Cutting edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase.
One-third of the world's population is infected with Mycobacterium tuberculosis (Mtb), and three million people die of tuberculosis each year. Following its ingestion by macrophages (MPs), Mtb inhibits the maturation of its phagosome, preventing progression to a bactericidal phagolysosome. Phagocytosis of Mtb is uncoupled from the elevation in MP cytosolic Ca(2+) that normally accompanies microbial ingestion, resulting in inhibition of phagosome-lysosome fusion and increased intracellular viability. This study demonstrates that the mechanism responsible for this failure of Ca(2+)-dependent phagosome maturation involves mycobacterial inhibition of MP sphingosine kinase. Thus, inhibition of sphingosine kinase directly contributes to survival of Mtb within human MPs and represents a novel molecular mechanism of pathogenesis.
Malik
Zulfiqar A
ZA
Inflammation Program, Graduate Program in Immunology, University of Iowa and Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
Thompson
Christopher R
CR
Hashimi
Samad
S
Porter
Brandon
B
Iyer
Shankar S
SS
Kusner
David J
DJ
D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology*; D002458:Cell Fractionation; D006224:Cricetinae; D004789:Enzyme Activation; D006801:Humans; D008246:Lysophospholipids; D016177:Macrophage-1 Antigen / Q000502:physiology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology* / Q000472:pathogenicity; D010587:Phagocytosis / Q000276:immunology; D010588:Phagosomes / Q000201:enzymology / Q000276:immunology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism; D032581:Tuberculosis Vaccines / Q000494:pharmacology; D015164:Vaccines, Inactivated / Q000494:pharmacology; D000099157:Sphingosine Kinase
D002118:Calcium; D008246:Lysophospholipids; D016177:Macrophage-1 Antigen; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D032581:Tuberculosis Vaccines; D015164:Vaccines, Inactivated; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate