Variable gene expression and parasite load predict treatment outcome in 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.

Unbalanced production of LTB 4 /PGE 2 driven by diabetes increases susceptibility to cutaneous leishmaniasis

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Molecular signatures of anthroponotic cutaneous leishmaniasis in the lesions of patients infected with Leishmania tropica

“…Further, GSEA pathways involved in "induction of B-cell receptors" and "NF-κB activation in B cells" involved in B-cell development and activation 43 were positively enriched in the UCL group. Previous human studies have suggested that B-cell activation can lead to the exacerbation of CL disease 19,44 . The involvement of B-cell responses to Leishmania appears to be complex, and whether they participate in parasite persistence or killing remains unclear.…”

Differential expression of polyamine biosynthetic pathways in skin lesions and in plasma reveals distinct profiles in diffuse cutaneous leishmaniasis

“…Differentially expressed genes (DEGs) were examined by edgeR package 44 . The parasite burden from RNAseq data was measured by normalizing the library size 45 . The gene expression values used were the TMM-normalized log CPM values.…”