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Chapter category: Infectious Disease

Targeting SHP-1 to Prevent Macrophage Activation Promotes Leishmania Pathogenesis

Chapter authors:
Devki Nandan and Neil E. Reiner

Protozoa of the genus Leishmania have evolved mechanisms to sabotage host-cell signaling pathways to enhance their intracellular survival and perpetuate infection. Recent findings have shown that the Src-homology-2 domain containing tyrosine phosphatase-1 (SHP-1) is targeted in Leishmania-infected cells. Activation of SHP-1 contributes to macrophage deactivation and to disease pathogenesis. Interference with macrophage cell regulation is a dynamic process and is mediated by Leishmania effector proteins and other molecules that target critical pathways. This chapter highlights the remarkable strategies employed by Leishmania to attenuate host-cell signaling and identifies some of the key molecules involved. Leishmania spp. are obligate intracellular protozoa that reside within mononuclear phagocytes of their mammalian hosts. They have two distinct developmental stages. These include nonmotile amastigotes that reside intracellularly within mammalian macrophages and extracellular motile promastigotes that multiply within the alimentary tract of their sandfly vectors. The human Leishmaniases span a diverse set of tropical and subtropical diseases. The majority of deaths result from the visceral form of Leishmaniasis caused by L. donovani or L. chagasi. Infections with Leishmania represent a major health problem of global importance. According to the latest WHO report, twelve million people are infected with various Leishmania species have clinical evidence of Leishmaniasis worldwide, and two million new cases occur each year (Leishmaniases Control, home page www.who.int/health-topics/Leishmaniasis.htm, updated 2000). Moreover, the incidence of Leishmaniasis has been on the rise because of the AIDS epidemic, increased international travel, lack of effective vaccines, difficulty in controlling vectors, and the development of resistance to chemotherapy.

Devki Nandan
Department of Medicine, Division of Infectious Diseases, University of British Columbia

Neil E. Reiner
Departments of Microbiology and Immunology and Medicine, Division of Infectious Diseases, University of British Columbia

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