Abstract

Leishmaniasis is a major health problem to humans and is caused by protozoan parasites of the genus Leishmania. Lipophosphoglycan (LPG) is an important macromolecule on the surface of the promastigote form of these parasites and is believed to be multifunctional. Structurally, LPG is composed of four domains: (i) a lyso-l-O-alkylphosphatidylinositol anchor, (ii) a phosphosaccharide core, (iii) a polymer of repeating saccharide units linked together by phosphodiester bridges, and (iv) a small, capping oligosaccharide at the terminal, non-reducing end. The lipid anchor and phosphosaccharide core regions of LPG are conserved among various Leishmania species, whereas there is variability of sugar composition and sequence in the repeating phosphorylated saccharide units and the capping structure. While significant progress has been made on structure-function relationships of LPG, much more remains to be learned concerning interspecies differences, and intraspecies developmental modifications of LPG structure. Determining these structural differences along with the biosynthesis and turnover of this important glycoconjugate will also be a focus of our research.
The specific aims of this application are as follows: l. Continuation of structural analysis of LPGs. Specifically, the structure of LPG from Indian isolates of L. donovani and from isolates of L. braziliensis and L. amazonensis will be elucidated. 2. Biochemical analysis of LPG biosynthesis. Two key enzymes (mannosylphosphate transferase and arabinosyltransferase) involved in LPG biosynthesis will be purified and characterized. 3. Characterization of LPG turnover. The turnover of LPG by the parasite and the fate of LPG upon infection of macrophages by promastigotes will be investigated. From these studies, we hope to contribute to the understanding of the role LPG plays in the pathogenesis of leishmaniasis and to provide a biochemical rationale for the design of chemotherapeutic regimens that exploit its unique structure.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI020941-18
Application #
6533993
Study Section
Special Emphasis Panel (NSS)
Program Officer
Rogers, Martin J
Project Start
1985-09-01
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
18
Fiscal Year
2002
Total Cost
$325,995
Indirect Cost

  Institution

Name
University of Kentucky
Department
Biochemistry
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506

  Publications

Phillips, Megan R; Turco, Salvatore J (2015) Characterization of a ricin-resistant mutant of Leishmania donovani that expresses lipophosphoglycan. Glycobiology 25:428-37
Soares, Rodrigo P; Margonari, Carina; Secundino, Nagila C et al. (2010) Differential midgut attachment of Leishmania (Viannia) braziliensis in the sand flies Lutzomyia (Nyssomyia) whitmani and Lutzomyia (Nyssomyia) intermedia. J Biomed Biotechnol 2010:439174
Dobson, Deborah E; Kamhawi, Shaden; Lawyer, Phillip et al. (2010) Leishmania major survival in selective Phlebotomus papatasi sand fly vector requires a specific SCG-encoded lipophosphoglycan galactosylation pattern. PLoS Pathog 6:e1001185
Dobson, Deborah E; Scholtes, Luella D; Myler, Peter J et al. (2006) Genomic organization and expression of the expanded SCG/L/R gene family of Leishmania major: internal clusters and telomeric localization of SCGs mediating species-specific LPG modifications. Mol Biochem Parasitol 146:231-41
Barron, Tamara L; Turco, Salvatore J (2006) Quantitation of Leishmania lipophosphoglycan repeat units by capillary electrophoresis. Biochim Biophys Acta 1760:710-4
Goswami, Mamta; Dobson, Deborah E; Beverley, Stephen M et al. (2006) Demonstration by heterologous expression that the Leishmania SCA1 gene encodes an arabinopyranosyltransferase. Glycobiology 16:230-6
Segawa, Hiroaki; Soares, Rodrigo P; Kawakita, Masao et al. (2005) Reconstitution of GDP-mannose transport activity with purified Leishmania LPG2 protein in liposomes. J Biol Chem 280:2028-35
Dermine, Jean-Francois; Goyette, Guillaume; Houde, Mathieu et al. (2005) Leishmania donovani lipophosphoglycan disrupts phagosome microdomains in J774 macrophages. Cell Microbiol 7:1263-70
Soares, Rodrigo P P; Cardoso, Tatiana L; Barron, Tamara et al. (2005) Leishmania braziliensis: a novel mechanism in the lipophosphoglycan regulation during metacyclogenesis. Int J Parasitol 35:245-53
Soares, Rodrigo P P; Barron, Tamara; McCoy-Simandle, Kessler et al. (2004) Leishmania tropica: intraspecific polymorphisms in lipophosphoglycan correlate with transmission by different Phlebotomus species. Exp Parasitol 107:105-14

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