A team of researchers led by Dr. John Adams from the USF College of Public Health (COPH) have recently published an article looking at the pathways some deadly malaria-causing parasites use to survive not just human fever—the body’s natural defense against pathogens—but also the drugs designed to attack them.

The article, “The apicoplast link to fever-survival and artemisinin-resistance in the malaria parasite,” was published in the journal Nature Communications in July. The study’s three lead authors are the COPH’s Drs. Min Zhang, Chengqi Wang and Jenna Oberstaller, all of whom work in the college’s Center for Global Health and Infectious Disease Research and USF genomics program.

Malaria is still the most devastating parasitic disease of humans, with over 200 million cases each year. Resistance to frontline antimalarial drugs, such as artemisinin, is rising—threatening to undo decades of progress against the disease.

“There are no other drugs poised to replace artemisinin, and it’s critical we continue to study parasite biology to find weaknesses we can exploit to develop new interventions,” Dr. Oberstaller emphasized. “Ideal targets would be parasite-specific, as they would provide fewer worries about off-target effects on humans. We focused on studying how parasites survive human fever because the ability to survive such harsh conditions is a fairly unique talent—which we hypothesized to involve unique parasite pathways essential for parasite survival that could be promising targets for intervention.”

The research employed the use of a genome-editing technique called piggyBac-transposon mutagenesis that the team previously used to uncover genes essential for malaria parasite survival in ideal conditions.

“This technology was also successfully applied here to study parasite growth in response to human febrile temperatures,” Dr. Zhang said. “More than 200 piggyBac-mutant parasites were identified with differential responses to increased temperature, allowing us to determine which genes drive parasite survival of fever.”

Unexpectedly, the researchers discovered that malaria parasites use ancient pathways co-opted from plants to survive human fever—and further, they are now repurposing the same pathways to evolve resistance to front-line antimalarial drugs. A small parasite organelle derived from algae, called the apicoplast, is the key to surviving both the heat and artemisinin derivatives.

“We noticed similarities between processes driving parasite fever-response and the mechanism of drug resistance to artemisinin—which made us investigate the connection further. We discovered that parasite genes with plant orthologs [genes in two different species that evolved from the same ancestral gene] tend to increase their expression level in response to fever conditions, and many of those same genes are also increased in drug-resistant parasites taken from clinical patients,” Drs. Wang and Oberstaller said. “This leads us to speculate that these ancestral genes enable parasite survival of extreme temperatures and artemisinins.”

The research will help scientists develop multiple antimalarial drugs that target multiple, unrelated pathways.

“Knowing not only how a drug works, but also which pathway(s) it targets, enables us to develop the smartest types of intervention,” Dr. Oberstaller explained. “This will lead to better combination therapies to combat emerging resistance.”

Story by Donna Campisano, USF College of Public Health