Article

Rab5 activation by Toll-like receptor 2 is required for Trypanosoma cruzi internalization and replication in macrophages.

Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Traffic (impact factor: 4.92). 07/2008; 9(8):1299-315. DOI:10.1111/j.1600-0854.2008.00760.x pp.1299-315
Source: PubMed

ABSTRACT Trypanosoma cruzi can infect and replicate in macrophages. During invasion, T. cruzi interacts with different macrophage receptors to induce its own phagocytosis. However, the nature of those receptors and the molecular mechanisms involved are poorly understood. In this study, we demonstrate that T. cruzi metacyclic trypomastigotes but not epimastigotes were able to induce Rab5 activation and binding to the early endosomes in peritoneal macrophages. In this process, active Rab5 colocalized with parasites in the phagosome and with the Rab5A effector molecule early endosomal antigen 1. Phagosome formation and T. cruzi internalization were inhibited in Raw 264.7 macrophages expressing a dominant-negative form of Rab5 [(S34N)Rab5]. Using T. cruzi membrane extracts, we verified that the Rab5 activation depends on the interaction between parasite surface molecules and macrophages surface molecule. In addition, during infection of macrophages, phosphatidylinositol 3-kinase (PI3K) pathway was activated. Assays carried out using a selective PI3K inhibitor (LY294002) showed that the PI3K activation is essential for Rab5 activation by T. cruzi infection and for the entrance and intracellular replication of T. cruzi in macrophages. Moreover, using macrophages from knockout mice, we found that activation of Rab5, fusion of early endosomes and phagocytosis induced by T. cruzi infection involved Toll-like receptor (TLR)2 but were independent of TLR4 receptors.

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    [show abstract] [hide abstract]
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Keywords

active Rab5 colocalized
 
different macrophage receptors
 
induce Rab5 activation
 
intracellular replication
 
macrophages surface molecule
 
molecular mechanisms
 
own phagocytosis
 
parasite surface molecules
 
peritoneal macrophages
 
phagocytosis induced
 
PI3K activation
 
Rab5 activation
 
Rab5A effector molecule
 
selective PI3K inhibitor
 
T. cruzi
 
T. cruzi interacts
 
T. cruzi internalization
 
T. cruzi membrane
 
TLR4 receptors
 
Trypanosoma cruzi
 

Elena Maganto-Garcia