Research ArticleLeishmaniasis

Variable gene expression and parasite load predict treatment outcome in cutaneous leishmaniasis

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Science Translational Medicine  20 Nov 2019:
Vol. 11, Issue 519, eaax4204
DOI: 10.1126/scitranslmed.aax4204

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Calling healing lesions

Cutaneous leishmaniasis results in skin sores that can be difficult to treat, resulting in further complications. Amorim et al. performed dual RNA sequencing of host and parasite gene expression in pretreatment lesional skin biopsies from two cohorts of patients infected with Leishmania braziliensis. A prognostic signature comprising expression of three cytolytic genes plus pathogen load predicted treatment response in both cohorts and could potentially be used to triage patients who are unlikely to respond to conventional treatment as candidates for alternate therapies. This study also provides evidence that inflammasome-mediated IL-1β production influences treatment outcome in patients, strengthening the argument that therapies targeting these components could treat cutaneous leishmaniasis.

Abstract

Patients infected with Leishmania braziliensis develop chronic lesions that often fail to respond to treatment with antiparasite drugs. To determine whether genes whose expression is highly variable in lesions between patients might influence disease outcome, we obtained biopsies of lesions from patients before treatment with pentavalent antimony and performed transcriptomic profiling on these clinical samples. We identified genes that were highly variably expressed between patients, and the variable expression of these genes correlated with treatment outcome. 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. We demonstrated that treatment failure was linked to the cytolytic pathway activated during infection. Using a host-pathogen marker profile of as few as three genes, we showed that eventual treatment outcome could be predicted before the start of treatment in two separate cohorts of patients with cutaneous leishmaniasis (n = 21 and n = 25). These findings 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. This work more broadly demonstrates the value of identifying genes of high variability in other diseases to better understand and predict diverse clinical outcomes.

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