Parasites of the trypanosomatid protozoan genus Leishmania are responsible for a spectrum of tropical diseases that afflict more than 10 million people worldwide, and depending on the specific speciesand mmune status of the infected person, can be severe or fatal. In several countries, leishmaniasis is a common opportunistic infection in AIDS patients, and many USsolidiers stationed in the Middle East have been infected. The goal of our research is to develop and apply new methods for the identification of genes used by this parasite to carry out its infectious cycle. Our premise is that the availability of powerful molecular genetic tools, and identification of genes important to parasite virulence, will radically advance our ability to develop improved control strategies. In previous studies methods were developed for manipulating the parasite genome in a variety ofways by forward or reverse genetics, and to develop functional genomic approaches such as transposon mutagenesis and expression profiling. Success with expression profiling now enables us to incorporate this powerful methodology more comprehensively into our research program, and undertake a broader survey of patterns and mechanisms of gene expression in Leishmania, making use of both genetic and biological methodological advances from the prior grant period. The goal is to identify genes showing patterns of expression suggestive of functional roles in the infectious cycle, for example stage-specific expression or alterations in response to relevant stimuli, whose predictions and implications can then be tested experimentally. One example that will be pursued involves a new perspective on the differentiation of the parasite into the infectious metacyclic form transmitted by sand flies, involving global changes in parasite gene expression probably mediated by changes in chromating structure, specific changes in expression arising from a combination of mechanisms, and biological changes involving massive cellular remodeling and 'shrinkage'possibly mediated by autophagy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI029646-21
Application #
7758218
Study Section
Pathogenic Eukaryotes Study Section (PTHE)
Program Officer
Mcgugan, Glen C
Project Start
1990-03-01
Project End
2011-01-31
Budget Start
2010-02-01
Budget End
2011-01-31
Support Year
21
Fiscal Year
2010
Total Cost
$657,134
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
Kuhlmann, F Matthew; Robinson, John I; Bluemling, Gregory R et al. (2017) Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor. Proc Natl Acad Sci U S A 114:E811-E819
Matveyev, Andrey V; Alves, João M P; Serrano, Myrna G et al. (2017) The Evolutionary Loss of RNAi Key Determinants in Kinetoplastids as a Multiple Sporadic Phenomenon. J Mol Evol 84:104-115
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Rossi, Matteo; Castiglioni, Patrik; Hartley, Mary-Anne et al. (2017) Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis. Proc Natl Acad Sci U S A 114:4987-4992
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Parmentier, Laurent; Cusini, Alexia; Müller, Norbert et al. (2016) Severe Cutaneous Leishmaniasis in a Human Immunodeficiency Virus Patient Coinfected with Leishmania braziliensis and Its Endosymbiotic Virus. Am J Trop Med Hyg 94:840-3
Macedo, Diego H; Menezes-Neto, Armando; Rugani, Jeronimo M et al. (2016) Low frequency of LRV1 in Leishmania braziliensis strains isolated from typical and atypical lesions in the State of Minas Gerais, Brazil. Mol Biochem Parasitol 210:50-54
Brettmann, Erin A; Shaik, Jahangheer S; Zangger, Haroun et al. (2016) Tilting the balance between RNA interference and replication eradicates Leishmania RNA virus 1 and mitigates the inflammatory response. Proc Natl Acad Sci U S A 113:11998-12005

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