Growth Characteristics ofAtypical Mycobacteria inWaterand ...
Adaptations of mycobacteria for survival in macrophages sameer tiwari
-
Upload
sameer-tiwari -
Category
Education
-
view
575 -
download
0
description
Transcript of Adaptations of mycobacteria for survival in macrophages sameer tiwari
![Page 1: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/1.jpg)
Adaptations of mycobacteria for survival in macrophages
Sameer Tiwari
![Page 2: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/2.jpg)
Flaunty
mycobacterium
![Page 3: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/3.jpg)
![Page 4: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/4.jpg)
Interaction of macrophage with mycobacteria
Peters J., Cell Host & Microbe, 2008
![Page 5: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/5.jpg)
Cells involved in Phagocytosis
Kuby., Immunology, 4th Edi
Dendritic cellMonocyte Macrophage
![Page 6: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/6.jpg)
Phagocytosis of a bacterium
Kuby, Immunology, Edi 4th
PAMP
CR
MR
CD14
Collectins
Scavengers
Fc receptors
![Page 7: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/7.jpg)
M. tuberculosis recognition by membrane-bound receptors
O. Neyrolles, C. Guilhot ,Tuberculosis 91 (2011) 187-195
![Page 8: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/8.jpg)
Entry of M. tuberculosis in macrophage
Phagocytosis of M.tb involves different receptors on the phagocytic cell which either bind to nonopsonized M.tb or recognize opsonins on the surface of M.tb.
Complement receptors (CRl, CR2, CR3 and CR4), mannose receptors (MR), CD14 receptor, collectins, scavenger receptors play important roles in binding of the organisms to the phagocytes (Schlesinger et al., 1996, Hoheisel et al., 1995, Gaynor et al., 1995).
Mycobacteria can invade host macrophages after opsonization with complement factor C3, which is followed by binding and uptake through CR1, CR3, and CR4 (Aderem et al., 1999, Hirsch et al., 1994, Schlesinger et al., 1993). In the absence of CR3, phagocytosis of M.tb by human macrophages and monocytes is reduced by approximately 70 to 80% in vitro (Schlesinger et al., 1993, Schlesinger et al., 1990).
![Page 9: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/9.jpg)
Inhibition of phagosomal maturation
01
02
03
Phagosome-lysosome fusion block
Incomplete Luminal acidification
Absence of proton -ATPase
04 Absence of mature lysosomal hydrolase
![Page 10: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/10.jpg)
Rab effectors & mycobacterial phagolysosomes
Rab5 & 7EEA1LAMP1Cathepsin DTACO
![Page 11: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/11.jpg)
Role of Ca2+ in phagosomal maturation
Ca2+- binding protein calmodulin
recruitment of the PI3K hVPS34
interference with Ca2+ fluxes by LAM
![Page 12: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/12.jpg)
![Page 13: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/13.jpg)
PI3P and phagosomal maturation
Vergne I,et al,Traffic 2003;4:600–606
![Page 14: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/14.jpg)
Other host mechanisms altered by mycobacteria
Antigen processing and presentation
![Page 15: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/15.jpg)
Generation of ROI & RNI
MacMicking Nature Medicine 14, 809 - 810 (2008)
![Page 16: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/16.jpg)
Vandal OH et al,JOURNAL OF BACTERIOLOGY, Aug. 2009, p. 4714–4721
![Page 17: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/17.jpg)
Modulation of MAPK Signalling & JAK/STAT signalling
Modulation of macrophage signaling by mycobacteria
![Page 18: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/18.jpg)
Mycobacteria alter host apoptotic pathways
![Page 19: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/19.jpg)
Manipulation of host cell actin dynamics
Actin forms part of the eukaryotic cytoskeletal network
Migration Memabrane ruffling Cellular adherence
![Page 20: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/20.jpg)
Activity of Coronin 1 in Macrophages
![Page 21: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/21.jpg)
Protein Kinases
500 kinases
2% of all proteins
30% of all proteins modified by kinase activity
Phosphorylation occurs on serine, threonine & tyrosine residues
Human geome conatins
Variety of cellular processesIncluding protein trafficking
![Page 22: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/22.jpg)
Protein Kinase C
![Page 23: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/23.jpg)
Role of PKC in macrophage functions
Production of cytokines, chemokines and immune effector molecule
![Page 24: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/24.jpg)
Role of PKC in mycobacterial infection
Reduced activation of MAP Kinases
Decreased production of NOS2 and TNF-α
![Page 25: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/25.jpg)
Serine/Threonine Protein Kinases of Mtb
![Page 26: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/26.jpg)
Alber T, Current Opinion in Structural Biology 2009,19:650–65
Model for Mtb receptor STPK regulation
![Page 27: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/27.jpg)
Structural analysis of M.tb STPKs
![Page 28: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/28.jpg)
![Page 29: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/29.jpg)
PknA
Impairment in GTPase activity of FtsZ
phosphorylate FtsZ
![Page 30: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/30.jpg)
PknB
Functional STPK expressed in active TB infection
Slow growth & cell morphology (cell shape)
![Page 31: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/31.jpg)
PknD
Anchoring sensor domain
phosphorylate MmpL7 Virulence
MmpL7 is essential for virulence, it transports polyketide virulence factors such as phthiocerol dimycocerosate (PDIM) to the cell wall
![Page 32: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/32.jpg)
PknE
Transduction of externa
l signals
![Page 33: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/33.jpg)
PknF
Regulation in Glucose transport
Slow cell growth
Septum formation
![Page 34: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/34.jpg)
PknH
Phosphorylation of EmbR (phosphoprotein recognition domain)
DNA binding activity towards promoter regions of embCAB genes
Differential expression of a mycobacterial kinase in response to stress conditions which can indicate its ability to regulate cellular events promoting bacterial adaptation to environmental change i.e. low pH & heat shock
![Page 35: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/35.jpg)
PknK
Regulate the expression of the mycobacterial monooxygenase (mymA) operon
Expression of mymA operon genes is regulated through PknK-mediated phosphorylation of VirS
Phosphorylates FabD
![Page 36: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/36.jpg)
PknG
Interfere with host signal transduction processes
Cellular glutamate and glutamine levels
Phosphorylate protein(s) possibly involved in host trafficking pathways
Blocking the maturation of mycobacterial phagosome into lysosomes
Establishment of an intracellular infection by blocking phagosome-lysosomal fusion within macrophages
Phosphorylated GarA (glutamate metabolism)
![Page 37: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/37.jpg)
PknG in mycobacterial trafficking in macrophages
![Page 38: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/38.jpg)
Conclusion
Knowledge of the mycobacterial tactics for survival inside macrophages might help not only to control tuberculosis and other mycobacterial diseases but also to uncover novel aspects of host cell biology
Further studies, with the help of new techniques in genomics and proteomics, will elucidate the precise mechanisms by which pathogenic mycobacteria are able to downregulate host-signalling pathways involving TLRs, MAPKs and JAK/STATs.
Mycobacterial gene products that disrupt host defences during infection represent potential drug targets.
Mycobacterial Kinases could be potential targets for the development of new TB drugs
![Page 39: Adaptations of mycobacteria for survival in macrophages sameer tiwari](https://reader035.fdocuments.in/reader035/viewer/2022062307/556bd1bad8b42ab2138b45bd/html5/thumbnails/39.jpg)
THANKS