Transcriptome Patterns from Primary Cutaneous Leishmania braziliensis Infections Associate with Eventual Development of Mucosal Disease in Humans

Abstract

IntroductionLocalized Cutaneous Leishmaniasis (LCL) and Mucosal Leishmaniasis (ML) are two extreme clinical forms of American Tegumentary Leishmaniasis that usually begin as solitary primary cutaneous lesions. Host and parasite factors that influence the progression of LCL to ML are not completely understood. In this manuscript, we compare the gene expression profiles of primary cutaneous lesions from patients who eventually developed ML to those that did not.MethodsUsing RNA-seq, we analyzed both the human and Leishmania transcriptomes in primary cutaneous lesions.ResultsLimited number of reads mapping to Leishmania transcripts were obtained. For human transcripts, compared to ML patients, lesions from LCL patients displayed a general multi-polarization of the adaptive immune response and showed up-regulation of genes involved in chemoattraction of innate immune cells and in antigen presentation. We also identified a potential transcriptional signature in the primary lesions that may predict long-term disease outcome.ConclusionsWe were able to simultaneously sequence both human and Leishmania mRNA transcripts in primary cutaneous leishmaniasis lesions. Our results suggest an intrinsic difference in the immune capacity of LCL and ML patients. The findings correlate the complete cure of L. braziliensis infection with a controlled inflammatory response and a balanced activation of innate and adaptive immunity.

The past, present, and future of Leishmania genomics and transcriptomics

“…The outcomes from this study highlighted significant upregulation of genes involved in biological pathways linked to the recruitment and activation of immune cells (including lymphocytes, granulocytes, natural killer cells, and antigen-presenting cells) and to regulation of inflammatory responses in tissues from subjects with CL [24]. This suggested that the inability of the host to mount effective immune responses against the parasite at the site of cutaneous infection is linked to the progression of disease [24]. In an effort to characterise differences in macrophage gene expression that might contribute to the ability of different Leishmania spp.…”

Blood Transcriptional Profiling Reveals Immunological Signatures of Distinct States of Infection of Humans with Leishmania infantum

“…Similar numbers of patients infected with L . braziliensis and controls were evaluated by pioneering studies that not only identified unique transcriptional signatures, but were also able to recapitulate previously described immunopathological responses in lesions of individuals with cutaneous leishmaniasis [21,22,40]. Of note, samples from patients under remission of disease were collected during distinct time points after the beginning of therapy, which could influence their blood transcriptional profiles.…”

“…Genome-wide profiling strategies have been employed to evaluate in vitro systems of infection with Leishmania and in vivo models of VL [17–20], while studies in humans are limited to biopsies from patients with cutaneous leishmaniasis [21,22]. We hypothesized that a global overview of gene expression in the peripheral blood of humans presenting with distinct states of infection with L .…”

Quantitative Kinetoplast DNA Assessment During Treatment of Mucosal Leishmaniasis as a Potential Biomarker of Outcome: A Pilot Study

“…Future longitudinal studies should evaluate host-related factors such as inflammatory and immune responses, which play a major role in the development and prognosis of ML. [27][28][29] Studies comparing cellular and cytokine responses in peripheral blood mononuclear cells stimulated with L. (V.) braziliensis antigens during active disease and after clinical cure have identified possible beneficial immunological parameters associated with clinical cure of ML. [28][29][30] In addition, immunologic studies of ML lesions from patients that evolved to cure or treatment failure have provided markers that may be useful for predicting treatment outcome of ML.…”

“…[27][28][29] Studies comparing cellular and cytokine responses in peripheral blood mononuclear cells stimulated with L. (V.) braziliensis antigens during active disease and after clinical cure have identified possible beneficial immunological parameters associated with clinical cure of ML. [28][29][30] In addition, immunologic studies of ML lesions from patients that evolved to cure or treatment failure have provided markers that may be useful for predicting treatment outcome of ML. 31,32 Certainly, combining the assessment of human immune response markers, PL kinetics in tissue before, during, and after treatment, and parasitic factors that may contribute to clinical treatment failure (e.g., infecting Leishmania species, parasite adaptations such as virulence or quiescence [reviewed in 21]) will contribute to better understanding the prognosis of ML and to identifying host and parasite biomarkers of outcome.…”