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Host Expression Provides Treatment Response Clues in Cutaneous Leishmaniasis

NEW YORK – Using skin biopsy-based gene expression profiling, a team from the US and Brazil has identified host genetic features that seem to coincide with response to treatment for cutaneous leishmaniasis — a serious skin condition caused by Leishmania parasites that are transmitted by sand flies.

The new research builds on previous studies and "is allowing us to take the step from describing the biology of this disease to identifying which patients might need alternative treatments," co-senior author Phillip Scott, a pathobiology researcher and vice dean at the University of Pennsylvania's School of Veterinary Medicine, said in a statement.

For a paper appearing in Science Translational Medicine, he and his colleagues did RNA sequencing on pre-treatment skin biopsy samples from dozens of individuals from Brazil with or without Leishmania braziliensis infections. Along with relatively subtle differences in parasite load in patients with distinct responses to the current standard of care in Brazil — a pentavalent antimony treatment — they saw variable expression for hundreds of genes in treatment responders and non-responders, including genes from immune signaling, cytolytic, and inflammatory pathways.

"Among the most variable genes in all the patients were components of the cytolytic pathway, and the expression of these genes correlated with parasite load in the skin," Scott and his co-authors wrote, noting that "treatment failure was linked to the cytolytic pathway activated during infection."

Through a series of follow-up analyses, the team took a closer look at the biological pathways at play in host samples and in parasites when treatment response was poor, while whittling down the differentially expressed gene set to a handful of the genes for predicting treatment outcome.

"In addition to identifying pathways leading to disease in patients infected with L. braziliensis, this study identified potential markers of treatment failure," the authors reported, "which could have a significant impact on patient treatment."

Past studies suggest that individuals who do not respond to L. braziliensis treatments are at risk of developing chronic infections marked by excess inflammatory CD8 T immune cell responses, the team explained.

In an effort to first find transcriptomic features that distinguished cutaneous leishmaniasis cases from controls, the researchers did RNA-seq on pre-treatment skin biopsy samples from 21 cutaneous leishmaniasis patients and seven unaffected controls, identifying almost 4,300 genes expressed at different levels in the infected individuals. The set included genes from cytotoxicity, B cell activation, and other pathways.

Some of the same pathways turned up in subsequent analyses placing patient transcriptomes side by side. From more than 2,000 genes with enhanced expression in leishmaniasis lesions, the team focused in on 250 of the most differentially expressed genes dubbed the "variable transcripts associated with lesions," or ViTALs set.

After 90 days of treatment, the researchers noted, Leishmania infections resolved for 14 of the 21 patients, but persisted for the remaining seven patients. That differential treatment response appeared to coincide with slight increases in parasite representation in resistant lesions, altered CD8 T cell and natural killer cell levels in hosts, and with altered skin expression of 31 ViTALs genes.

The set included eight genes from cytolytic machinery, T cell, and other pathways with significant ties to lack of treatment response in the new study and in cutaneous leishmaniasis cases profiled for a past study, the team reported, and just three of the genes appeared to predict pentavalent antimony treatment response with between 86 percent and 96 percent accuracy.

"We're moving into the realm of figuring out how to translate this to patients," co-senior author Daniel Beiting, a pathobiology researcher at UPenn's vet med school, said in a statement. "If we can quickly and non-invasively monitor the targets we found, it could be important not only for leishmaniasis, but potentially also for other skin diseases, like chronic wounds or psoriasis — anything where these genes are playing a role."

Indeed, he and his co-authors noted that the current results "raise the possibility of point-of-care diagnostic screening to identify patients at high risk of treatment failure and provide a rationale for a precision medicine approach to drug selection in cutaneous leishmaniasis."

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