Plasmodium parasite

infecting a red blood cell

Image courtesy of St. Jude

Children’s Research Hospital

Researchers say they have documented how competition among different malaria parasite strains in human hosts could influence the spread of drug resistance.

“We found that when hosts are co-infected with drug-resistant and drug-sensitive strains, both strains are competitively suppressed,” said Mary Bushman, of Emory University in Atlanta, Georgia.

“Antimalarial therapy, by clearing drug-sensitive parasites from mixed infections, may result in competitive release of resistant strains.”

Bushman and her colleagues described these findings in Proceedings of the Royal Society B.

The researchers focused on the parasite Plasmodium falciparum, which has developed resistance to former first-line therapies chloroquine and sulfadoxine-pyrimethamine.

“We’re now down to our last treatment, artemisinin combination therapy, or ACT, and resistance to that recently emerged in Southeast Asia,” Bushman said. “If ACT resistance continues to follow the same pattern, the world may soon be without reliable antimalarial drugs.”

In addition, people infected with P falciparum often have multiple strains of the parasite, especially in high-transmission areas such as sub-Saharan Africa, where infectious mosquito bites occur frequently. Many people have developed partial immunity, making asymptomatic infections common and further complicating control efforts.

With previous work in lab mice, the researchers found that competition between mixed strains of malaria parasites were a crucial determinant to the spread of resistance.

“In the mouse studies, we found that drug-sensitive parasites suppress resistant parasites,” said Jaap de Roode, PhD, of Emory University.

“We also found that by clearing these sensitive parasites with drugs, the resistant parasites had a big advantage, growing up to high numbers and transmitting to mosquitoes at high rates. Ever since doing that work, I have wanted to see if the same could apply to humans.”

To find out, Dr de Roode and his colleagues analyzed 1341 blood samples from untreated children with malaria living in Angola, Ghana, and Tanzania.

The researchers extracted the DNA of malaria parasites from the blood samples and used polymerase chain reaction technology to determine the densities of drug-resistant strains and drug-sensitive ones. About 15% of the samples had mixtures of both types.

Analyses showed that, in mixed-strain infections, densities of chloroquine-sensitive and chloroquine-resistant strains were reduced in the presence of competitors.

The results also showed that, in the absence of chloroquine, the resistant strains had lower densities than sensitive strains.

“The results were really clear cut, which rarely happens in human studies,” Bushman said. “We found almost complete consistency between the 3 data sets [divided by country].”

Bushman added that the tendency is to use a “one-size-fits-all” strategy for controlling malaria, but this research suggests that more tailored approaches are needed.

For example, a strategy of mass drug administration might be effective in a place with a low prevalence of malaria and less likelihood of mixed-strain infections. However, that same strategy might actually boost drug resistance without reducing the burden of disease in areas where most of the population is infected with multiple strains of malaria parasites.

“The epidemiology of malaria infection is different for different places and different conditions,” Bushman said. “We hope that our work will spur development of new strategies to minimize resistance while maximizing the benefits of control measures.”

However, more questions must be answered to guide the development of these new strategies.

“As a first step, we need to determine if the observed suppression of resistance in humans also results in reduced transmission to mosquitoes,” Dr de Roode said.

Another avenue to explore is resistance among patients who have received antimalarial treatment.

“We need to find out if drug treatment of people infected with malaria removes competition and gives resistance a boost, as we have found in mice before,” Dr de Roode noted.

Parasite competition influences drug resistance