Major changes in chromosomal somy, gene expression and gene dosage driven by SbIII in Leishmania braziliensis and Leishmania panamensis

Abstract

Leishmania braziliensis and Leishmania panamensis are two species clinically and epidemiologically important, among others because of their relative resistance to first-line drugs (antimonials). The precise mechanism underlying the ability of these species to survive antimony treatment remains unknown. Therefore, elucidating the pathways mediating drug resistance is essential. We herein experimentally selected resistance to trivalent antimony (Sb III ) in the reference strains of L . braziliensis (MHOM/BR75/M2904) and L . panamensis (MHOM/COL/81L13) and compared whole genome and transcriptome alterations in the culture promastigote stage. The results allowed us to identify differences in somy, copy number variations in some genes related to antimony resistance and large-scale copy number variations (deletions and duplications) in chromosomes with no somy changes. We found mainly in L . braziliensis , a direct relation between the chromosomal/local copy number variation and the gene expression. We identified differentially expressed genes in the resistant lines that are involved in antimony resistance, virulence, and vital biological processes in parasites. The results of this study may be useful for characterizing the genetic mechanisms of these Leishmania species under antimonial pressure, and for clarifying why the parasites are resistant to first-line drug treatments.

Trans-Atlantic Spillover: Deconstructing the Ecological Adaptation of Leishmania infantum in the Americas

“…The primary mechanisms are little understood even though they may play important roles in driving parasite fitness gain in new reservoirs and host tissues, or in response to drug pressure. Some of Leishmania's adaptative strategies have been described, including the ability to modulate the gene dosage of therapeutic targets (or other determinants of resistance) [40] by chromosomal amplification or the generation of episomal amplicons [41]. A recent series of publications has indeed associated Leishmania adaptation to its remarkable genome plasticity, with frequent changes in chromosome and gene copy number generating important intra-strain heterogeneity and complex mosaic populations that are substrates for environmental selection.…”

Trans-Atlantic Spill Over: Deconstructing the Ecological Adaptation of Leishmania Infantum in the Americas

“…The primary mechanisms are little understood even though they may play important roles in driving parasite fitness gain in new reservoirs and host tissues, or in response drug pressure. Some of Leishmania's adaptative strategies have been described, including the ability to modulate gene dosage of therapeutic targets (or other determinants of resistance) [40] by chromosomal amplification or the generation of episomal amplicons [41]. A recent series of publications has indeed associated Leishmania adaptation to its remarkable genome plasticity, with frequent changes in chromosome and gene copy number generating important intra-strain heterogeneity and complex mosaic populations that are substrate for environmental selection.…”

RNA Polymrase II gene expression in clinical Leishmania major isolates with no-response-to-drug pattern

“…There are some documents that showed the over expression of a gene in the absence of a promoter may result from either gene duplication following multicopy arrays of identical/semi-identical genes or supernumerary chromosomes [29][30][31][32][33]. The last has been involved in drug resistance in Leishmania [10,34].…”