Proteomic analysis of miltefosine-resistant Leishmania reveals the possible involvement of eukaryotic initiation factor 4A (eIF4A)

Singh, Gaganmeet; Chavan, Hemantkumar; Dey, Chinmoy Sankar

doi:10.1016/j.ijantimicag.2008.01.032

Cited by 15 publications

(5 citation statements)

References 10 publications

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“…Traditionally, one of the challenges faced by proteomics is attaining a significant detection threshold for changes in membrane-bound proteins that are difficult to resolve by mass spectrometry proteomics, since the technologies are biased toward soluble hydrophilic peptides (64). In fact, of the comparative proteomics studies addressing drug resistance (65)(66)(67)(68), only one stressed the importance of PgP (a membrane glycoprotein) expression as a beacon for HePC resistance, underscoring the importance of complementary omics to acquire the most comprehensive insight for multifaceted processes, such as HePC resistance. In this regard, other complementary proteomic approaches concerning the lines described in this study are in progress.…”

Section: Discussionmentioning

confidence: 99%

Genomic Appraisal of the Multifactorial Basis forIn VitroAcquisition of Miltefosine Resistance in Leishmania donovani

Vacchina

Norris-Mullins

Abengózar

et al. 2016

Antimicrob Agents Chemother

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HePC]), an antitumoral drug, is the only successful oral treatment for VL. In the current study, we describe the phenotypic traits of L. donovani clonal lines that have acquired resistance to HePC. We performed whole-genome and RNA sequencing of these resistant lines to provide an inclusive overview of the multifactorial acquisition of experimental HePC resistance, circumventing the challenge of identifying changes in membrane-bound proteins faced by proteomics. This analysis was complemented by assessment of the in vitro infectivity of HePC-resistant parasites. Our work underscores the importance of complementary "omics" to acquire the most comprehensive insight for multifaceted processes, such as HePC resistance.

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Section: Discussionmentioning

confidence: 99%

Genomic Appraisal of the Multifactorial Basis forIn VitroAcquisition of Miltefosine Resistance in Leishmania donovani

Vacchina

Norris-Mullins

Abengózar

et al. 2016

Antimicrob Agents Chemother

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“…Among the identified antigens associated with the post-VL subset, four of them (LieIF4A, LieEF1B, enolase and MAT2) have been reported as highly expressed in drug-resistant strains [12]–[14] and have been implicated in the survival of the parasite inside the host [15], [16]. For the six identified antigens that reacted with sera from the VL naturally resistant people (PDI, alpha- and beta-tubulin, vacuolar ATP synthase subunit B and HSP83), drug resistance implications and host parasite survival properties have been previously described too [13], [17]–[21].…”

Section: Discussionmentioning

confidence: 99%

Immunodominant Antigens of Leishmania chagasi Associated with Protection against Human Visceral Leishmaniasis

Abánades

Arruda

et al. 2012

PLoS Negl Trop Dis

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Background Protection and recovery from visceral leishmaniasis (VL) have been associated with cell-mediated immune (CMI) responses, whereas no protective role has been attributed to humoral responses against specific parasitic antigens. In this report, we compared carefully selected groups of individuals with distinct responses to Leishmania chagasi to explore antigen-recognizing IgG present in resistant individuals. Methodology and Principal Findings VL patients with negative delayed-type hypersensitivity (DTH) were classified into the susceptible group. Individuals who had recovered from VL and converted to a DTH+ response, as well as asymptomatic infected individuals (DTH+), were categorized into the resistant group. Sera from these groups were used to detect antigens from L. chagasi by conventional and 2D Western blot assays. Despite an overall reduction in the reactivity of several proteins after DTH conversion, a specific group of proteins (approximately 110–130 kDa) consistently reacted with sera from DTH converters. Other antigens that specifically reacted with sera from DTH+ individuals were isolated and tandem mass spectrometry followed by database query with the protein search engine MASCO were used to identify antigens. The serological properties of recombinant version of the selected antigens were tested by ELISA. Sera from asymptomatic infected people (DTH+) reacted more strongly with a mixture of selected recombinant antigens than with total soluble Leishmania antigen (SLA), with less cross-reactivity against Chagas disease patients' sera. Significance Our results are the first evidence of leishmania proteins that are specifically recognized by sera from individuals who are putatively resistant to VL. In addition, these data highlight the possibility of using specific proteins in serological tests for the identification of asymptomatic infected individuals.

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“…Interestingly, eIF4A inhibitors have been shown to act as dual-targeting therapeutic agents by interfering with both pathogen and host eIF4A activity during malaria, an infection caused by protozoan parasites of the genus Plasmodium [12]. Of note, a strain of L. donovani resistant to miltefosine had increased levels of eIF4A [63] and high-throughput screenings identified Leishmania eIF4A as a potential druggable target [64][65][66][67]. Collectively, our data along with previous studies warrant further investigation on the potential of targeting eIF4A-dependent host and parasite mRNA translation to treat L. donovani infections.…”

Section: Plos Pathogensmentioning

confidence: 99%

Translational profiling of macrophages infected with Leishmania donovani identifies mTOR- and eIF4A-sensitive immune-related transcripts

et al. 2020

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The protozoan parasite Leishmania donovani (L. donovani) causes visceral leishmaniasis, a chronic infection which is fatal when untreated. Herein, we investigated whether in addition to altering transcription, L. donovani modulates host mRNA translation to establish a successful infection. Polysome-profiling revealed that one third of protein-coding mRNAs expressed in primary mouse macrophages are differentially translated upon infection with L. donovani promastigotes or amastigotes. Gene ontology analysis identified key biological processes enriched for translationally regulated mRNAs and were predicted to be either activated (e.g. chromatin remodeling and RNA metabolism) or inhibited (e.g. intracellular trafficking and antigen presentation) upon infection. Mechanistic in silico and biochemical analyses showed selective activation mTOR-and eIF4A-dependent mRNA translation, including transcripts encoding central regulators of mRNA turnover and inflammation (i.e. PABPC1, EIF2AK2, and TGF-β). L. donovani survival within macrophages was favored under mTOR inhibition but was dampened by pharmacological blockade of eIF4A. Overall, this study uncovers a vast yet selective reprogramming of the host cell translational landscape early during L. donovani infection, and suggests that some of these changes are involved in host defense mechanisms while others are part of parasite-driven survival strategies. Further in vitro and in vivo investigation will shed light on the contribution of mTORand eIF4A-dependent translational programs to the outcome of visceral leishmaniasis.

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Proteomic analysis of miltefosine-resistant Leishmania reveals the possible involvement of eukaryotic initiation factor 4A (eIF4A)

Cited by 15 publications

References 10 publications

Genomic Appraisal of the Multifactorial Basis forIn VitroAcquisition of Miltefosine Resistance in Leishmania donovani

Genomic Appraisal of the Multifactorial Basis forIn VitroAcquisition of Miltefosine Resistance in Leishmania donovani

Immunodominant Antigens of Leishmania chagasi Associated with Protection against Human Visceral Leishmaniasis

Translational profiling of macrophages infected with Leishmania donovani identifies mTOR- and eIF4A-sensitive immune-related transcripts

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