Geographical Distribution http://www.who.int/emc-documents/surveillance/docs/whocdscsrisr2001.html 14 million cases (2 million new cases each year), distributed in 88 countries (350 million people at risk). cutaneous leishmaniasis visceral leishmaniasis
Clinical syndromes Cutaneous leishmaniasis – L. braziliensis, L. amazonensis, L. guyanensis L. major Diffuse leishmaniasis – L. amazonensis Mucocutaneous leishmaniasis – L. braziliensis Visceral leishmaniasis – L. chagasi, L. donovani New World species Old World species
Clinical picture AIDS (Persistence) Chemotherapy Gene regulation Virulence
Sacks, David L. (2001) Cellular Microbiology 3 (4), 189-196. Development in the insect vector Stage-regulated gene expression
2.1 kb L S rRNA Characterisation of the meta 1 gene in L. major - 12 kDa, pI 9.7 - expressed in promastigotes, upregulated in metacyclics - localises to vacuoles close to the flagellar pocket - conserved in all Leishmania species
A BALC/c 46810121416 5 10 15 20 25 Lesion Index Weeks WT HE B Meta 1 overexpressor in vivo promastigotes amastigotes
0 100 200 300 400 500 600 PBS pVXORF-1 pVX-mcp3 pVX-M1 pVX-mcp3- M1 Concentration (ng/mL) IgG1 IgG2a * * Meta 1 DNA Vaccine meta 1 is a strong Th2 inducer
L. major L. amaz. L. donovani META domain: Small domain family found in proteins of of unknown function. Some are secreted and implicated in motility in bacteria. Also occurs in Leishmania spp. as an essential gene. Over-expression in L.amazonensis increases virulence. A pair of cysteine residues show correlated conservation, suggesting that they form a disulphide bond. Taxa: cellular organisms cellular organisms
Conclusions Meta 1 and meta 2 genes- conserved in Leishmania, synteny with Trypanosoma Meta 1 related to virulence; Meta 2 ? Meta genes: several copies in Trypanosoma – evaluate function in T. brucei (RNAi) Meta 2 protein: Calcium? regulation of calpain activity? Meta locus: other stage-regulated genes - virulence ?
Camila S. Ramos Fernando A. L. Franco Amanda R. Franco Mariana Wajc Carlos H. Serezani Jenicer K. U. Yokoyama-Yasunaka Silvia R. B. Uliana Deborah F. Smith ICB - USP Imperial College University of London
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