how does M. tuberculosis survive in macrophages Flashcards
how dies M.tuberculosis affect phagosome
- arrests the normal maturation of the phagosome
- the Mttb containing phagosome does not fuse with lysosomes
how does mycobacterium tuberculosis inhibit cytosolic calcium rise
no recruitment of lysosomal hydrolases
no acidification
- inhibits cytosolic calcium rise
virulence determinants of M. tuberculosis involved in intra macrophage survival: cell wall components (lipoarabinomannan)
lipoarabinomannan
- complex glycolipid that contains repeating arabinose-mannose disaccharide subunits
- prevents acidification of the phagosomal vacuole (REQUIRED FOR PHAGO-LYSOSOMAL FUSION):
- blocks recruitment of PI3K to phagosomal membrane
- blocks lysosome recruitment
- scavenges reactive oxygen radicals
- blocks macrophages activation IFN gamma
- suppresses T cell proliferation
- inhibits host protein kinase C
virulence determinants of M. tuberculosis involved in intra macrophage survival: cell wall components - phosphatidylinositol mannoside
- enhances the fusion of phagosomes to early endosomes
virulence determinants of M. tuberculosis involved in intra macrophage survival: cell wall components: cell wall mycolic acids
- inactivates the respiratory burst
- prevents toxic effects of cationic proteins and lysosyme
- inhibits phagolysosomal fusion
virulence determinants of M. tuberculosis involved in intra macrophage survival: cell wall components - sulphated lipids
- polyanionic nature inhibits phagolysosomal fusion
virulence determinants of M. tuberculosis involved in intra macrophage survival: disruption of host signalling networks within the macrophage via secreted phosphatases and kinases
- secreted phosphoinositide phosphatases
secreted phosphoinositide phosphatases (SampM, MptpA and MptpB)
maintain low levels of PI3P
- SapM hydrolyses PI3P
- MptpA dephosphorylates and inactivated host protein VPS33B (a regulator of membrane fusion)
->block lysosome recruitment
virulence determinants of M. tuberculosis involved in intra macrophage survival: disruption of host signalling networks within the macrophage via secreted phosphatases and kinases - MTB possesses eukaryotic type protein kinases
secreted into the macrophage cytosol
- phosphorylates host proteins involved in the trafficking pathway
->promotes intracellular survival (blocks phagolysosomal fusion, promotes lysosomal escape, stress resistance, metabolic adaptation, antibiotic resistance)
virulence determinants of M. tuberculosis involved in intra-macrophage survival: adaptation to the nutrient-poor, ‘stressful’ environment of the macrophage
- involves recognition of environmental stress and the up-regulation of genes requires to survive within macrophages
- 2 component regulators/ sigma factors/ other transcriptional regulators
- superoxide dismutases, catalase, metal/ copper resistance determinants etc
virulence determinants of M. tuberculosis involved in intra-macrophage survival: adaptation to the nutrient-poor, ‘stressful’ environment of the macrophage
- urease (NH4)
- counter effects of a drop in pH
- inhibits phagolysosomal fusion
mycobacterium tuberculosis type 7 secretion systems
- Mtb has 5 specific type VII/ early secretory antigenic target protein family secretion (ESX) systems: ESX-1, ESX-2, ESX-3, ESX-4 and esx-5
- specialised secretion systems that enable the transport of selected substrates across the complex, thick mycobacterial cell envelope
- exported effector proteins help Mtb resist or evade host immune response
secretion systems
ESX-1:exports a number of substrates including ESAT6 - role in phagosomal rupture
ESX-3: involved in iron acquisition
ESX-5: involved in the secretion of PE and PPE proteins
ESX-2 and ESX-4: functions unknown
ESX-1 permeabilisation of the phagosomal membrane
ESX-1 system is a major Mtb virulence determinant:
- responsible for phagosomal rupture
factors that affect host cell susceptibility
- bcg locus influences host susceptibility
- gene - Nramp1 (natural resistance-associated macrophage protein)
- encodes a divalent metal transporter
M tuberculosis latency and persistence
- M. tuberculosis can survive in host for decades (latency) - can be reactivated to give active TB
- probably resides within tubercles of lungs
- thought to be metabolically inactive : capable of reverting to replicating form
- host fatty acids/ lipids are main carbon source in vivo: - uses the glyoxylate shunt of the tricarboxylic acid cycle
- key enzymes of glyoxylate cycle, isocitrate lyase and malate synthase, essential for succesful growth and persistence in macrophages
