title: Cutting edge: Mycobacterium tuberculosis blocks Ca2+ signaling and phagosome maturation in human macrophages via specific inhibition of sphingosine kinase.
abstract: 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.
authors.affiliation: Inflammation Program, Graduate Program in Immunology, University of Iowa and Veterans Affairs Medical Center, Iowa City, IA 52242, USA.
authors.forename: Zulfiqar A
authors.initials: ZA
authors.lastname: Malik
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Thompson
authors.forename: Samad
authors.initials: S
authors.lastname: Hashimi
authors.forename: Brandon
authors.initials: B
authors.lastname: Porter
authors.forename: Shankar S
authors.initials: SS
authors.lastname: Iyer
authors.forename: David J
authors.initials: DJ
authors.lastname: Kusner
mesh_terms: 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
chemical_list: 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