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Natalie Melrose

Mentor: David Kusner, M.D./Ph.D.
Lab Phone: 335-4323

Mycobacterium tuberculosis, the causative agent of Tb, infects a third of the world’s population and causes 3 million deaths annually. The fate of an M.tb bacillus within a MΦ depends on the cell surface receptor that it engages. M.tb that are phagocytosed via FCγ receptors (FcγR) are enclosed in phagosomes that mature to phagolysosomes, where the bacteria are destroyed. In vivo, the majority of M.tb enters MΦs through complement receptors (CRs), which results in the inhibition of phagosome maturation, and survival of the bacteria, a central characteristic of M.tb pathogenesis.

M.tb inhibits both the localized increase in cytosolic calcium that normally precedes phagosome maturation and the enzyme sphingosine kinase (SK), a lipid kinase that phosphorylates sphingosine. SK is involved in a variety of cell functions, including proliferation and the release of calcium from the endoplasmic reticulum. SK1, the only isoform found in MΦs, translocates to the phagosomal membrane when model particles are phagocytosed, but not upon phagocytosis of live M.tb. We hypothesize that M.tb inhibits phagosome maturation in MΦs when the bacilli enter by the CR but not by the FcγR due to a differential reliance on SK1 for calcium signaling in the downstream pathways of the two receptors.

Thompson CR, Iyer SS, Melrose N, VanOosten R, Johnson K, Pitson SM, Obeid LM, Kusner DJ. Sphingosine kinase 1 (SK1) is recruited to nascent phagosomes in human macrophages: inhibition of SK1 translocation by Mycobacterium tuberculosis. J Immunol. 2005 Mar 15;174(6):3551-61. PubMed PMID: 15749892.

Daines DA, Bothwell M, Furrer J, Unrath W, Nelson K, Jarisch J, Melrose N, Greiner L, Apicella M, Smith AL. Haemophilus influenzae luxS mutants form a biofilm and have increased virulence. Microb Pathog. 2005 Sep;39(3):87-96. PubMed PMID: 16099134.

Kusner DJ, Thompson CR, Melrose NA, Pitson SM, Obeid LM, Iyer SS. The localization and activity of sphingosine kinase 1 are coordinately regulated with actin cytoskeletal dynamics in macrophages. J Biol Chem. 2007 Aug 10;282(32):23147-62. Epub 2007 May 22. Erratum in: J Biol Chem. 2008 Feb 29;283(9):5972. PubMed PMID: 17519232.