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

ABSTRACT: Anthroponotic cutaneous leishmaniasis (CL) caused by Leishmania tropica (L. tropica) represents a public health challenge in several resource poor settings. We herein employed a systems analysis approach to study molecular signatures of CL caused by L. tropica in the skin lesions of ulcerative CL (UCL) and non-ulcerative CL (NUCL) patients. Results from RNA-seq analysis determined shared and unique functional transcriptional pathways in the lesions of the UCL and NUCL patients. Several transcriptional pathways involved in inflammatory response were positively enriched in the CL lesions. A multiplexed inflammatory protein analysis showed differential profiles of inflammatory cytokines and chemokines in the UCL and NUCL lesions. Transcriptional pathways for Fcγ receptor dependent phagocytosis were among shared enriched pathways. Using L. tropica specific antibody (Ab)-mediated phagocytosis assays, we could substantiate Ab-dependent cellular phagocytosis (ADCP) and Ab-dependent neutrophil phagocytosis (ADNP) activities in the lesions of the UCL and NUCL patients, which correlated with L. tropica specific IgG Abs. Interestingly, a negative correlation was observed between parasite load and L. tropica specific IgG/ADCP/ADNP in the skin lesions of CL patients. These results enhance our understanding of human skin response to CL caused by L. tropica.

SUBMITTER: Masoudzadeh N

PROVIDER: S-EPMC7529897 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Masoudzadeh Nasrin N Östensson Malin M Persson Josefine J Mashayekhi Goyonlo Vahid V Agbajogu Christopher C Taslimi Yasaman Y Erfanian Salim Reza R Zahedifard Farnaz F Mizbani Amir A Malekafzali Ardekani Housein H Gunn Bronwyn M BM Rafati Sima S Harandi Ali M AM

Scientific reports 20201001 1

Anthroponotic cutaneous leishmaniasis (CL) caused by Leishmania tropica (L. tropica) represents a public health challenge in several resource poor settings. We herein employed a systems analysis approach to study molecular signatures of CL caused by L. tropica in the skin lesions of ulcerative CL (UCL) and non-ulcerative CL (NUCL) patients. Results from RNA-seq analysis determined shared and unique functional transcriptional pathways in the lesions of the UCL and NUCL patients. Several transcrip ...[more]

PMID: 33004861

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Project description:BackgroundDrug resistance is a common phenomenon frequently observed in countries where leishmaniasis is endemic. Due to the production of the pteridine reductase enzyme (PTR1), drugs lose their efficacy, and consequently, the patient becomes unresponsive to treatment. This study aimed to compare the in vitro effect of meglumine antimoniate (MA) on non- healing Leishmania tropica isolates and on MA transfected non-healing one to PTR1.MethodsTwo non-healing and one healing isolates of L. tropica were collected from patients who received two courses or one cycle of intralesional MA along with biweekly liquid nitrogen cryotherapy or systemic treatment alone, respectively. After confirmation of L. tropica isolates by polymerase chain reaction (PCR), the recombinant plasmid pcDNA-rPTR (antisense) was transfected via electroporation and cultured on M199. Isolates in form of promastigotes were treated with different concentrations of MA and read using an enzyme-linked immunosorbent assay (ELISA) reader and the half inhibitory concentration (IC50 ) value was calculated. The amastigotes were grown in mouse macrophages and were similarly treated with various concentrations of MA. The culture glass slides were stained, and the mean number of intramacrophage amastigotes and infected macrophages were assessed in triplicate for both stages.ResultsAll three transfected isolates displayed a reduction in optical density compared with the promastigotes in respective isolates, although there was no significant difference between non-healing and healing isolates. In contrast, in the clinical form (amastigotes), there was a significant difference between non-healing and healing isolates (p < 0.05).ConclusionThe results indicated that the PTR1 gene reduced the efficacy of the drug, and its inhibition by antisense and could improve the treatment of non-healing cases. These findings have future implications in the prophylactic and therapeutic modality of non- healing Leishmania isolates to drug.

Project description:BackgroundIn the Mediterranean basin, three Leishmania species have been identified: L. infantum, L. major and L. tropica, causing zoonotic visceral leishmaniasis (VL), zoonotic cutaneous leishmaniasis (CL) and anthroponotic CL, respectively. Despite animal models and genomic/transcriptomic studies provided important insights, the pathogenic determinants modulating the development of VL and CL are still poorly understood. This work aimed to identify host transcriptional signatures shared by cells infected with L. infantum, L. major, and L. tropica, as well as specific transcriptional signatures elicited by parasites causing VL (i.e., L. infantum) and parasites involved in CL (i.e., L. major, L. tropica).Methodology/principal findingsU937 cells differentiated into macrophage-like cells were infected with L. infantum, L. major and L. tropica for 24h and 48h, and total RNA was extracted. RNA sequencing, performed on an Illumina NovaSeq 6000 platform, was used to evaluate the transcriptional signatures of infected cells with respect to non-infected cells at both time points. The EdgeR package was used to identify differentially expressed genes (fold change > 2 and FDR-adjusted p-values < 0.05). Then, functional enrichment analysis was employed to identify the enriched ontology terms in which these genes are involved. At 24h post-infection, a common signature of 463 dysregulated genes shared among all infection conditions was recognized, while at 48h post-infection the common signature was reduced to 120 genes. Aside from a common transcriptional response, we evidenced different upregulated functional pathways characterizing L. infantum-infected cells, such as VEGFA-VEGFR2 and NFE2L2-related pathways, indicating vascular remodeling and reduction of oxidative stress as potentially important factors for visceralization.ConclusionsThe identification of pathways elicited by parasites causing VL or CL could lead to new therapeutic strategies for leishmaniasis, combining the canonical anti-leishmania compounds with host-directed therapy.

Project description:BackgroundCutaneous leishmaniasis (CL), caused by Leishmania (L.) species, remains a neglected tropical disease in many developing countries. We and others have shown that different Leishmania species can alter the gene expression profile of human host cells. Long non-coding RNAs (lncRNAs) have been found to play a role in the pathogenesis of leishmaniasis through dysregulation of transcriptome signatures. Understanding the regulatory roles of lncRNAs in the biological networks involved in leishmaniasis can improve our understanding of the disease.MethodsHerein, we used our previous RNA sequencing data (GSE216638) to investigate the profile of lncRNAs in the skin lesions of L. tropica-infected patients. We employed the weighted gene correlation network analysis (WGCNA) algorithm to establish co-expression networks of shared genes between CL patients and infer the potential role of lncRNAs in CL patients. We identified hub genes and trans- and cis-acting lncRNAs, and carried out functional enrichment analysis on a key co-expressed module related to L. tropica-infected patients.ResultsWe found substantial involvement of lncRNAs in the CL patient dataset. Using the WGCNA method, we classified all included genes into seven modules, with a module (turquoise) being significantly correlated with the studied clinical traits and identified as the key module. This module was mainly involved in the "interferon gamma signaling" and "cytokine signaling" pathways. We highlighted several lncRNAs and their co-expressed mRNA pairs, like SIRPG-AS1, IL21R-AS1, IL24, and TLDC2, as hub genes of the key module. Quantitative RT-PCR validated the expression of several genes in the lesions of an independent cohort of L. tropica-infected patients.ConclusionsThese findings enhance our understanding of the human skin response to L. tropica infection. Furthermore, the hub genes identified in this study are worthy of further evaluation as potential targets in the development of more effective treatments and preventive measures for CL caused by L. tropica.

Dataset Information

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

Publications

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

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