Abstract
Neglected Tropical Diseases include a broad range of pathogens, hosts, and vectors, which represent evolving complex systems. Leishmaniasis, caused by different Leishmania species and transmitted to humans by sandflies, are among such diseases. Leishmania and other Trypanosomatidae display some peculiar features, which make them a complex system to study. Leishmaniasis chemotherapy is limited due to high toxicity of available drugs, long-term treatment protocols, and occurrence of drug resistant parasite strains. Systems biology studies the interactions and behavior of complex biological processes and may improve knowledge of Leishmania drug resistance. System-level studies to understand Leishmania biology have been challenging mainly because of its unusual molecular features. Networks integrating the biochemical and biological pathways involved in drug resistance have been reported in literature. Antioxidant defense enzymes have been identified as potential drug targets against leishmaniasis. These and other biomarkers might be studied from the perspective of systems biology and systems parasitology opening new frontiers for drug development and treatment of leishmaniasis and other diseases. Our main goals include: 1) Summarize current advances in Leishmania research focused on chemotherapy and drug resistance. 2) Share our viewpoint on the application of systems biology to Leishmania studies. 3) Provide insights and directions for future investigation.
Highlights
Leishmania is a complex biological system in itself
These results show that the mechanism of antimony-resistance in Leishmania is complex and multifactorial, identifying several candidate genes that may be further evaluated as molecular targets for chemotherapy of leishmaniasis
Computational modeling of the molecular components of drug resistance in Leishmania through the biophysicochemical monitoring of genes and proteins involved in the processes is important
Summary
Leishmania is a complex biological system in itself. In the lack of an effective vaccine, human treatment relies on chemotherapy since the early 1920’s. The transcriptomic profile showed that many pathways upregulated in L. infantum antimony-resistant lines are associated with protein phosphorylation, microtubule-based movement, protein ubiquitination, stress response, regulation of membrane lipid distribution, proteins involved in RNA metabolism, and other important metabolic pathways (Andrade et al, 2020) Together, these results show that the mechanism of antimony-resistance in Leishmania is complex and multifactorial, identifying several candidate genes that may be further evaluated as molecular targets for chemotherapy of leishmaniasis. The resulting association among specific transcriptional states of all genes involved in drug resistance will represent a key tool for the study and modeling of this complex biological process These studies have the potential to lead the identification of better drug targets and markers for pathogenesis
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