IMMUNE RESPONSE TO MYCOBACTERIAL INFECTION Awalia Febriana Hardyanto Soebono Agnes Sri Siswati Faculty of Medicine Gadjah Mada University

Mycobacteria Most Mycobacteria non-pathogenic: soil & water organisms more named each year (sampling) Pathogenic Mycobacteria: Can be environmental-humans accidental host E.g. Mycobacterium avium Can be obligate pathogens with no known environmental reservoir E.g. Mycobacterium leprae

Pathogenic Mycobacteria: Properties Most slow growing, doubling on order of day (c.f. E coli 30 min.) Gram-positive, but don’t gram stain Mycolic acid cell wall acid fast staining Wall protects bacteria from environment, molecular biology Wall immunostimulatory: Freund’s

Non-tuberculous Mycobacteria pathogenic to humans Mycobacterium avium sp. avium: Avian tuberculosis In humans: disease in AIDS Chronic pneumonia Lymph node disease in children M. avium sp. paratuberculosis: Inflammatory bowel disease in ruminants, primates (Johne’s disease) In humans: implicated by some in Crohn’s M. leprae The agent of leprosy

Mycobacteria are not limited to the tropics Leprosy in Norway, 1851-1920 Rates low in cities where TB rates high

Mycobacteria Slow growing, aerobic, intracellular bacilli Contain high concentration of lipids Acid resistant staining

Importance of Study Immunology Immunopathogenesis of the diseases Development more accurate diagnostic tests Development effective vaccines

Mycobacteria Antigenic components of mycobacteria Host Immune Response Innate immunity Adaptive immunity Development of Diagnostic tools Vaccine development

Structure of M leprae cell wall PGL-I Mycolic acids Arabinogalactans Peptidoglycan P Membran sel P P

ANTIGENIC COMPONENTS OF M. LEPRAE Cell wall : PGL (phenolic glycolipid) LAM (lipoarabinnomannan) Cell membrane : 30 – 32 kDa 35 kDa 45 kDa Hsp (heat shock proteins) : 18, 28, 36, 65, 70 kDa

Immunity to mycobacteria Control of infection NK CD8 IFN-γ IL-12 CD4 Eradication of infection IFN-γ Neutrophils Macrophages Macrophages 7 Innate immunity Adaptive immunity 14

Components of innate immunity Epithelial barriers Phagocytes (neutrophils/monocytes/macrophages) Natural killer cells Complement system Other plasma proteins (mannose binding lectin, C-reactive protein)

After infection with mycobacteria Macrophages are infected and used as host cells Clinical disease may develop in 5 % cases Some clinical damages are caused by immune response

Mycobacteria is intracellullar parasites Antibody response is of little use The most effective immune response is immunocompetent cells able to kill infected cells The most important cells to protect against mycobacterial infection : CD4+ T cells Macrophages

Adaptive Immunity Akira et al, Nature Immunol 2001;2:675-80

Subclinical infection M. leprae Spontaneous heal CLINICAL SPECTRUM CMI BI TT BT BB BL LL

TT TH1 IL-4 IL-5 IL-6 IL-10 IL-13 IL-2 IFN- TNF IL-12 LL TH2

DIAGNOSTIC TESTS Skin tests  Cellular imunity MLSA Peptide antigens Serology  Antibody assay ELISA MLPA

VACCINES DEVELOPMENT How do we distinguish protective immunity from pathological immunity ? How do we induce one and avoid the other ? Can we identify those protective antigens by immunological methods ?

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Non-tuberculous mycobacterial infections in Swedish children Rates increasing where TB gone, BCG stopped BCG discontinued