Transcriptomic Analysis in Human Macrophages Infected with Therapeutic Failure Clinical Isolates of Leishmania
Ana Perea-Martínez1, Raquel García-Hernández1, José Ignacio Manzano1
1Instituto de Parasitología y Biomedicina "López-Neyra", IPBLN-CSIC, Parque Tecnológico de Ciencias de la Salud, Avda del Conocimiento 17, 18016 Armilla, Granada, Spain.
Abstract:
Leishmaniasis is one of the neglected tropical diseases with a worldwide distribution, affecting humans and animals. In the absence of an effective vaccine, current treatment is through the use of chemotherapy; however, existing treatments have frequent appearance of drug resistance and therapeutic failure (TF). The identification of factors that contribute to TF in leishmaniasis will provide the basis for a future therapeutic strategy more efficient for the control of this disease. In this article, we have evaluated the transcriptomic changes in the host cells THP-1 after infection with clinical Leishmania infantum isolates from leishmaniasis patients with TF. Our results show that distinct L. infantum isolates differentially modulate host cell response, inducing phenotypic changes that probably may account for parasite survival and TF of patients. Analysis of differential expression genes (DEGs), with a statistical significance threshold of a fold change ≥ 2 and a false discovery rate value ≤ 0.05, revealed a different number of DEGs according to the Leishmanialine. Globally, there was a similar number of genes up- and downregulated in all the infected host THP-1 cells, with exception of Hi-L2221, which showed a higher number of downregulated DEGs. We observed a total of 58 DEGs commonly modulated in all infected host cells, including upregulated (log2FC ≥ 1) and downregulated (log2FC ≤ -1) genes. Based on the results obtained from the analysis of RNA-seq, volcano plot, and GO enrichment analysis, we identified the most significant transcripts of relevance for their possible contribution to the TF observed in patients with leishmaniasis.
Insights
Leishmaniasis treatment failure stems from distinct parasite strains altering host cell responses. Understanding these transcriptomic changes in THP-1 cells is key to developing more effective leishmaniasis therapies.
Area of Science:
- Molecular Biology
- Parasitology
- Immunology
Background:
- Leishmaniasis is a neglected tropical disease treated with chemotherapy.
- Drug resistance and therapeutic failure (TF) are significant challenges in leishmaniasis treatment.
- Identifying factors contributing to TF is crucial for developing better therapeutic strategies.
Purpose of the Study:
- To investigate transcriptomic changes in host THP-1 cells infected with clinical Leishmania infantum isolates from patients experiencing TF.
- To identify host cell modulations that may contribute to parasite survival and therapeutic failure in leishmaniasis.
Main Methods:
- RNA sequencing (RNA-seq) was used to analyze gene expression in THP-1 cells after infection with L. infantum.
- Differential gene expression analysis was performed with a fold change threshold of ≥ 2 and a false discovery rate ≤ 0.05.
- Gene Ontology (GO) enrichment analysis and volcano plots were utilized to identify significant transcripts.
Main Results:
- Distinct L. infantum isolates differentially modulated host THP-1 cell responses, inducing phenotypic changes.
- A total of 58 differentially expressed genes (DEGs) were commonly modulated across all infected host cells.
- One isolate, Hi-L2221, showed a higher number of downregulated DEGs compared to others.
Conclusions:
- Differential modulation of host cell transcriptomics by L. infantum isolates likely contributes to therapeutic failure in leishmaniasis patients.
- Specific host transcripts identified may play a role in parasite survival and the development of drug resistance.
- This study provides insights into host-parasite interactions relevant for future leishmaniasis treatment strategies.
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