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Finding more effective ways to combat leishmaniasis by working with parasites

Finding possible solutions through working with parasites
Schematic representation of the experimental design. a Experimental conditions. Three experimental conditions were tested: WT and HR strains growing without drug challenge, and HR strains growing under drug challenge. Four types of samples were evaluated per experimental condition (input, monosome, light polysomes, and heavy polysomes). The experiment was done in three biologically independent replicates. A total of 36 (3X4X3 = 36) samples were used for RNA-seq followed by bioinformatic analysis. DESeq2 algorithm was used for differential translational analysis (DTA). Variant calling analysis (VCA) was used to detect gene variants exclusively present in HR strain using the FreeBayes algorithm. Then, the two bioinformatic analyses were matched based on the affected genes. b Detailed strategy for differential translational analysis (DTA) to estimate the basal changes in the translatome after the selection for drug resistance (basal changes), and changes associated with active drug resistance (changes to combat the drug). A total of six dual comparisons were performed including monosomes, and light and heavy polysomes. c Differential expression analyses were independently performed to identify changes in the total transcriptome (total mRNA used as input for polysome profiling) and translatome (heavy polysomes fraction). The identified genes were matched and classified into four groups. Group 1: genes that were detected as differentially expressed only in heavy polysomes. Group 2: genes that were detected as differentially expressed only in the total transcriptome. Group 3: genes that were detected as differentially expressed in both total transcriptome and heavy polysomes. Group 4: genes that were not differentially expressed. Credit: Nature Communications (2023). DOI: 10.1038/s41467-023-38221-1

Zemfira Karamysheva wanted to understand why a 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.

"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 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."

There are three major types of the disease: one that affects the skin, one that attacks the 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 .

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," she said, "and there are many processes affected during . These 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 were activated at multiple levels."

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.

More information: Sneider Alexander Gutierrez Guarnizo et al, Translational reprogramming as a driver of antimony-drug resistance in Leishmania, Nature Communications (2023). DOI: 10.1038/s41467-023-38221-1

Journal information: Nature Communications

Citation: Finding more effective ways to combat leishmaniasis by working with parasites (2023, June 1) retrieved 27 September 2023 from
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