Parasites of the trypanosomatid protozoan genus Leishmania are responsible for a spectrum of tropical diseases, afflicting more than 10 million people worldwide; depending on the species and immune status of the infected person, this disease can be severe or fatal. In Brasil, Africa and the Mediterranean basin, leishmaniasis is a common opportunistic infection in AIDS patients, many US soldiers now stationed in the Middle East have been infected, and there is a worrisome sense that Leishmania species may be emerging or expanding in the US. The surface of the Leishmania parasite is covered by a complex carbohydrate glycocalyx, whose structure and activities are tailored to meet the parasite's needs when growing in the sand fly vector as flagellated promastigotes, or within vertebrate macrophage phagolysosome as the roundish amastigote, where it survives happily in a hostile environment and evades immune defenses. Our group and collaborators pioneered powerful methods for the generation of mutants defect in the synthesis of the surface coat, originally focusing on the abundant lipophosphoglycan (LPG) as well as structurally related carbohydrates such as proteophosphoglycan (PPG), and more recently on molecules synthesized by the action of a novel mitochondrial fucosyltransefase. These mutants define vital biosynthetic proteins required for glycoconjugate synthesis and virulence, and the study of their impact on specific aspects of the infectious cycle enables a deeper understanding of their unique vs. overlapping roles. Several of the enzymes identified show considerable promise as targets for chemotherapy, or in the development of strategies focusing on parasite vaccination and interruption of transmission.

Public Health Relevance

Leishmania are important tropical parasites, causing disease in more than 10 million people worldwide, with more than 400 million people at risk, and with some possibility that it is expanding its range in the USA. Our work focuses on the parasite surface coat, which is comprised of complex carbohydrates. We will study several key genes required for its synthesis, which will inform us about mechanisms used for survival in both the human and animal hosts, and transmission by the sand fly vector. Several genes identify pathways with great potential as chemotherapeutic targets. Additionally, they may be adapted for 'glycoengineering' strategies aimed towards vaccination and/or interrupting transmission.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI031078-25
Application #
9597883
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
O'Neil, Michael T
Project Start
1992-07-01
Project End
2019-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
25
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Washington University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Mandell, Michael A; Beverley, Stephen M (2017) Continual renewal and replication of persistent Leishmania major parasites in concomitantly immune hosts. Proc Natl Acad Sci U S A 114:E801-E810
Guo, Hongjie; Novozhilova, Natalia M; Bandini, Giulia et al. (2017) Genetic metabolic complementation establishes a requirement for GDP-fucose in Leishmania. J Biol Chem 292:10696-10708
Mandell, Michael A; Beverley, Stephen M (2016) Concomitant Immunity Induced by Persistent Leishmania major Does Not Preclude Secondary Re-Infection: Implications for Genetic Exchange, Diversity and Vaccination. PLoS Negl Trop Dis 10:e0004811
Favila, Michelle A; Geraci, Nicholas S; Jayakumar, Asha et al. (2015) Differential Impact of LPG-and PG-Deficient Leishmania major Mutants on the Immune Response of Human Dendritic Cells. PLoS Negl Trop Dis 9:e0004238
Hsu, Fong-Fu; Kuhlmann, F Matthew; Turk, John et al. (2014) Multiple-stage linear ion-trap with high resolution mass spectrometry towards complete structural characterization of phosphatidylethanolamines containing cyclopropane fatty acyl chain in Leishmania infantum. J Mass Spectrom 49:201-9
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Ibraim, Izabela Coimbra; de Assis, Rafael Ramiro; Pessoa, Natalia Lima et al. (2013) Two biochemically distinct lipophosphoglycans from Leishmania braziliensis and Leishmania infantum trigger different innate immune responses in murine macrophages. Parasit Vectors 6:54
Mou, Zhirong; Muleme, Helen M; Liu, Dong et al. (2013) Parasite-derived arginase influences secondary anti-Leishmania immunity by regulating programmed cell death-1-mediated CD4+ T cell exhaustion. J Immunol 190:3380-9

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