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Clin Immunol. 2005 Mar;114(3):239-47.

Mechanisms of mycobacterial persistence in tuberculosis.

Author information

1
Inflammation Program and Division of Infectious Diseases, Department of Internal Medicine and Physiology, Graduate Programs in Immunology and Molecular Biology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. david-kusner@uiowa.edu

Abstract

Tuberculosis is one of the world's most devastating diseases, with more than two million deaths and eight million new cases occurring annually. Mycobacterium tuberculosis evades the innate antimicrobial defenses of macrophages by inhibiting the maturation of its phagosome to a bactericidal phagolysosome. Phagosome maturation is dependent on macrophage Ca(2+) signaling, which results in the recruitment of cytosolic calmodulin (CaM) to the phagosome membrane and subsequent focal activation of CaM kinase II (CaMKII). M. tuberculosis blocks this process via inhibition of a macrophage enzyme, sphingosine kinase, which is a proximal generator of Ca(2+) signaling during phagocytosis. This results in a failure of assembly of the Ca(2+)/CaM/CaMKII signaling complex on the membrane of the mycobacterial phagosome and the bacilli's persistence and replication in a protective intracellular niche. Pharmacologic or physiologic reversal of this inhibition of macrophage Ca(2+) signaling restores the normal sequence of phagosome maturation, resulting in decreased intracellular viability of M. tuberculosis.

PMID:
15721834
DOI:
10.1016/j.clim.2004.07.016
[Indexed for MEDLINE]
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