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Professor of Microbial Pathogenesis and Cell Biology |
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| Andrews lab website Phone: (203) 737-2410 Fax: (203) 737-2630 Lab: (203) 737-2411 e-mail: norma.andrews@yale.edu |
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Section of Microbial Pathogenesis <Courier Address> |
Invasion and intracellular survival of protozoan parasites
Our studies of the cell invasion mechanism of Trypanosoma cruzi uncovered a previously unrecognized, ubiquitous
process of calcium-triggered recruitment and fusion of lysosomes with the plasma membrane. This pathway is
subverted by the parasites as a strategy to form a vacuole, through which they gain entry to host cells. Current
projects include the study of signaling pathways involved in trypanosome entry, molecular mechanisms of intracellular
survival of the related trypanosomatid parasite Leishmania, and the role of a novel family of agonist-processing
serine oligopeptidases we identified in trypanosomatids and several bacterial pathogens.
Regulation of lysosomal exocytosis and membrane repair
We found that a ubiquitously-expressed member of the synaptotagmin family of calcium sensors, Syt VII, is
localized on the membrane of lysosomes in many cell types. Experiments using inhibitory reagents and Syt VII-deficient
mice demonstrated that this protein is required for lysosomal exocytosis and for the normal resealing of plasma
membrane wounds. In addition to a dissection of the mechanism by which lysosomal exocytosis promotes membrane repair,
we are investigating the role of Syt VII in the maturation of dendritic cells, and in the killing activity of cytotoxic
lymphocytes.
for PDF Roy D, Liston DR, Idone VJ, Di A, Nelson DJ, Pujol C, Bliska JB, Chakrabarti S, Andrews NW. (2004) A process for controlling intracellular bacterial infections induced by membrane injury. Science 304: 1515-1518.
Andrade LO and Andrews NW. (2004) Lysosomal fusion is essential for the retention of Trypanosoma cruzi inside host cells. J Exp Med, 200: 1135-1143.
Huynh C, Roth D, Ward DM, Kaplan J, Andrews NW. (2004) Defective lysosomal exocytosis and plasma membrane repair in Chediak-Higashi cells. Proc Natl Acad Sci. 101: 16795-16800.
Chakrabarti S, Kobayashi K, Flavell RA, Miyak, K, Liston D, Fowler K, Gorelick FS, Andrews NW. (2003) Impaired
membrane resealing and autoimmune myositis in synaptotagmin VII-deficient mice. J Cell Biol. 162(4): 543-549.
Jaiswal JK, Andrews NW, Simon SM. (2002) Membrane proximal lysosomes are the major vesicles responsible for calcium-dependent exocytosis in nonsecretory cells. J Cell Biol. 159: 625-635.
Andrews NW. (2002) Lysosomes and the plasma membrane: trypanosomes reveal a secret relationship. J Cell Biol. 158: 389-394.
Morehead J, Coppens I, Andrews NW. (2002) Opsonization modulates Rac-1 activation during cell entry by Leishmania amazonensis. Inf Immun. 70: 4571-4580.
Reddy A, Caler EV, Andrews NW. (2001) Plasma membrane repair is mediated by Ca2+-regulated exocytosis of lysosomes. Cell 106: 157-169.
Caler EV, Chakrabarti S, Fowler K, Rao S, Andrews NW. (2001) The exocytosis-regulatory protein synaptotagmin VII mediates cell entry by Trypanosoma cruzi. J Exp Med. 193: 1097-1104.
Martinez I, Chakrabarti S, Hellevik T, Morehead J, Fowler K, Andrews NW. (2000) Synaptotagmin VII regulates Ca2+- dependent exocytosis of lysosomes in fibroblasts. J Cell Biol. 148: 1141-1149.
Andrews NW. (2000) The regulated secretion of conventional lysosomes. Trends in Cell Biology 10: 316-321.
Figure 1: Scanning electron micrographs of Trypanosoma cruzi attached (left image) and invading (right image) a mammalian cell. Invasion occurs by formation of a tight vacuole, derived from intracellular lysosomal membranes.
Figure 2: Lysosomes fuse with the plasma membrane of injured cells. Cells were wounded by scratching in the presence of membrane-impermeable fluorescent dextran, which penetrates into the cytosol of wounded cells (red). The lysosomal glycoprotein Lamp-1 is exposed on the surface of wounded cells (green), but not on intact cells (nuclei are stained in blue).
