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Global burden of tuberculosis

Global burden of tuberculosis. (The economist’s view). An estimated 15 million active cases, leading to….. An estimated 9 million new infections Approx 2 million deaths Approx 2 Billion USD in direct control costs And an uncounted indirect cost in lost lives and productivity.

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Global burden of tuberculosis

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  1. Global burden of tuberculosis (The economist’s view) An estimated 15 million active cases, leading to….. An estimated 9 million new infections Approx 2 million deaths Approx 2 Billion USD in direct control costs And an uncounted indirect cost in lost lives and productivity

  2. Development of Tuberculosis (the clinician’s view) TB (5%) TB (3%) TB (1%) TB (less than 0.1%/year) Healthy (95%) Healthy (92%) Healthy (91%) Healthy (approx. 90%) Exposure Year 1 Year 2 Year 3 thereafter

  3. Response to infection (the immunologist’s view) These individuals do not apparently skin-test convert Early bacterial growth arrested at early time point. May (or may not) result in latent infection 67% Initial exposure 33% 22% 24% Early bacterial growth not contained. Leads to clinical illness Subsequent bacterial growth contained. Symptoms abate but latent infection established. Remain healthy but latently infected 9% 2% Bacterial growth not contained. Progressive disease unless treated Reactivation of latent infection at a later point in life These individuals generally skin-test convert. They often have characteristic patterns on X-ray.

  4. Study Sites in Ethiopia Butajira Hospital Hossana Hospital

  5. Recruitment in Ethiopia • Index cases (TB, n=76) • smear /culture positive • X-ray confirmed • Symptomatic • Community Control (CC, n=40) • smear/culture negative • X-ray normal • Asymptomatic • No known TB contact • Healthy Household Contact (HHC, n=104) • smear/culture negative • X-ray normal • Asymptomatic • Symptomatic Household Contact (XHC, n=58) • smear/culture negative • X-ray often, but not always, suspicious • Symptomatic

  6. Methods Culture with specific antigens PBMC Frozen in liquid N2 Thawed Blood Plasma RNA 24/48 hr cultured cells 96 hr Culture supernatant HIV Double ELISA cDNA IFN-  ELISpot IFN- g ELISA frozen at -20 0C ELISA: sTNFR2 IL-10 Ag-specific Ab PCR OD reading 12 bit CCD camera Agarose gel Real Time PCR

  7. TB-specific antigens Shared TB complex Antigens (4000+) M. tuberculosis BCG M.tuberculosis specific Antigens (100+): ESAT-6 Common mycobacterial Antigens (1000+) Ag85A/B Rv2031c Atypical mycobacteria

  8. Risk of TB in ESAT+ healthy contacts from Ethiopia 35 healthy household contacts of TB patients were tested by ELISA for their response to ESAT-6 or PPD Over the next two years their clinical status was monitored Doherty et al., JCM , Feb. 2002

  9. High ESAT-6 immune reactivity reflects high levels of M. tuberculosis replication People who fail to control bacterial replication become ESAT+ and get TB “Clinical disease” threshold CFU “positivity” threshold People who fail to control initial bacterial replication become ESAT+, but if they control later infection, become latently infected Time after infection People who control initial bacterial replication remain ESAT-, and may or may not be latently infected

  10. Differential cytokine expression in clinical cohorts

  11. Differential cytokine expression in healthy contacts IL-4 mRNA expressed as percentage -actin + -

  12. Differential cytokine expression in community controls IFN-g mRNA expressed as percentage -actin IL-4d2 mRNA expressed as percentage -actin 1.5 1.0 IL-4 mRNA expressed as percentage -actin 0.5 0

  13. Change in cytokine expression over time (TB patients) mRNA relative to b-actin

  14. Change in cytokine expression over time (contacts) mRNA relative to b-actin mRNA relative to b-actin

  15. A lowered ratio of IL-4 to IFN-g and IL-4d2 reflects a shift from acute to latent TB People who fail to control bacterial replication become ESAT+ and get TB “Clinical disease” threshold Th2 CFU “positivity” threshold Th1 Th2 People who fail to control initial bacterial replication become ESAT+, but if they control later infection, become latently infected Th1 Th1? People who control initial bacterial replication remain ESAT-, and may or may not be latently infected Time after infection

  16. Response to infection (the immunologist’s view) These individuals do not apparently skin-test convert or become ESAT-6 positive Early bacterial growth arrested at early time point. May (or may not) result in latent infection Immunologically, little is known about these individuals as they cannot be distinguished from uninfected individuals 67% Initial exposure 33% 22% 24% Early bacterial growth not contained. Leads to clinical illness Subsequent bacterial growth contained. Symptoms abate but latent infection established. Remain healthy but latently infected 9% 2% Bacterial growth not contained. Progressive disease unless treated Reactivation of latent infection at a later point in life These individuals generally skin-test convert and become ESAT-6 positive. They often have characteristic patterns on X-ray. Immunologically these individuals tend to express elevated levels of IL-4 and in advanced disease, decreased IFN-g and IL-12 Immunologically, these individuals tend to express elevated levels of IFN-g and IL-12, and while IL-4 often remains slightly increased, its antagonist IL-4d2 is greatly increased

  17. Bacterial response to infection Acute infectionLatent infection Expression of early phase Expression of late phase genes genes such as Ag85 such as a-crystallin and and ESAT-6 the DosR regulon Acute Disease Reactivation of infection CFU Immune conversion Latency? Latent infection Elimination? 1-3 4-50 Years after exposure

  18. Alteration of antigen recognition as disease progresses (ET) 10000 1000 100 10 TB HHC LTBI ESAT-6 response in clinical groups IFN-g (pg/ml) p<0.001 p<0.001 10000 1000 100 10 TB HHC LTBI Rv2031c response in clinical groups

  19. Alteration of antigen recognition as disease progresses (Ga and NL) Slope of linear regression no. of spots from ESAT-6 stimulation vs Rv2031c Slope of linear regression no. of spots from ESAT-6 stimulation vs Rv2031c Slope of linear regression IFN-g from ESAT-6 stimulation vs Rv2031c

  20. ratio nHBHA-IFN-g /ESAT-6-IFN-g Log IFN-g conc. (pg/ml) p< 0.005 400 p< 0.005 100000 300 200 10000 100 1000 1.00 0.75 100 0.50 Active TB Active TB 10 0.25 Latent TB Latent TB 0.00 Active TB Latent TB nHBHA ESAT-6 Comparison of the IFN-g secretions induced by nHBHA and by ESAT-6 Figure kindly provided by Camille Locht and François Mascart

  21. A lowered ratio of ESAT-6 immune reactivity to Rv2031c reactivity reflects a shift from acute to latent TB People who fail to control bacterial replication become ESAT+ and get TB “Clinical disease” threshold CFU “positivity” threshold People who fail to control initial bacterial replication become ESAT+, but if they control later infection, become latently infected Rv2031c ESAT-6 Rv2031c Rv2031c ESAT-6 ESAT-6 People who control initial bacterial replication remain ESAT-, and may or may not be latently infected Time after infection

  22. Response to infection (the immunologist’s view) These individuals do not apparently skin-test convert or become ESAT-6 positive Early bacterial growth arrested at early time point. May (or may not) result in latent infection Immunologically, little is known about these individuals as they cannot be distinguished from uninfected individuals 67% Initial exposure 33% 22% 24% Early bacterial growth not contained. Leads to clinical illness Subsequent bacterial growth contained. Symptoms abate but latent infection established. Remain healthy but latently infected 9% 2% Bacterial growth not contained. Progressive disease unless treated Reactivation of latent infection at a later point in life Immunologically, these individuals tend to express elevated levels of IFN-g and IL-12, and while IL-4 often remains slightly increased, its antagonist IL-4d2 is greatly increased. They strongly recognise Rv2031c Immunologically these individuals tend to express elevated levels of IL-4 and in advanced disease, decreased IFN-g and IL-12. They weakly recognise Rv2031c These individuals generally skin-test convert and become ESAT-6 positive. They often have characteristic patterns on X-ray.

  23. Summary • Immunity to M. tuberculosis is dependent on the generation of Th1 immunity, particularly IL-12, IFN-g and TNF-a • As the bacteria persists in the face of this Th1 response, it begins to alter its proteome towards a pattern characteristic of latency, downregulating some antigens, upregulating others • At the same time, a Th2 response seems to develop • Susceptibility to infection therefore appears to correlate not so much with inability to generate a Th1 response, as with inability to maintain it long term, or perhaps inability to direct it to relevant antigens • We are starting to see evidence that M. tuberculosis-derived antigens are driving some of this Th2 response

  24. Activation of the immune response (the molecular biologist’s view) M.tuberculosis Peptidoglycans Lipoproteins The activation of the inflammatory cascade is essential for protection. Defects in this pathway in either humans or animals are associated with extreme susceptibility to mycobacteria Blocking either IFN- g or TNF-a after induction of immunity also blocks control of infection However - M. tuberculosis also needs these cytokines to cause pathology so that it can spread TLR4 TLR2 IRAK TRAF6 TIRAP MYD88 +MAL NFKB NEMO/IKK IL-18,etc TNF-a, IL-12, IL-18, IL-6, etc IRF3

  25. Generation of protective immunity (the cell biologist’s view) Mycolic acids, lipoproteins M. tuberculosis PAMP binding IL-18 IL-18R IL-12 Jak/Stat activation Uptake/ Phagocytosis IL-12R Specific T cell proliferation Presented antigen Lysosome maturation and bacterial killing TCR Stat1 activation IFN-g IFN-gR TNF-a-R TNF-a T cell Antigen presenting cell

  26. What can go wrong with protective immunity Mycolic acids, lipoproteins M. tuberculosis Blocking of phagocytic maturation PAMP binding IL-18 IL-18R IL-12 Jak/Stat activation Elevated IL-10 Uptake/ Phagocytosis IL-12R Specific T cell proliferation Presented antigen Lysosome maturation and bacterial killing IL-10R TCR Stat1 activation IFN-g IFN-gR IL-10R TNF-a-R Elevated IL-4/13 TNF-a T cell Antigen presenting cell

  27. Effect of mycobacterial products on the immune response PGL Mycolic acids, lipoproteins M. tuberculosis ESAT-6/ CFP10 LAM PAMP binding IL-18 IL-18R IL-12 DC-SIGN Jak/Stat activation IL-10 Uptake/ Phagocytosis Decoy antigens (27 kDa, PE/PPE family) IL-12R Specific T cell proliferation 19 kDa Lysosome maturation and bacterial killing IL-10R Presented antigen TCR Stat1 activation IFN-g IFN-gR IL-10R TNF-a-R Bacterial lipid-induced IL-4/13 TNF-a T cell Antigen presenting cell

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