Leishmaniasis is a global term for cutaneous and visceral anthroponotic and zoonotic diseases caused by the vector-borne parasites of the genus Leishmania. These diseases afflict at least 2 million people each year with more than 350 million at risk in 98 countries worldwide. These are diseases mostly of the impoverished making prevention, diagnosis and treatment difficult. Therapy of leishmaniasis ranges from local treatment of cutaneous lesions to systemic, often toxic, therapy for disseminated cutaneous, mucocutaneous and deadly visceral disease. This review is a summary of the clinical syndromes caused by Leishmania and treatment regimens currently used for various forms of leishmaniasis.
Antimicrobial peptides are components of the innate immune systems of a wide variety of eukaryotic organisms and are being developed as antibiotics in the fight against bacterial and fungal infections. We explored the potential activities of antimicrobial peptides against the African trypanosome Trypanosoma brucei, a vector-borne protozoan parasite that is responsible for significant morbidity and mortality in both humans and animals. Three classes of mammalian antimicrobial peptides were tested: alpha-defensins, beta-defensins, and cathelicidins. Although members of all 3 classes of antimicrobial peptides showed activity, those derived from the cathelicidin class were most effective, killing both insect and bloodstream forms of the parasite. The mechanism of action of the cathelicidins against T. brucei involves disruption of surface membrane integrity. Administration of cathelicidin antimicrobial peptides to mice with late-stage T. brucei infection acutely decreased parasitemia and prolonged survival. These results highlight the potential use of antimicrobial peptides for the treatment of African trypanosomiasis.
Leishmania species engineered to express high levels of the surface metalloprotease gp63 have enhanced capacity of migration through extracellular matrix in vitro. This correlates with gp63 degradation of extracellular matrix components, such as collagen type IV and fibronectin, and suggests an important role for gp63 in the pathogenesis of leishmaniasis.Leishmania species are digenetic protozoa that alternately parasitize their sand fly vectors and mammalian macrophages. Parasites are deposited in the mammalian skin by infected sand flies and thereafter must interact with and overcome a variety of obstacles, including extracellular matrix (ECM) and basement membrane (BM) proteins, to establish infection within macrophage phagolysosomes (6). The 63-kDa glycoprotein gp63 is a zinc-dependent metalloprotease found on the surface of the parasite that facilitates complement inactivation in serum (3), interaction with the host macrophage (2, 10, 11) and intraphagolysosomal survival (8, 11). Structural and biochemical similarities exist between gp63 and members of the matrix metalloproteases (4, 14). The latter are important for enhancing the migration of some tumor cells through the ECM and BM, aiding in their metastasis (15,16).To test the hypothesis that gp63 facilitates parasite migration through the ECM, we employed a commercial invasion system in which parasites are placed in a cell culture insert and assessed for their ability to pass through the insert's ECM (Matrigel)-impregnated 8-m-diameter pores (Becton Dickinson, Franklin Lakes, N.J.) (16). An attenuated, gp63-deficient variant of Leishmania amazonensis (12) was transfected with the following plasmid constructs for use in this study: (i) pX, an episomal expression vector; (ii) pX-gp63, which expresses wildtype gp63; and (iii) pX-E265D, which expresses an equivalent level of a proteolytically inactive form of gp63 (12). Stationaryphase promastigotes of each transfectant line were washed and suspended at a concentration of 10 8 cells ml Ϫ1 in Hanks buffered saline solution (Invitrogen, Carlsbad, Calif.). One milliliter of each parasite solution was applied to two cell culture inserts, one embedded with Matrigel and the other without Matrigel (control insert). At increasing times postinoculation, the numbers of parasites present in the lower wells were determined and the percentage of migration was calculated by dividing the number of parasites migrating through the inserts containing Matrigel by the number migrating through the control inserts. No differences were seen in the migrations of different transfectants across control inserts, with complete equilibration of parasite density achieved within 20 min.Migration was assessed over a 48-h period (Fig. 1A). Approximately 40% of the pX-gp63 promastigotes had migrated into the lower chamber at 12 h after inoculation, while only 7% of pX transfectants had migrated by this time. At 24 and 48 h after inoculation, the differences were even more pronounced, with 80 and nearly 100% of the pX-gp63 transfectants, res...
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