Tuberculosis and Immunity

Latent Tuberculosis: Sleeping with the enemy : 

Latent Tuberculosis: Sleeping with the enemy Mechanisms of host and bacillus that contribute to persistent infection Dag Gundersen Storla 2007

Millennium Target Goals : 

Millennium Target Goals Case Detection Rate above 70 % Cure Rate above 85 % Millennium Development Goals - A complete listing of the goals, targets, and indicators for MDGs. 2003 Available from: http://www.developmentgoals.org/Goals.htm.

DOTS for 6 months? : 

DOTS for 6 months? In 2004, an estimated 53% of new smear-positive cases were detected under DOTS Treatment success in the 2003 DOTS cohort of 1.7 million patients was 82% on average, edging closer to the 85% target

2 reasons for 6 months DOTS : 

2 reasons for 6 months DOTS 1. Chemotherapy kills the vast majority of the bacteriae, but ”persisters” remain Sleeping with the enemy TB Bacillae in a Macrophage

2 reasons for 6 months DOTS : 

2 reasons for 6 months DOTS 2.The Koch phenomena; a necrotizing, inappropriate response pattern Does not correct itself during treatment! Caseous necrosis

The Koch Phenomena : 

The Koch Phenomena Guinea Pigs inoculated with TB  Infection established Intradermal Challenge with TB culture filtrate after 4-6 weeks  NECROSIS A. LOCALLY B. At the ORIGINAL TUBERCULOSIS LESION

The Koch Phenomena : 

The Koch Phenomena Necrosis is not an unevitable consequence of the delayed hypersensitivity response to tuberculin Necrosis does not occur when positive skin-tests to tuberculin are elicited in normal BCG recipients or in tuberculoid leprocy patients Tuberculin skin injection Tuberculosis patients NECROSIS BCG Immunized Tuberculoid leprocy patients NO NECROSIS NO NECROSIS

The Koch Phenomena : 

The Koch Phenomena Koch sought to exploit this phenomena in the treatment of tuberculosis patients: Old Tuberculin subcutaneously evoced necrosis in cutaneous tuberculosis  healed BUT: disastrous with further necrotic tissue in deep lesions in e.g. spine and lungs! Tuberculin skin injection Tuberculosis patients DISASTROUS! Cutaneous TB (Lupus vulgaris, usually caused by bovine strains) HEALED

Ultra short threapy? : 

Ultra short threapy? Graham Rookes: YES, If we can modulate the immune response from the disastrous necrosis of the Koch Phenomen to a protective immunity  if we can create a PROMPT AND CONSISTANT TYPE 1 RESPONSE

All infected start out so well… : 

All infected start out so well… Th1 Confined, small granulomas Caseous necrosis chronicity Mixed Th1/Th2 after ~ 50 days

Same substance – different responses : 

Mixed Th1/Th2 Th1 Caseous necrosis Granuloma formation TNFα enhances necrosis TNFα enhances Th1 response M . vacca 109 107 High dose enhances necrosis Low dose; immuno therapy? Same substance – different responses

Mechanisms of Protective immunity : 

Mechanisms of Protective immunity TYPE 1 RESPONSE Th1 T Cells IL-2 IL-12 IFNγ

Mechanisms of Protective immunity : 

Mechanisms of Protective immunity Gene knock-out mices Th1 T Cells  Susceptible to avirulent Mycobacterium bovis IFNγ  VERY Susceptible to Mycobacterium tuberculosis; death within 3 weeks

Mechanisms of Protective immunity : 

Mechanisms of Protective immunity MHC CLASS 1 – Restricted cells Β2 microglobulines  CD8+ Susceptible to Mycobacterium tuberculosis: CD8+ cytotoxic cells could might release TB bacillae from Macrophages (Φ) that were failing to kill them and allow fresh Φ to kill them TB exposed to the immune system

Mechanisms of Protective immunity : 

Mechanisms of Protective immunity On the other hand: Virulent strains of MTB can escape the phagosome, BCG cannot explaining the limited effect of Β2 microglobulines knock-out in mices infected with BCG ??

Mechanisms of Protective immunity : 

Mechanisms of Protective immunity A role of other T-cell subsets? γ/δ Cells proliferate in response to TB infection – partly regulatory? CD1 restricted (CD4-/CD8-) cells recognizes mycolic acid (making up the bulk of the MTB cell wall) Balb mouse TB exposed to the immune system

Mechanisms of Protective immunity : 

Mechanisms of Protective immunity Nitric Oxide (NO) Ultimately most TB bacillae are killed by macrophages A relevant effector pathway is dependent on NO Important signaling and second messenger function as well as the cytotoxic. NO  aggravation of infection

Mechanisms of Protective immunity : 

Mechanisms of Protective immunity Nitric Oxide (NO) Ultimately most TB bacillae are killed by macrophages A relevant effector pathway is dependent on NO Important signaling and second messenger function as well as the cytotoxic. NO  aggravation of infection

The immunological aspects of latency – sleeping with the enemy : 

The immunological aspects of latency – sleeping with the enemy 1. Evading the toxic effects of nitric oxide (NO) and reactive nitrogen intermediates L-arginine nitric oxide reactive nitrogen intermediates NOS2 NOS2 MTB RNI RNI RNI RNI RNI RNI RNI RNI resistance is coded by the genes NoxR1 and NoxR2

The immunological aspects of latency – sleeping with the enemy : 

The immunological aspects of latency – sleeping with the enemy ANTIOXIDANT COMPLEX FORTRESS MTB Dihydrolipoamid succinyltransferase (SucB) Peroxinitrite reductase activity Truncated Hb AhpC peroxiredoxin Dihydrolipoamide dehydrogenase (Lpd) Thioreductin-like AphD NAD dependend peroxidase

The immunological aspects of latency – sleeping with the enemy : 

The immunological aspects of latency – sleeping with the enemy HIJACKING THE PHAGOSOME Inhibiting the H+-ATPases  Lysosymes less acidic and hostile INHIBITION by MTB Lysosome - - - -

The immunological aspects of latency – sleeping with the enemy : 

The immunological aspects of latency – sleeping with the enemy HIJACKING THE PHAGOSOME Modulating SNARE proteins TACO retention MTB fails to fuse with lysosymes Rab5  Rab7 ManLAM  inhibation of EEA1 MTB inhibits the maturation of lysosomes

The immunological aspects of latency – sleeping with the enemy : 

The immunological aspects of latency – sleeping with the enemy Intercepting antigen presentation reduced Macrophage expression of HLA class II molecules Inside the macrophage MTB TL2 19kDa manLAM 25kDa manLAM 19 kDa 25 kDa  TL2 receptors

Summary : 

Summary The switch to a mixed Th1/Th2 response  Necrotizing pattern. If we could reverse  ultra short therapy MTB makes the macrophages a ”sanctuary” by Resisting RNI Building an antioxidant complex Hijacking the phagosome Disrupting the antigen presentation