Studies on the CPA cysteine peptidase in the Leishmania infantum genome strain JPCM5

Denise, Hubert; Poot, Jacqueline; Jiménez, Maribel; Ambit, Audrey; Herrmann, Daland; Vermeulen, A.N.; Coombs, Graham H.; Mottram, Jeremy C.

doi:10.1186/1471-2199-7-42

Cited by 47 publications

(28 citation statements)

References 49 publications

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“…The reads of the 20 L. infantum isolates were mapped to the reference genome L. infantum clone JPCM5, which was derived from the spleen of a naturally infected dog in the Madrid area of Spain in 1998 (Denise et al, 2006). After alignment and removal of duplicates, the genome coverage was more than 90-fold.…”

Section: Resultsmentioning

confidence: 99%

Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil

Teixeira

Monteiro

Martins

et al. 2017

International Journal for Parasitology

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The genomic sequences of 20 Leishmania infantum isolates collected in northeastern Brazil were compared with each other and with the available genomic sequences of 29 L. infantum/donovani isolates from Nepal and Turkey. The Brazilian isolates were obtained in the early 1990s or since 2009 from patients with visceral or non-ulcerating cutaneous leishmaniasis, asymptomatic humans, or dogs with visceral leishmaniasis. Two isolates were from the blood and bone marrow of the same visceral leishmaniasis patient. All 20 genomic sequences display 99.95% identity with each other and slightly less identity with a reference L. infantum genome from a Spanish isolate. Despite the high identity, analysis of individual differences among the 32 million base pair genomes showed sufficient variation to allow the isolates to be clustered based on the primary sequence. A major source of variation detected was in chromosome somy, with only four of the 36 chromosomes being predominantly disomic in all 49 isolates examined. In contrast, chromosome 31 was predominantly tetrasomic/pentasomic, consistent with its regions of synteny on two different disomic chromosomes of Trypanosoma brucei. In the Brazilian isolates, evidence for recombination was detected in 27 of the 36 chromosomes. Clustering analyses suggested two populations, in which two of the five older isolates from the 1990s clustered with a majority of recent isolates. Overall the analyses do not suggest individual sequence variants account for differences in clinical outcome or adaptation to different hosts. For the first known time, DNA of isolates from asymptomatic subjects were sequenced. Of interest, these displayed lower diversity than isolates from symptomatic subjects, an observation that deserves further investigation with additional isolates from asymptomatic subjects.

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Section: Resultsmentioning

confidence: 99%

Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil

Teixeira

Monteiro

Martins

et al. 2017

International Journal for Parasitology

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“…JPCM5 is a clone obtained from the JPC strain isolated from a naturally infected dog (MCAN/ES/98/LLM-877) and maintained at the WHO Collaborating Center for Leishmaniasis, Parasitology Department, Instituto de Salud Carlos III (ISCIII), Madrid, Spain. This clone was used for L. infantum genome sequencing [ 39 ] and has been widely utilized for experimental challenge [ 40 ].…”

Section: Methodsmentioning

confidence: 99%

Natural transmission of Leishmania infantum through experimentally infected Phlebotomus perniciosus highlights the virulence of Leishmania parasites circulating in the human visceral leishmaniasis outbreak in Madrid, Spain

Martín-Martín

Jiménez

González

et al. 2015

Vet Res

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A human leishmaniasis outbreak is occurring in the Madrid region, Spain, with the parasite and vector involved being Leishmania infantum and Phlebotomus perniciosus respectively. The aim of this study was to investigate the virulence of L. infantum isolates from the focus using a natural transmission model. Hamsters were infected by intraperitoneal inoculation (IP) or by bites of sand flies experimentally infected with L. infantum isolates obtained from P. perniciosus collected in the outbreak area (IPER/ES/2012/BOS1FL1 and IPER/ES/2012/POL2FL6) and a well characterized L. infantum strain JPCM5 (MCAN/ES/98/LLM-877). Hamster infections were monitored by clinical examination, serology, culture, parasite burden, Giemsa-stained imprints, PCR, histopathology and xenodiagnostic studies. Establishment of infection of L. infantum was achieved with the JPCM5 strain and outbreak isolates by both P. perniciosus infective bites or IP route. However, high virulence of BOS1FL1 and POL2FL6 isolates was highlighted by the clinical outcome of disease, high parasite detection in spleen and liver, high parasitic loads and positivity of Leishmania serology. Transmission by bite of POL2FL6 infected flies generated a slower progression of clinical disease than IP infection, but both groups were infective to P. perniciosus by xenodiagnosis at 2 months post-infection. Conversely, hamsters inoculated with JPCM5 were not infective to sand flies. Histopathology studies confirmed the wide spread of POL2FL6 parasites to several organs. A visceral leishmaniasis model that mimics the natural transmission in nature allowed us to highlight the high virulence of isolates that are circulating in the focus. These findings contribute to a better understanding of the outbreak epidemiology.

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“…There are some previous reports of only partial phenotype recovery when an attempt is made to reexpress a previously deleted gene in Leishmania, but all studies were done with null mutants. When the L. infantum cysteine peptidase gene (LiCPA) was reintroduced into the CPA locus of ΔLicpa parasites, the loss of virulence of the null mutant was only partially restored in one of the complemented clones and virulence did not show any recovery at all when the parasites were tested in in vivo experiments (58).…”

Section: Discussionmentioning

confidence: 99%

ABCI3 Is a New Mitochondrial ABC Transporter from Leishmania major Involved in Susceptibility to Antimonials and Infectivity

Arcari

Manzano

Gamarro

2017

Antimicrob Agents Chemother

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We have identified and characterized ABCI3 as a new mitochondrial ABC transporter from Leishmania major. Localization studies using confocal microscopy, a surface biotinylation assay, and trypsin digestion after digitonin permeabilization suggested that ABCI3 presents a dual localization in both mitochondria and the plasma membrane. From studies using parasites with a single knockout of ABCI3 (ABCI3 ϩ/Ϫ ), we provide evidence that ABCI3 is directly involved in susceptibility to the trivalent form of antimony (SbIII) and metal ions. Attempts to obtain parasites with a double knockout of ABCI3 were unsuccessful, suggesting that ABCI3 could be an essential gene in L. major. ABCI3 ϩ/Ϫ promastigotes were 5-fold more resistant to Sb III than the wild type, while ABCI3 ϩ/Ϫ amastigotes were approximately 2-fold more resistant to pentavalent antimony (Sb V ). This resistance phenotype was associated with decreased Sb III accumulation due to decreased Sb III uptake. ABCI3 ϩ/Ϫ parasites presented higher ATP levels and generated less mitochondrial superoxide after Sb III incubation. Finally, we observed that ABCI3 ϩ/Ϫ parasites showed a slightly higher infection capacity than wild-type and add-back ABCI3 ϩ/Ϫ ::3ϫFABCI3 parasites; however, after 72 h the number of ABCI3 ϩ/Ϫ intracellular parasites per macrophage increased significantly. Our results show that ABCI3 is responsible for Sb III transport inside mitochondria, where it contributes to enhancement of the general toxic effects caused by Sb III . To our knowledge, ABCI3 is the first ABC transporter which is involved in susceptibility toward antimony, conferring Sb III resistance to parasites when it is partially deleted.

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Studies on the CPA cysteine peptidase in the Leishmania infantum genome strain JPCM5

Cited by 47 publications

References 49 publications

Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil

Comparative analyses of whole genome sequences of Leishmania infantum isolates from humans and dogs in northeastern Brazil

Natural transmission of Leishmania infantum through experimentally infected Phlebotomus perniciosus highlights the virulence of Leishmania parasites circulating in the human visceral leishmaniasis outbreak in Madrid, Spain

ABCI3 Is a New Mitochondrial ABC Transporter from Leishmania major Involved in Susceptibility to Antimonials and Infectivity

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