mosquito’s natural blood feeding behaviour shortens the parasite’s incubation time.
Malaria causes about 435,000 deaths each year, primarily in young children in sub-Saharan Africa. Despite a long-term global response, efforts to control the disease are hampered by the rise of drug-resistant strains of the parasite species that cause malaria. Sulfadoxine-pyrimethamine (SP), for example, was once a first-line antimalaria treatment, but now primarily is used to prevent infection in pregnant women and children.
Mutations in two genes in the parasite Plasmodium falciparum offer resistance to SP, but recently mutations related to resistance were discovered in a third gene, pfgch1. To understand the extent and spread of these new mutations, researchers from The London School of Hygiene & Tropical Medicine (LSHTM) analysed genome sequences from 4134 blood samples collected from 29 countries where malaria is endemic. They discovered at least 10 different versions of pfgch1, which occur in about one-quarter of the samples from Southeast Asia and in one-third of the samples from Africa, where strains carrying the mutations may be on the rise.
Writing in the journal PLOS Genetics, the researchers said the growth in the number of malaria parasites with pfgch1 mutations is concerning, because the mutations enhance resistance to SP and may encourage the evolution of new resistant strains. As a result, their growth may threaten efforts to use SP to prevent malaria in vulnerable groups.
“SP is an established drug for malaria prevention and treatment in vulnerable groups such as pregnant women and children,” said study co-author Colin Sutherland, Co-Director of the LSHTM Malaria Centre. “We may have underestimated its vulnerability to parasite resistance, as these new data show.”
With the identification of these pfgch1 mutations through the new study, scientists can at least monitor their presence in parasite populations, to understand where SP can be used effectively, and where rates of drug resistance are already too high. As noted by study leader Taane Clark, “We need to understand how these mutations work and monitor them as part of malaria surveillance programs.”
Meanwhile, researchers from the Harvard T.H. Chan School of Public Health and Virginia Tech have reported in PLOS Pathogens that multiple bouts of blood feeding by mosquitoes shorten the incubation period for malaria parasites and increase malaria transmission potential. Given that mosquitoes feed on blood multiple times in natural settings, the results suggest that malaria elimination may be substantially more challenging than suggested by previous experiments, which typically involve a single blood meal.
In natural settings, the female Anopheles gambiae mosquito — the major malaria vector — feeds on blood multiple times in her lifespan. Such complex behaviour is regularly overlooked when mosquitoes are experimentally infected with malaria parasites, limiting our ability to accurately describe potential effects on transmission. In the new study, the researchers examine how additional blood feeding affects the development and transmission potential of Plasmodium falciparum malaria parasites in An. gambiae females.
“We wanted to capture the fact that, in endemic regions, malaria-transmitting mosquitoes are feeding on blood roughly every 2–3 days,” said W Robert Shaw, a lead author on the study from the Harvard T.H. Chan School of Public Health. “Our study shows that this natural behaviour strongly promotes the transmission potential of malaria parasites, in previously unappreciated ways.”
The results show that an additional blood feed three days after infection with P. falciparum accelerates the growth of the malaria parasite, thereby shortening the incubation period required before transmission to humans can occur. Incorporating these data into a mathematical model across sub-Saharan Africa reveals that malaria transmission potential is likely higher than previously thought, making disease elimination more difficult.
In addition, parasite growth is accelerated in genetically modified mosquitoes with reduced reproductive capacity, suggesting that control strategies using this approach, with the aim of suppressing Anopheles populations, may inadvertently favour malaria transmission. The data also suggests that parasites can be transmitted by younger mosquitoes, which are less susceptible to insecticide killing, with negative implications for the success of insecticide-based strategies.
Taken together, the results suggest that younger mosquitoes and those with reduced reproductive ability may provide a larger contribution to infection than previously thought. According to the authors, the findings have important implications for accurately understanding malaria transmission potential and estimating the true impact of current and future mosquito control measures.