Interactions between Leishmania parasites and host cells.
Several species of protozoa belonging to the genus Leishmania are pathogenic for humans, causing visceral and cutaneous diseases. They are transmitted by phlebotomine sandflies as flagellated promastigotes to mammals hosts, where they live as aflagellated amastigotes mainly within macrophages. Studies performed on mice infected with Leishmania major demonstrated that host defence against this infection depends on the interleukin-12-driven expansion of the T helper 1 cell subset, with production of cytokines such as interferon-gamma, which activate macrophages for parasite killing through the release of nitric oxide. The parasitocidal role of this radical is now emerging also in the human and canine model. Healing or progression of the infection is related to the genetic and immune status of the host, and to the virulence of different species and strains of Leishmania. The parasite survival ultimately depends on the ability to evade the host immune response by several mechanisms. Among them, inhibition of the signal transduction pathway of the host cells is particularly important. In fact, promastigotes inhibit protein kinase C activation, cause Ca++ influx into the host cell and decrease the levels of myristoylated alanine-rich C kinase substrate-related proteins, which are substrates for PKC. In addition, Leishmania infection blocks IFN-gamma-induced tyrosine kinase phosphorylation, with consequent impairment of signalling for IL-12 and nitric oxide production. Finally, Leishmania activates protein phosphotyrosine phosphatases, which down-regulate mitogen-activated protein kinase signalling and c-fos and nitric oxide synthase expression. New pharmacological applications, including protein tyrosine phosphatase and protein farnesyltransferase inhibitors, are being evaluated against leishmaniosis in vitro and in vivo in the murine model.
Brandonisio
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Dipartimento di Clinica Medica, Immunologia e Malattie Infettive, Sezione di Microbiologia e Immunologia, Università di Bari, Policlinico, Piazza G. Cesare, 70124 Bari, Italy. brandoni@cimedoc.uniba.it
Panaro
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MA
Sisto
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M
Acquafredda
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A
Fumarola
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L
Leogrande
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D000818:Animals; D000953:Antigens, Protozoan / Q000276:immunology; D002448:Cell Adhesion; D003165:Complement System Proteins / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D006790:Host-Parasite Interactions; D006801:Humans; D007111:Immunity, Cellular; D007891:Leishmania / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000953:Antigens, Protozoan; D016207:Cytokines; D003165:Complement System Proteins