Proteophosphoglycan is differentially expressed in sodium stibogluconate-sensitive and resistant Indian clinical isolates of<i>Leishmania donovani</i>

Samant, Mukesh; Sahasrabuddhe, Amogh A.; Singh, Nasib; Gupta, Suman; Sundar, Shyam; Dube, Anuradha

doi:10.1017/s0031182007002569

Cited by 28 publications

(30 citation statements)

References 30 publications

(60 reference statements)

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“…Molecular studies investigating antimonial resistance in L. donovani clinical isolates have implicated modifications to proteins topologically predisposed to faster adaptation (Kim et al 2007;Sackton et al 2007;Cui et al 2009) such as surface proteins (Samant et al 2007) and transporters in the SSGresistance phenotype. Here, we provide evidence of ancient and recent adaptive evolution both between Leishmania species and in the L. donovani lineage at the highly immunogenic amastin surface glycoproteins (Wu et al 2000;Stober et al 2006;Jackson 2010).…”

Section: )mentioning

confidence: 99%

“…In addition, these isolates were the subjects of several recent studies, providing a unique clinical, biological, and epidemiological background (Decuypere et al 2005(Decuypere et al , 2008Laurent et al 2007;Alam et al 2009;Rijal et al 2010;Vanaerschot et al 2010). Importantly, these parasites are highly variable in terms of susceptibility to antimonial drugs such as sodium stibogluconate (SSG; Rijal et al 2007;Samant et al 2007;Kumar et al 2009). …”

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confidence: 99%

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Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance

Downing¹,

Imamura²,

Decuypere³

et al. 2011

Genome Res.

384

516

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Visceral leishmaniasis is a potentially fatal disease endemic to large parts of Asia and Africa, primarily caused by the protozoan parasite Leishmania donovani. Here, we report a high-quality reference genome sequence for a strain of L. donovani from Nepal, and use this sequence to study variation in a set of 16 related clinical lines, isolated from visceral leishmaniasis patients from the same region, which also differ in their response to in vitro drug susceptibility. We show that wholegenome sequence data reveals genetic structure within these lines not shown by multilocus typing, and suggests that drug resistance has emerged multiple times in this closely related set of lines. Sequence comparisons with other Leishmania species and analysis of single-nucleotide diversity within our sample showed evidence of selection acting in a range of surface-and transport-related genes, including genes associated with drug resistance. Against a background of relative genetic homogeneity, we found extensive variation in chromosome copy number between our lines. Other forms of structural variation were significantly associated with drug resistance, notably including gene dosage and the copy number of an experimentally verified circular episome present in all lines and described here for the first time. This study provides a basis for more powerful molecular profiling of visceral leishmaniasis, providing additional power to track the drug resistance and epidemiology of an important human pathogen.[Supplemental material is available for this article.]Leishmaniases are a complex of diseases that range from self-curing lesions to gross disfigurations and potentially deadly visceral disease. The diseases are caused by protozoan parasites that are transmitted by sandflies in 88 countries and infect an estimated 12 million people (www.who.int/leishmaniasis/en/). Parasites of the Leishmania genus are remarkably biologically, clinically, and epidemiologically diverse and present enormous differences in disease tropism. The mildest form is cutaneous leishmaniasis, which is caused by Leishmania major and other species, and is largely limited to lesions around the area of a sandfly bite-though a diffuse form can also occur. Disfiguring mucocutaneous leishmaniasis is due to the destruction of nasopharyngeal tissue by parasites such as L. braziliensis. More significantly, visceral leishmaniasis is caused by parasites of the L. donovani species complex that can spread to internal organs and cause death.In 2005, sequencing the genome of L. major identified 8311 protein-coding genes and provided a framework for future comparative genomic studies (Ivens et al. 2005). The genome elucidated the full structural architecture of Leishmania chromosomes, which includes an unusual pattern of genes distributed in large directional clusters. Subsequently, the genomes of L. braziliensis and L. infantum were described-the latter is a member of the L. donovani complex (Peacock et al. 2007). A detailed comparison of these first three Leishmania genomes re...

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Section: )mentioning

confidence: 99%

mentioning

confidence: 99%

Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance

Downing¹,

Imamura²,

Decuypere³

et al. 2011

Genome Res.

384

516

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“…The structure and function of PPGs are species and stage specific as in the case of Leishmania major and Leishmania mexicana, but no such information has hitherto been available for Leishmania donovani (8 -11). We have very recently demonstrated the expression of PPG to be higher in sodium stibogluconate-resistant clinical isolates of L. donovani as compared with the sensitive ones (11).…”

Section: Immunization With the Dna-encoding N-terminal Domain Of Protmentioning

confidence: 99%

“…Eluted product was FIGURE 1. The schematic structure of PPG (11,75) (A) and Ag determinants in ppg using Ag determination software (B).…”

Section: Parasitesmentioning

confidence: 99%

Immunization with the DNA-Encoding N-Terminal Domain of Proteophosphoglycan of Leishmania donovani Generates Th1-Type Immunoprotective Response against Experimental Visceral Leishmaniasis

Samant

Gupta

Kumari

et al. 2009

The Journal of Immunology

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Leishmania produce several types of mucin-like glycoproteins called proteophosphoglycans (PPGs) which exist as secretory as well as surface-bound forms in both promastigotes and amastigotes. The structure and function of PPGs have been reported to be species and stage specific as in the case of Leishmania major and Leishmania mexicana; there has been no such information available for Leishmania donovani. We have recently demonstrated that PPG is differentially expressed in sodium stibogluconate-sensitive and -resistant clinical isolates of L. donovani. To further elucidate the structure and function of the ppg gene of L. donovani, a partial sequence of its N-terminal domain of 1.6 kb containing the majority of antigenic determinants, was successfully cloned and expressed in prokaryotic as well as mammalian cells. We further evaluated the DNA-encoding N-terminal domain of the ppg gene as a vaccine in golden hamsters (Mesocricetus auratus) against the L. donovani challenge. The prophylactic efficacy to the tune of ∼80% was observed in vaccinated hamsters and all of them could survive beyond 6 mo after challenge. The efficacy was supported by a surge in inducible NO synthase, IFN-γ, TNF-α, and IL-12 mRNA levels along with extreme down-regulation of TGF-β, IL-4, and IL-10. A rise in the level of Leishmania-specific IgG2 was also observed which was indicative of enhanced cellular immune response. The results suggest the N-terminal domain of L. donovani ppg as a potential DNA vaccine against visceral leishmaniasis.

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“…Hence, these glycoconjugates are considered as important markers of virulence. Differences in the distribution of proteophosphoglycans on promastigotes and amastigotes in pentavalent antimony resistant and sensitive clinical isolates suggest the implications of surface topology in determining the clinical outcome of the disease [48]. Therefore glycoconjugates and their association with leishmania have always instigated the scientific community to unravel their importance.…”

Section: Glycoconjugates Of Leishmania and Their Significancementioning

confidence: 99%

A Perspective on the Emergence of Sialic Acids as Potent Determinants AffectingLeishmaniaBiology

Ghoshal

Mandal

2011

Molecular Biology International

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Leishmaniasis caused by Leishmania sp. has a wide range of manifestations from cutaneous to the deadly visceral form. They shuttle between the invertebrate and vertebrate hosts as promastigotes and amastigotes having adaptations for subverting host immune responses. Parasite-specific glycoconjugates have served as important determinants influencing parasite recognition, internalization, differentiation, multiplication, and virulence. Despite the steady progress in the field of parasite glycobiology, sialobiology has been a less traversed domain of research in leishmaniasis. The present paper focuses on identification, characterization, and differential distribution of sialoglycotope having the linkage-specific 9-O-acetylated sialic acid in promastigotes of different Leishmania sp. causing different clinical ramifications emphasizing possible role of these sialoglycotopes in infectivity, virulence, nitric oxide resistance, and host modulation in Leishmania spp. asserting them to be important molecules influencing parasite biology.

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Proteophosphoglycan is differentially expressed in sodium stibogluconate-sensitive and resistant Indian clinical isolates ofLeishmania donovani

Cited by 28 publications

References 30 publications

Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance

Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance

Immunization with the DNA-Encoding N-Terminal Domain of Proteophosphoglycan of Leishmania donovani Generates Th1-Type Immunoprotective Response against Experimental Visceral Leishmaniasis

A Perspective on the Emergence of Sialic Acids as Potent Determinants AffectingLeishmaniaBiology

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