Study Uncovers Genetic Factors Behind Leishmaniasis Outcomes

Patients with cutaneous leishmaniasis often undergo burdensome courses of therapy, with many failing multiple courses and requiring alternative treatments. Treatment for the parasitic infection, which is transmitted by phlebotomine sand flies, presents risks for side effects ranging from irritation to serious complications.

A new study, published in Science Translational Medicine, reveals that genetic testing can identify patients unlikely to respond to conventional treatments, allowing clinicians to find candidates for alternative therapies ahead of time. The study also provides evidence that inflammasome-mediated IL-1β production affects treatment outcomes, which suggests therapies targeting these components may be useful for the patient population.

The study team, led by experts from the University of Pennsylvania School of Veterinary Medicine and investigators from Brazil, found biomarkers that predicted treatment response in 2 cohorts of patients infected with Leishmania braziliensis.

Investigators predicted that treatment outcome could be predicted by looking at variations in the magnitude of expression of cytolytic genes, which are induced early in cutaneous leishmaniasis lesions. The team performed RNA sequencing of lesion biopsies to address their hypothesis.

RNA sequencing was performed on 21 patients with Leishmania braziliensis infections and 7 uninfected endemic controls. Investigators found 4225 genes differentially expressed between the 2 groups, which they narrowed down to the top 250 most variable. They then identified a subset which correlated with treatment failure, and in comparisons with a second data set from 25 other patients, confirmed that 8 of the genes identified were predictive of treatment failure in both groups.

The study team also used genetic sequencing methods to determine the number of parasites in patient samples. In keeping with previous studies, their analysis revealed that lesions tend to contain a small number of parasites. Yet they also discovered that precisely how few parasites were found mattered to treatment outcomes.

“Very few versus very, very few apparently makes a difference. There's a small but significant cut-off between failure and cure,” Phillip Scott, PhD, professor of microbiology and immunology at the University of Pennsylvania School of Veterinary Medicine, and a co-senior author of the study, said in a press release.

Another co-senior author, Daniel P. Beiting, PhD, assistant professor at the University of Pennsylvania School of Veterinary Medicine, discussed the possibilities for future research and expansion of the study results to different conditions in the press release.

“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.”