%0 Journal Article
%T Host Cell Signalling and Leishmania Mechanisms of Evasion
%A Marina Tiemi Shio
%A Kasra Hassani
%A Amandine Isnard
%A Benjamin Ralph
%A Irazu Contreras
%A Maria Adelaida Gomez
%A Issa Abu-Dayyeh
%A Martin Olivier
%J Journal of Tropical Medicine
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/819512
%X Leishmania parasites are able to secure their survival and propagation within their host by altering signalling pathways involved in the ability of macrophages to kill pathogens or to engage adaptive immune system. An important step in this immune evasion process is the activation of host protein tyrosine phosphatase SHP-1 by Leishmania. SHP-1 has been shown to directly inactivate JAK2 and Erk1/2 and to play a role in the negative regulation of several transcription factors involved in macrophage activation. These signalling alterations contribute to the inactivation of critical macrophage functions (e.g., Nitric oxide, IL-12, and TNF-¦Á). Additionally, to interfere with IFN-¦Ã receptor signalling, Leishmania also alters several LPS-mediated responses. Recent findings from our laboratory revealed a pivotal role for SHP-1 in the inhibition of TLR-induced macrophage activation through binding to and inactivating IL-1-receptor-associated kinase 1 (IRAK-1). Furthermore, we identified the binding site as an evolutionarily conserved ITIM-like motif, which we named kinase tyrosine-based inhibitory motif (KTIM). Collectively, a better understanding of the evasion mechanisms utilized by Leishmania parasite could help to develop more efficient antileishmanial therapies in the near future. 1. Background Apart from the impact of Leishmania on world health, Leishmaniasis represents an elegant infection model that can teach us a lot about host-parasite interactions and immune evasion. This parasite has the ability to enter host macrophages (M£¿s) safely and replicate inside the very same phagocytes that were recruited to destroy it. The inability of M£¿s to kill the parasite and activate cells of the adaptive immune system is a product of the parasite¡¯s long-reported capacity to alter several key signalling pathways in the host. Many signalling alterations are seen early in the course of infection suggesting they start upon the initial contact between the parasite and the M£¿. These rapid alterations of signalling pathways serve at least two main functions: firstly, inhibition of M£¿ killing mechanisms that are triggered upon phagocytosis of foreign particles (e.g., production of reactive oxygen species), and secondly, inhibition of leishmanicidal functions that can be triggered in response to M£¿ activation in infected tissues in response to stimuli such as lipopolysaccharides (LPS) or interferon-¦Ã (IFN-¦Ã) (e.g., nitric oxide production). In this review, we will discuss the roles of Leishmania in disease establishment, focusing on the signalling pathways that they
%U http://www.hindawi.com/journals/jtm/2012/819512/