Integrated genomic and metabolomic profiling of ISC1, an emerging Leishmania donovani population in the Indian subcontinent

Abstract

Leishmania donovani is the responsible agent for visceral leishmaniasis (VL) in the Indian subcontinent (ISC). The disease is lethal without treatment and causes 0.2 to 0.4 million cases each year. Recently, reports of VL in Nepalese hilly districts have increased as well as VL cases caused by L. donovani from the ISC1 genetic group, a new and emerging genotype. In this study, we perform for the first time an integrated, untargeted genomics and metabolomics approach to characterize ISC1, in comparison with the Core Group (CG), main population that drove the most recent outbreak of VL in the ISC. We show that the ISC1 population is very different from the CG, both at genome and metabolome levels. The genomic differences include SNPs, CNV and small indels in genes coding for known virulence factors, immunogens and surface proteins. Both genomic and metabolic approaches highlighted dissimilarities related to membrane lipids, the nucleotide salvage pathway and the urea cycle in ISC1 versus CG. Many of these pathways and molecules are important for the interaction with the host/extracellular environment. Altogether, our data predict major functional differences in ISC1 versus CG parasites, including virulence. Therefore, particular attention is required to monitor the fate of this emerging ISC1 population in the ISC, especially in a post-VL elimination context.

Evidence that interspeciesLeishmaniahybrids contribute to changes in disease pathology

“…This demonstrates that the Sri Lanka isolates in groups SL2 and SL3, despite being geographically close to India, are quite different in origin from the SL1 group and that the SL2 group is very unique from any other L. donovani strain. All Indian subcontinent (ISC) genomes cluster closely together including the slightly divergent ISC1 or “Yeti” group consistent with previous phylogenetic analyses 29,30 . Parasites from Africa formed three separate clusters, largely determined by their geographical isolation location, as previously reported 7 .…”

In Search of Biomarkers for Pathogenesis and Control of Leishmaniasis by Global Analyses of Leishmania-Infected Macrophages

“…Another aspect that should be taken into consideration is metabolic changes induced in host cells by Leishmania parasites. While we recognize that metabolomic analysis represents an important aspect that has recently been explored in the field of leishmaniasis (Armitage et al, 2018 ; Cuypers et al, 2018 ), which certainly contributes to the understanding of disease, the results from these studies fall outside the scope of the present study. The present review instead focuses on global transcriptome analysis of macrophages in response to infection, which has been poorly investigated using RNA-seq technology (Dillon et al, 2015 ; Fernandes et al, 2016 ).…”

Intraspecific Genomic Divergence and Minor Structural Variations in Leishmania (Viannia) panamensis

“…Subsequently, we analyzed the structural changes to chromosome level using the copy number variation as an indicator. Various studies have described that some Leishmania species (L. infantum, L. major, L. donovani, L. amazonensis, L. braziliensis, and L. panamensis) generate changes in the number of chromosomes as an environment-dependent mechanism, as well as an adaptation process in response to stress [24,25,28,37,[59][60][61]. However, although this mechanism is shared between Old and New World Leishmania species, the changes in the number of chromosomes vary considerably across species.…”

“…All positions with a read depth of >1 standard deviation away from this initial median were then removed, and the di was recalculated from high-quality reads. Subsequently, the median depth of the 35 chromosomes (dm) for L. panamensis was calculated, and the somy (S-value) of each chromosome was obtained with the following formula: S = 2 × di/dm [37]. The somy values calculated from sequencing data are averages across the potentially variable somy of these cells.…”