Novel PI 3-kinase-dependent mechanisms of trypanosome invasion and vacuole maturation

Aaron M Woolsey; Lisa Sunwoo; Christine A Petersen; Saskia M Brachmann; Lewis C Cantley; Barbara A Burleigh

doi:10.1242/jcs.00666

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Novel PI 3-kinase-dependent mechanisms of trypanosome invasion and vacuole maturation

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Novel PI 3-kinase-dependent mechanisms of trypanosome invasion and vacuole maturation

Aaron M Woolsey, Lisa Sunwoo, Christine A Petersen, Saskia M Brachmann, Lewis C Cantley and Barbara A Burleigh

Journal of cell science, Vol.116(17), pp.3611-3622

09/01/2003

DOI: 10.1242/jcs.00666

PMID: 12876217

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Abstract

Mammalian cell invasion by the protozoan parasite, Trypanosoma cruzi, is facilitated by the activation of host cell phosphatidylinositol 3 (PI 3)-kinases. We demonstrate that the well-characterized Ca2+-regulated lysosome-mediated parasite entry pathway is abolished by wortmannin pretreatment. In addition, we have characterized a novel route of T. cruzi invasion unexpectedly revealed in the course of this study. For over a decade, targeted exocytosis of lysosomes at the host cell plasma membrane was considered as the primary mechanism for T. cruzi entry into non-professional phagocytic cells. We now provide evidence that a significant fraction (50% or greater) of invading T. cruzi trypomastigotes exploit an alternate actin-independent entry pathway that involves formation of a tightly associated host cell plasma membrane-derived vacuole enriched in the lipid products of class I PI 3-kinases, PtdInsP3/PtdIns(3,4)P2. Initially devoid of lysosomal markers, the resultant parasite-containing vacuoles gradually acquire lysosome associated membrane protein 1 (lamp-1) and fluid phase endocytic tracer from the lysosomal compartment. In striking contrast to latex bead phagosomes, few T. cruzi vacuoles associate with the early endosomal marker, EEA1 and the 'maturation' process becomes refractory to PI 3-kinase inhibition immediately following parasite internalization. Jointly, these data provide a new paradigm for T. cruzi invasion of non-professional phagocytic cells and reveal a novel vacuole maturation process that appears to bypass the requirement for EEA1.

Details

Title: Subtitle: Novel PI 3-kinase-dependent mechanisms of trypanosome invasion and vacuole maturation
Creators: Aaron M Woolsey - Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Lisa Sunwoo - Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Christine A Petersen - Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Saskia M Brachmann - Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA, Institut fuer Biochemie, Freie Universitaet Berlin, Berlin, Germany
Lewis C Cantley - Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
Barbara A Burleigh - Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA
Resource Type: Journal article
Publication Details: Journal of cell science, Vol.116(17), pp.3611-3622
DOI: 10.1242/jcs.00666
PMID: 12876217
NLM abbreviation: J Cell Sci
ISSN: 0021-9533
eISSN: 1477-9137
Language: English
Date published: 09/01/2003
Academic Unit: Epidemiology; Internal Medicine
Record Identifier: 9984214856202771

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