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Rab5 activation by Toll-like receptor 2 is required for Trypanosoma cruzi internalization and replication in
Elena Maganto-Garcia1, Carmen Punzon, Cox Terhorst
1Centro de Biología Molecular Severo Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
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.
Insights
Trypanosoma cruzi uses macrophage Toll-like receptor 2 (TLR2) to activate Rab5 and phosphatidylinositol 3-kinase (PI3K), enabling parasite entry and replication within host cells.
Area of Science:
- Cell biology
- Immunology
- Parasitology
Background:
- Trypanosoma cruzi infects macrophages, utilizing host cell receptors for invasion.
- The specific receptors and molecular pathways governing T. cruzi phagocytosis remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms and macrophage receptors involved in T. cruzi invasion.
- To investigate the role of Rab5 activation, PI3K pathway, and Toll-like receptors (TLRs) in T. cruzi internalization.
Main Methods:
- Utilized peritoneal macrophages and Raw 264.7 cell lines.
- Employed dominant-negative Rab5 mutants and a PI3K inhibitor (LY294002).
- Investigated T. cruzi interaction with macrophages from TLR2 and TLR4 knockout mice.
Main Results:
- T. cruzi metacyclic trypomastigotes induced Rab5 activation and colocalization with early endosomal markers.
- Inhibition of Rab5 and PI3K pathways blocked T. cruzi entry and replication.
- T. cruzi-induced phagocytosis and Rab5 activation were dependent on Toll-like receptor 2 (TLR2) but not TLR4.
Conclusions:
- T. cruzi invasion involves TLR2-mediated activation of the PI3K/Rab5 pathway.
- This pathway is crucial for parasite entry, phagosome maturation, and intracellular replication in macrophages.
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