Christiane Brohm26.01.2009 (1) M. tuberculosis profile (2) Infection route (3) Survival strategies...
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Transcript of Christiane Brohm26.01.2009 (1) M. tuberculosis profile (2) Infection route (3) Survival strategies...
Christiane Brohm 26.01.2009
(1) M. tuberculosis profile
(2) Infection route
(3) Survival strategies of M. tuberculosis
Mycobacterium Tuberculosis Profile
Family: Mycobacteriaceae
Genus: Mycobacterium
Feature: waxy coating gram-positive obligate aerobe
Disease: Tuberculosis
Prevalence: 2 billion worldwide 10% casuality
Therapy: antimycobacterial therapy (e.g. isoniazid, rifampicin)
Infection Route of M. tuberculosis
(1) Inhalation of aerosols containing bacilli
(2) Phagocytosis in lung by resident macrophages
(3) Lysosomal degradation or survival within macrophage
Infection Route of M. tuberculosis- Phagosomal Way -
Nature Reviews Immunology 1, 20-30 (October 2001) | doi:10.1038/35095558
(1) Internalization into phagosome→ delivery to antigen processing/presentation pathway
(2) Activation of T-cells by peptide-loaded MHC class II molecules; mycobacterial lipids presented to γδ T cells→ adaptive immune response
But:
Escape of immune defense mechanisms
Survival Strategies of M. tuberculosis
(1) Phagocytosis into macrophage→ receptor dependent macrophage activation
(6) Subversion of macrophage activation→ reaction on oxygen/nitrogen
(5) Hijacking cellular calcineurin pathway→ preventing fusion/degradation
(4) Mimicking of host signaling molecules→ preventing fusion/degradation
(3) Prevention of phagosome-lysosome fusion→ no degradation but persistence
(2) Establishment of a balance: the granuloma→ persistence for long time
Bacteria – Host Balance : The Granuloma
- T cell activation following presentation of mycobacterial antigens
- actively dividing bacilli or „dormant“ state
- attenuated immune system can lead to development of tuberculosis
Mycobacterial Prevention of Phagosome-Lysosome-Fusion
Non-infected cells: Generation of PI3P regulates delivery of phagocytosed cargo to lysosomes
PI3P: phosphatidylinositol 3-phosphateLAM: mycobacterial cell-wall component lipoarabinomannanSapM: eukaryotic-like acid phosphatase secreted by M.t.
Infected cells: Interference with phagosome-lysosome fusion
M. tuberculosis
(1) prevents PI3P generation by mycobacterial LAM
(2) hydrolizes PI3P on phagosomal membranes by SapM
Production of Host-like Signaling Molecules
Nature Medicine 13, 282 - 284 (2007) doi:10.1038/nm0307-282
Mycobacterial production of eukaryotic-like serine/threonine kinases- two kinases are soluble and thereby released into the cytoplasm
PknGPrevention of phagosome-lysosome fusion
Drug targetSpecific kinase inhibitor interacting with the unique domain of PknG
Inhibitors do not need to aquire accessto impermeable mycobacterial cell wall
Interfering with Host Cell SignalingHijacking the Calcineurin Pathway
TACO, P57, Coronin 1Host factor that specifically prevents lysosomal delivery.Exclusively presence on phagosomes harboring mycobacteria.
Regulation of calcium-dependent signaling processes:
Infected macrophages respond with sustained calcium flux dependent on Coronin 1.
Activation of calcineurin blocks fusion.
Calcineurin blockers (cyclosporin A, FK506)fully block mycobacterial proliferation.
Macrophage Activation and Its Subversion by M. tuberculosis
Block of fusion only in non-activated macrophages.What happens in activated macrophages?
(1) Mycobacterial production of KatG: Inactivation of reactive oxygen
(2) Mycobacterial proteasome copes with nitric-oxid stress
KatG: mycobacterial catalase-peroxidase
Macrophage Activation and Its Subversion by M. tuberculosis
Cathelicidin
TLR-ligands can cause macrophage activation
Phagosome maturation through TLR adaptor MyD88 and p38MAPK
Upregulation of vitamin D receptor
Induction of cathelicidin (antimicrobial peptide)
MyD88: myeloid differentiation factor 88p38MAPK: mitogen-associated protein kinase p38 protein
Macrophage Activation and Its Subversion by M. tuberculosis
LAM interferes with macrophage by modulating signaling pathways
IFN-γ-mediated gene expressionTLR activationMAPK activationPhagosome-lysosome fusion
Modulation of bacterial metabolic pathways
fatty acids as carbon source within macrophagesSec-dependent secretion pathway (signal-sequence dependent transport)Tat-system (transport of folded molecules)ESX-1 secretion system (transport of virulence factors, escape of bacilli into cytoplasm)
LAM: cell-wall component lipoarabinomannanTat-system: twin-arginine transporter systemESX-1: early secretory antigenic target of 6kD (ESAT-6) system 1
Conclusions
M. tuberculosis
plays hide-and-seek in phagosomes within macrophages and granulomas within the lung.
prevents phagosome-lysosome fusion by mimicking and hijacking host signaling pathways.
actively reacts and persists in activated macrophages.
Prolonged coevolution of M. tuberculosis with its human host resulted in a number of survival strategies.