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Functional gene analysis of pneumocystis by complementation of yeast genes

English title Functional gene analysis of pneumocystis by complementation of yeast genes
Applicant Hauser Philippe
Number 112360
Funding scheme Project funding
Research institution Institut de Microbiologie - CHUV Faculté de Biologie et Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Medical Microbiology
Start/End 01.06.2006 - 31.08.2009
Approved amount 296'000.00
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All Disciplines (2)

Discipline
Medical Microbiology
Experimental Microbiology

Keywords (5)

Pneumocystis carinii; schizzosaccharomyces pombe; heterologous expression; gene functional analysis; gene deletion

Lay Summary (English)

Lead
Lay summary
The fungal pathogen Pneumocystis causes severe pneumonia in immuno-compromised individuals. However, because of the lack of a long-term in vitro culture system, many aspects of its biology remain poorly understood. The genome of Pneumocystis has been sequenced and 1042 expressed genes were identified. The function of ca. 50% of these genes cannot be inferred because they have no homologous genes in current databases, only weak homologous genes, or homologous genes with unknown function. About 50% of the fungal homologous genes with unknown function are in Schizosaccharomyces pombe, the closest known existing relative of Pneumocystis organisms. The function of the remaining 50% of P. carinii expressed genes could be inferred from their homologous genes present in current databases. 51 of these homologous genes are in Saccharomyces cerevisiae. In the absence of genetic systems in P. carinii, functional gene analysis will be carried out in S. pombe and S. cerevisiae, yeasts offers numerous tools for genetic manipulation. As a first phase, we will focus on genes which have been selected in order to increase the probability for identification of new useful drug targets by the absence of homologous genes in vertebrates. 15 S. pombe genes will be deleted, the resultant phenotype determined, and the mutants complemented with the P. carinii homologous genes to assess function. The available deletion mutants of 14 S. cerevisiae genes will be complemented with the P. carinii homologous genes. Very little is currently known about basic biological functions of Pneumocystis including, metabolic, signal transduction, or reproductive capacities. Results from the present proposal will identify genes and assess their functions in integral pathways, providing new information on such essential functions. This information can be used for a variety of therapeutic approaches including the design of novel drugs or combination therapy targeting two or more essential functions. This is important because resistance of Pneumocystis is developing towards antifolates, the most efficient drugs against Pneumocystis, as well as towards second-line drugs and that no other efficient alternative drug is available at the moment. These data may also reveal why Pneumocystis cannot grow outside the lung or suggest additives that may permit ex vivo growth, providing a key tool for research progress. Pneumocystis organisms are “opportunistic pathogens”. Results from this study may lead to new knowledge associated with the adaptive life style of these fungi which may have broader applications to other pathogenic fungi.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
124998 De novo sequencing of the genome of the human pathogenic fungus Pneumocystis jirovecii and study of Pneumocystis pneumonia lung microbiome 01.10.2009 Project funding

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