Study uncovers how Leishmania parasite adapts so quickly to drugs

Scientists probing the Leishmania parasite’s gene expression regulation during mRNA translation have discovered how it is able to preemptively and quickly adapt and respond to drug treatments.

Zemfira Karamysheva wanted to understand why the parasitic-borne disease can resist drugs so successfully in hopes of eventually applying the findings to treat humans.

“When the parasite is transmitted to a mammalian host through the bite of an insect, a huge change takes place because they are exposed to higher temperatures, the nutrition is different and the pH is different,” said Karamysheva, a research associate professor in Texas Tech University’s Department of Biological Sciences. “The lifestyles are totally different, and we wanted to know how these parasites go from their insect vector to a mammalian host and survive.”

Her laboratory at Texas Tech, as well as two others, that of Andrey Karamyshev, an associate professor in the School of Medicine at the Texas Tech University Health Sciences Center, and that of Carlos Muskus, a professor at the University of Antioquia in Colombia, collaborated on the research. The focus was Leishmania, a parasite that causes leishmaniasis, and their work has recently been published in the journal Nature Communications.

No good treatment

“There is no good treatment,” Karamysheva said. “It is transmitted through insect bites and can infect humans and different animals. It is already endemic in Texas, and people are not aware this is a problem. As a result, physicians are sometimes not familiar with how to diagnose it.”

Leishmaniasis is found throughout Latin America and Asia, but climate change has allowed it to become common in some parts of Texas.

“Dr. Karamysheva’s research on leishmaniasis and possible treatment will make a remarkable impact on those who are afflicted with this disease in the future,” said Tosha Dupras, dean of the College of Arts & Sciences. “We are very proud of the important and impactful research that Dr. Karamysheva is conducting in her field.”

Three major types

There are three major types of the disease: one that affects the skin, one that attacks the mucous membranes and one that focuses on internal organs and, if untreated is almost always fatal. About 12 million cases are known worldwide with 1 million new cases added each year. Approximately 30,000 deaths result around the world each year.

The focus of their research was on the parasite’s gene expression regulation during mRNA translation. Information in organisms is carried from genes to messenger RNA (mRNA) molecules, where the info is translated into proteins by ribosomes in the process of protein synthesis.

The scientists discovered two remarkable facts. First, they found the protein synthesis process (or mRNA translation) was very different in comparison with sensitive parasites. More than 2,000 genes changed how they expressed their information. It means the parasite is able to preemptively and quickly adapt and respond to drug treatments.

Targeted response

Second, when they compared resistant parasites’ response to the drug, they found it was much more targeted with only 189 genes changing how they expressed information. The drug produced a highly targeted response, and the researchers were able to look at which processes were affected as a result.

“We found they have a multifaceted response, and there are many processes affected during drug resistance. These parasites changed. They could pump the drug out more effectively or the drug uptake was reduced. The information was modulated in such a way as to avoid the effect of the drug. Their defense systems were activated at multiple levels,” she said.

As a result, more targeted drug treatments could be effective against the parasite. For example, future work could aim at removing certain genes, interrupting the flow of information and eliminating its previous resistance to a drug.