Leishmania LABCG1 and LABCG2 transporters are involved in virulence and oxidative stress: functional linkage with autophagy

Manzano, José Ignacio; Perea, Ana; León-Guerrero, David; Campos‐Salinas, Jenny; Piacenza, Lucı́a; Castanys, Santiago; Gamarro, Francisco

doi:10.1186/s13071-017-2198-1

Cited by 18 publications

(14 citation statements)

References 37 publications

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“…2b). This locus contains the ABCG1 and ABCG2 genes 23 that are associated with multiple activities 24 . The co-transfection of ABCG1-2 in mutant PMM25 modestly resensitized cells to PMM (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Coupling chemical mutagenesis to next generation sequencing for the identification of drug resistance mutations in Leishmania

Bhattacharya¹,

Leprohon²,

Bigot

et al. 2019

Nat Commun

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Current genome-wide screens allow system-wide study of drug resistance but detecting small nucleotide variants (SNVs) is challenging. Here, we use chemical mutagenesis, drug selection and next generation sequencing to characterize miltefosine and paromomycin resistant clones of the parasite Leishmania. We highlight several genes involved in drug resistance by sequencing the genomes of 41 resistant clones and by concentrating on recurrent SNVs. We associate genes linked to lipid metabolism or to ribosome/translation functions with miltefosine or paromomycin resistance, respectively. We prove by allelic replacement and CRISPR-Cas9 gene-editing that the essential protein kinase CDPK1 is crucial for paromomycin resistance. We have linked CDPK1 in translation by functional interactome analysis, and provide evidence that CDPK1 contributes to antimonial resistance in the parasite. This screen is powerful in exploring networks of drug resistance in an organism with diploid to mosaic aneuploid genome, hence widening the scope of its applicability.

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Section: Resultsmentioning

confidence: 99%

Coupling chemical mutagenesis to next generation sequencing for the identification of drug resistance mutations in Leishmania

Bhattacharya¹,

Leprohon²,

Bigot

et al. 2019

Nat Commun

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“…The most strongly regulated genes in P. dicentrarchi during infection were the ABC transporters, which were mainly UR. Protozoan ABC transporters are involved in nutrient transport but they also protect cells from both internally produced and exogenous toxins, and some have been associated with antiparasitic drug resistance as well virulence and oxidative stress [ 35 , 36 , 37 ]. These transporters are very abundant in ciliates, and 165 ABC transporter genes were identified in the macronuclear genome of the ciliate Tetrahymena thermophila [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Interactions between the Parasite Philasterides dicentrarchi and the Immune System of the Turbot Scophthalmus maximus. A Transcriptomic Analysis

Valle

Leiro

Pereiro

et al. 2020

Biology

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The present study analyses the interactions between Philasterides dicentrarchi (a ciliate parasite that causes high mortalities in cultured flatfish) and the peritoneal cells of the turbot Scophthalmus maximus during an experimental infection. The transcriptomic response was evaluated in the parasites and in the fish peritoneal cells, at 1, 2 and 4 h post-infection (hpi) in turbot injected intraperitoneally (ip) with 107 ciliates and at 12 and 48 hpi in turbot injected ip with 105 ciliates. Numerous genes were differentially expressed (DE) in P. dicentrarchi, relative to their expression in control ciliates (0 hpi): 407 (369 were up-regulated) at 1 hpi, 769 (415 were up-regulated) at 2 hpi and 507 (119 were up-regulated) at 4 hpi. Gene ontology (GO) analysis of the DE genes showed that the most representative categories of biological processes affected at 1, 2 and 4 hpi were biosynthetic processes, catabolic processes, biogenesis, proteolysis and transmembrane transport. Twelve genes of the ABC transporter family and eight genes of the leishmanolysin family were DE at 1, 2 and 4 hpi. Most of these genes were strongly up-regulated (UR), suggesting that they are involved in P. dicentrarchi infection. A third group of UR genes included several genes related to ribosome biogenesis, DNA transcription and RNA translation. However, expression of tubulins and tubulin associated proteins, such as kinesins or dyneins, which play key roles in ciliate division and movement, was down-regulated (DR). Similarly, genes that coded for lysosomal proteins or that participate in the cell cycle mitotic control, glycolysis, the Krebs cycle and/or in the electron transport chain were also DR. The transcriptomic analysis also revealed that in contrast to many parasites, which passively evade the host immune system, P. dicentrarchi strongly stimulated turbot peritoneal cells. Many genes related to inflammation were DE in peritoneal cells at 1, 2 and 4 hpi. However, the response was much lower at 12 hpi and almost disappeared completely at 48 hpi in fish that were able to kill P. dicentrarchi during the first few hpi. The genes that were DE at 1, 2 and 4 hpi were mainly related to the apoptotic process, the immune response, the Fc-epsilon receptor signalling pathway, the innate immune response, cell adhesion, cell surface receptors, the NF-kappaB signalling pathway and the MAPK cascade. Expression of toll-like receptors 2, 5 and 13 and of several components of NF-κB, MAPK and JAK/STAT signalling pathways was UR in the turbot peritoneal cells. Genes expressing chemokines and chemokine receptors, genes involved in prostaglandin and leukotriene synthesis, prostaglandins, leukotriene receptors, proinflammatory cytokines and genes involved in apoptosis were strongly UR during the first four hours of infection. However, expression of anti-inflammatory cytokines such as Il-10 and lipoxygenases with anti-inflammatory activity (i.e., arachidonate 15-lipoxygenase) were only UR at 12 and/or 48 hpi, indicating an anti-inflammatory state in these groups of fish. In conclusion, the present study shows the regulation of several genes in P. dicentrarchi during the early stages of infection, some of which probably play important roles in this process. The infection induced a potent acute inflammatory response, and many inflammatory genes were regulated in peritoneal cells, showing that the turbot uses all the protective mechanisms it has available to prevent the entry of the parasite.

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“…ABCG1 was found to be overexpressed in strains naturally sensitive to benznidazole (70,71), but its functionality has not been studied so far. In Leishmania, ABCG1 and ABCG2 are transporters of thiol and phosphatidylserine, implicated in oxidative metabolism, autophagy, metacyclogenesis and infectivity (72), observations that highlight possible roles for this transporter for T. cruzi that should be evaluated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

Costa

et al. 2020

Preprint

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The protozoan Trypanosoma cruzi is the etiologic agent for Chagas disease, which affects 6-7 million people worldwide. The parasite presents high biological diversity, reflecting on the inefficiency of benznidazole in chronic or older patients. ABC superfamily proteins contain active transporters involved in the xenobiotic and endobiotic efflux and overexpressed in MDR cells. An ABCC-like transport was identified in the T. cruzi Y strain, being able to extrude thiol-conjugated compounds. As non-protein thiols represent prime line of defense towards reactive species, ABCC-like activity could participate in the regulation of mediators implicated in responses to cellular stress arising from a variety of stimuli, as environmental or chemotherapeutic. This study shows that T. cruzi ABCC-like protein transports GSH, GSSG and ceramides, all implicated in cellular stress. Hemin, representative from the hematophagous feeding of the vector, was transported as well, suggesting a role for ABCC as a metal-thiol transporter. In addition, all strains evaluated showed ABCC-like activity, while no ABCB1-like activity was detected. Also, results suggest that ABCC-like does not associate to natural resistance to benznidazole, considering that the sensitive strains CL Brener and Berenice showed higher ABCC-like activity than the resistant strains Y and Colombiana. Instead, ABCC-like efflux increased after continuous exposure of Y strain to benznidazole. Moreover, ABCC does not perform direct efflux of drug and its participation in the machinery of protection against stress depends on the efflux of metabolites in conjugation to or in cotransport with thiol.

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Leishmania LABCG1 and LABCG2 transporters are involved in virulence and oxidative stress: functional linkage with autophagy

Cited by 18 publications

References 37 publications

Coupling chemical mutagenesis to next generation sequencing for the identification of drug resistance mutations in Leishmania

Coupling chemical mutagenesis to next generation sequencing for the identification of drug resistance mutations in Leishmania

Interactions between the Parasite Philasterides dicentrarchi and the Immune System of the Turbot Scophthalmus maximus. A Transcriptomic Analysis

Thiol efflux mediated by an ABCC-like transporter participates forTrypanosoma cruziadaptation to environmental and chemotherapeutic stresses

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