Transcript Folie 1 - MH

(1) M. tuberculosis profile
(2) Infection route
(3) Survival strategies of M. tuberculosis
Christiane Brohm
26.01.2009
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 (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
Nature Reviews Immunology 1, 20-30 (October 2001) | doi:10.1038/35095558
Survival Strategies of M. tuberculosis
(1) Phagocytosis into macrophage
→ receptor dependent macrophage activation
(2) Establishment of a balance: the
granuloma
→ persistence for long time
(3) Prevention of phagosome-lysosome
fusion
→ no degradation but persistence
(4) Mimicking of host signaling molecules
→ preventing fusion/degradation
(5) Hijacking cellular calcineurin pathway
→ preventing fusion/degradation
(6) Subversion of macrophage activation
→ reaction on oxygen/nitrogen
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
Infected cells: Interference with phagosome-lysosome fusion
M. tuberculosis
(1) prevents PI3P generation by mycobacterial LAM
(2) hydrolizes PI3P on phagosomal membranes by SapM
PI3P: phosphatidylinositol 3-phosphate
LAM: mycobacterial cell-wall component lipoarabinomannan
SapM: eukaryotic-like acid phosphatase secreted by M.t.
Production of Host-like Signaling Molecules
Mycobacterial production of eukaryotic-like serine/threonine kinases
- two kinases are soluble and thereby released into the cytoplasm
PknG
Prevention of phagosome-lysosome fusion
Drug target
Specific kinase inhibitor interacting with
the unique domain of PknG
Inhibitors do not need to aquire access
to impermeable mycobacterial cell wall
Nature Medicine 13, 282 - 284 (2007) doi:10.1038/nm0307-282
Interfering with Host Cell Signaling
Hijacking the Calcineurin Pathway
TACO, P57, Coronin 1
Host 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
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 88
p38MAPK: mitogen-associated protein kinase p38 protein
Cathelicidin
Macrophage Activation and Its Subversion by
M. tuberculosis
LAM interferes with macrophage
by modulating signaling pathways
IFN-γ-mediated gene expression
TLR activation
MAPK activation
Phagosome-lysosome fusion
Modulation of bacterial metabolic pathways
fatty acids as carbon source within macrophages
Sec-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 lipoarabinomannan
Tat-system: twin-arginine transporter system
ESX-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.
Thank you for your attention!