PMID- 11207296
OWN - NLM
STAT- MEDLINE
DCOM- 20010426
LR  - 20190515
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 166
IP  - 5
DP  - 2001 Mar 1
TI  - Mycobacterium tuberculosis phagosomes exhibit altered calmodulin-dependent signal 
      transduction: contribution to inhibition of phagosome-lysosome fusion and 
      intracellular survival in human macrophages.
PG  - 3392-401
AB  - Mycobacterium tuberculosis successfully parasitizes macrophages by disrupting the 
      maturation of its phagosome, creating an intracellular compartment with endosomal 
      rather than lysosomal characteristics. We have recently demonstrated that live M. 
      tuberculosis infect human macrophages in the absence of an increase in cytosolic 
      Ca(2+) ([Ca(2+)](c)), which correlates with inhibition of phagosome-lysosome 
      fusion and intracellular viability. In contrast, killed M. tuberculosis induces 
      an elevation in [Ca(2+)](c) that is coupled to phagosome-lysosome fusion. We 
      tested the hypothesis that defective activation of the Ca(2+)-dependent effector 
      proteins calmodulin (CaM) and CaM-dependent protein kinase II (CaMKII) 
      contributes to the intracellular pathogenesis of tuberculosis. Phagosomes 
      containing live M. tuberculosis exhibited decreased levels of CaM and the 
      activated form of CaMKII compared with phagosomes encompassing killed tubercle 
      bacilli. Furthermore, ionophore-induced elevations in [Ca(2+)](c) resulted in 
      recruitment of CaM and activation of CaMKII on phagosomes containing live M. 
      tuberculosis. Specific inhibitors of CaM or CaMKII blocked Ca(2+) 
      ionophore-induced phagosomal maturation and enhanced the bacilli's intracellular 
      viability. These results demonstrate a novel role for CaM and CaMKII in the 
      regulation of phagosome-lysosome fusion and suggest that defective activation of 
      these Ca(2+)-activated signaling components contributes to the successful 
      parasitism of human macrophages by M. tuberculosis.
FAU - Malik, Z A
AU  - Malik ZA
AD  - Inflammation Program, Graduate Program in Immunology, University of Iowa and 
      Veterans Administration Medical Center, Iowa City, IA 52242, USA.
FAU - Iyer, S S
AU  - Iyer SS
FAU - Kusner, D J
AU  - Kusner DJ
LA  - eng
GR  - R01 AI18571/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Calmodulin)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adult
MH  - Calcium/antagonists & inhibitors/physiology
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2
MH  - Calcium-Calmodulin-Dependent Protein Kinases/metabolism
MH  - Calmodulin/antagonists & inhibitors/metabolism/*physiology
MH  - Cytosol/immunology/metabolism/microbiology
MH  - Enzyme Activation/immunology
MH  - Humans
MH  - Intracellular Membranes/enzymology/immunology/metabolism/*microbiology
MH  - Lysosomes/immunology/*microbiology
MH  - Macrophages/enzymology/immunology/metabolism/*microbiology
MH  - Mycobacterium tuberculosis/growth & development/*immunology/*pathogenicity
MH  - Phagosomes/enzymology/immunology/*microbiology
MH  - Signal Transduction/*immunology
EDAT- 2001/02/24 11:00
MHDA- 2001/05/01 10:01
CRDT- 2001/02/24 11:00
PHST- 2001/02/24 11:00 [pubmed]
PHST- 2001/05/01 10:01 [medline]
PHST- 2001/02/24 11:00 [entrez]
AID - 10.4049/jimmunol.166.5.3392 [doi]
PST - ppublish
SO  - J Immunol. 2001 Mar 1;166(5):3392-401. doi: 10.4049/jimmunol.166.5.3392.