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M.R. Barbouche M.D., Ph.D.

Host-Pathogen interaction during mycobacterial infection. M.R. Barbouche M.D., Ph.D. Department of Immunology, Institut Pasteur de Tunis, Tunisia. Host-Pathogen interaction during mycobacterial infection. Host-Mycobacteria interaction is relevant in several aspects:.

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M.R. Barbouche M.D., Ph.D.

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  1. Host-Pathogen interaction during mycobacterial infection M.R. Barbouche M.D., Ph.D. Department of Immunology, Institut Pasteur de Tunis, Tunisia

  2. Host-Pathogen interaction during mycobacterial infection.

  3. Host-Mycobacteria interaction is relevant in several aspects: Pathogenesis of mycobacterial infection. Diagnosis of mycobacterial infection. Vaccine development.

  4. Host-pathogen interaction and pathogenesis of mycobacterial infection: Susceptibility may result in part from variability of the genes controlling the host immune responses due to: - genetically transmitted defects or polymorphisms - acquired disorders

  5. Host genetics and mycobacterial infections Humans may be exposed to a variety of mycobacteria: - Weakly pathogenic mycobacteria: either environmental (M. avium, M. smegmatis...) or live attenuated vaccine (BCG). - Pathogenic mycobacteria (M. tuberculosis, M. leprae) But, only a minority (~10%) of individuals exposed develop clinical disease, even if they are infected with virulent strains. The Lubeck vaccination accident in 1926 with 173 out of 249 babies who did survive. Twin studies have shown a higher concordance for TB among monozygotic twins compared to dizygotic twins. The identification of a genetic immunodeficiency with a selective susceptibility to mycobacteria i.e. Mendelien Susceptibility to Mycobacterial Disease (MSMD )

  6. Casanova J.L. and Abel L. Annu. Rev. Immunol 2002.

  7. IFN-g IL12-dependent pathway:

  8. Age at BCG vaccination Associated infections Age at onset of BCG infection Age at clinical dissemination Sex Patient Outcome Treatment Consanguinity History and clinical features of disseminated BCG infection (MSMD) in Tunisian patients * Indicates tissues with clinical, bacteriological, pathological and/or radiologic evidence compatible with BCG infection.

  9. IL-12p40 mutation In 3 patients, two siblings and an unrelated patient we have identified an identical 8pb deletion (295del8) within exon 3 of IL-12p40 gene (c2). The putative mRNA encodes for a theoretical 89 aa peptide but no protein is detected. Wild type sequence Mutated sequence

  10. ELISA measurement of IL-12p40 cytokine subunit

  11. CH family BO family IL-12Rb1 mutations In 2 patients, two new splice site mutations within the IL-12Rb1 have been identified: a1- Mutation 550-2AG b1- Mutation 64+5GA

  12. FACS analysis of IL12Rb1 expression

  13. ELISA measurement of IFNgcytokine

  14. Casanova J.L. and Abel L. Annu. Rev. Immunol 2002.

  15. Etude de polymorphismes d’autres gènes de la réponse immune et la susceptibilité à la tuberculose: Gène IL12RB1 Mutations en déséquilibre de liaison avec deux haplotypes différents (allele1: Q214-M365-G378; allele2: R214-T365-R378)

  16. Résultats préliminaires chez 20 couples discordants: L’allèle 2 (Arg214-Thr365-Arg378) semble plus fréquent chez les tuberculeux que chez les contrôles.

  17. TLR2 Gene - Recognition of different antigenic structures of M. tuberculosis by alveolar macrophage TLRs is a crucial step toward an efficient immune response - SNP polymorphisms in TLRs genes might have significant functional consequences

  18. IL-1; TNF; IL-6 Recognition TH1 IL-12,IL-18 Naïve T cell Co-stimulatory molecules Capture MHC APC Ag presentation TH2 ADAPTIVE INNATE Pathogen

  19. Alignement of TLR family members AA sequence: TLR2mut. Arg677Trp affects the intracellular domain

  20. A B wt/mut wt/wt TLR2 genomic DNA sequencing: A. Heterozygous wild type/mutated (wt/mut) genotype. B. Homozygous (wt/wt) genotype.

  21. Genotypes Tuberculosis patients (n = 33) Healthy controls (n = 33) C/C C/T T/T 2 (6%) 31 (94%) 0 (0%) 23 (69%) 10 (31%) 0 (0%) Distribution of TLR2 genotypes in patients and controls p< 0.0001 compared with normal controls as calculated by Fischer exact test. Percentages are shown in parentheses.

  22. Host-pathogen interaction and diagnosis of mycobacterial infection: Investigation of cellular immune response : • Tuberculin Skin Test (in vivo): Delayed Hypersensitivity Response • Interferon-g ELISA/ELISPOT assays (in vitro): IFN-g production of sensitized T lymphocytes IFN-g assays are comparable to TST for the ability to detect latent TB infection but are less affected by BCG vaccination, responses to non tuberculous mycobacteria? and avoid subjectivity associated to placing and reading the TST

  23. ELISA or ELISPOT

  24. Investigation of humoral immune response: • Serodiagnosis: Still controversial but there is some renewed interest in developing such an affordable and rapid ELISA assay Challenges: low sensitivity, variable spectrum of antigens recognized humorally, lack of standardization of antigen sources. Perspectives: use of a combination of antigens, recombinant antigens produced in more appropriate expression vectors than E. Coli

  25. IL-1; TNF; IL-6 Recognition TH1 IL-12,IL-18 Naïve T cell Co-stimulatory molecules Capture MHC APC Ag presentation TH2 ADAPTIVE INNATE Host-pathogen interaction and vaccine development: Pathogen

  26. Contributors: H. Elloumi M. Ben Ali S. Abdelhak R. Haltiti J. Chemli E. Brahem A. Harbi S. Bousnina M. Béjaoui A. Chabbou K. Dellagi M.R. Barbouche

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