LEPROSY BACILLUS,: FROM GENOTYPE TO PHENOTYPE

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DESCRIPTION (Adapted from the Applicant's Abstract): The purpose of this completely revamped resubmission is the identification and implementation of new antigens for the diagnosis and epidemiological monitoring of leprosy and is based on the just-sequenced contiguous M. leprae genome, on the investigators' singular access to the bacillus, and driven by the extraordinary epidemiological conundrum of a convergence of falling prevalence and rising incidence. The other hypothesis-driven thrust is that a defective genotype must be reflected in a truncated phenotype, the definition of which will also provide knowledge and tools to help explain the peculiarities of leprosy, such as obligate intracellularism, characteristic cell tropism and reactions. S. Cole (Institut Pasteur) will complete the analysis and annotation of the genome and generate databases to provide the means for a two-laboratory effort (L'Institut Pasteur; CSU) to define the transcriptome, polymorphism within the infectious agent, and the entire simplified proteome through cloning of targeted genes and definition of the full array of in vivo expressed proteins. CSU will apply the genome and the structural knowledge of mycobacteria to define the simplified secondary gene products (LepLAM; LM; new extracellular lipids; peptidoglycan; etc.). CSU, Fio-Cruz (C. Pessolani), and Yonsei University (S.-N. Cho) will combine to test new products in guinea pigs for DTH responses, against PBMC's of leprosy patients for appropriate T-cell reactivity, and against sera for antibody responses, with a view to advancing the new skin antigen initiative and providing new blood assays for early diagnosis and identification of a t risk populations.