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We work with the Leishmania protozoan parasite Leishmania… Leishmania Discovery of the infectious agent William Leishman Etienne Sergent Charles Donovan Edmond Sergent 1921:extracel. promastigote 1900: intracellular amastigote 2 Med Mol Para Leishmania • 88 countries/350 million at risk • 12 million cases/2 million new infected • 57,000 deaths annually/4 million DALY • second to malaria in mortality and disability • synergy with HIV co-infection • no vaccine, limited treatment 3 • emerging disease Med Mol Para Leishmania Introduction According to disease burden estimates, leishmaniasis ranks third in disease burden in disability-adjusted life years caused by neglected tropical diseases and is the second cause of parasite-related deaths after malaria Med Mol Para 4 Leishmania Disability adjusted life years lost • DALY: Number of years lost due to ill health disability or death WHO Region DALY (in thousands) Africa 328 Americas 45 Eastern Mediterranean 281 Southeast Asia 1,264 Western Pacific 51 Total: 1,969 Med Mol Para 5 Leishmania Med Mol Para 6 Leishmania 7 Med Mol Para Leishmania Med Mol Para 8 Leishmania: a digenetic life cycle Med Mol Para 9 Leishmania: a digenetic life cycle Med Mol Para10 Stage specific adhesion of Leishmania promastigotes to the Sand fly midgut Procyclic promastigote - LPG with galactose branching sugars - Able to bind midgut epithelium - non-infective stage Metacyclic promastigote http://www.youtube.com/watch?v=-HY_LbzQ9i4 - LPG with arabinose substituting galactose - LPG increases in size (Gal-Man-PO4) repetitive units - Not able to bind to midgut epithelium - Infective stage Pimenta et al (1992) Science 256:1812-1815 Med Mol Para11 Leishmania: a digenetic life cycle Forestier et al, (2011) Cell Host Microbe Med Mol Para12 Leishmaniasis cutaneous espundia chiclero ulcer white leprosy Andean sickness oriental sore Jericho boil Aleppo boil L. major uta muco-cutaneous L. tropica L. braziliensis L. mexicana visceral kala-azar Burdwan fever Shahib's disease L. donovani Med Mol Para13 Leishmaniasis L. major L. tropica L. aethiopica L. infantum L. mexicana L. guyanensis L. venezuelensis L. peruviana L. amazonensis L. chagasi L. braziliensis L. panamensis Localized Cutaneous Leishmaniasis Med Mol Para Leishmaniasis Types of Leishmaniasis L. aethiopica Diffuse Cutaneous Leishmaniasis L. mexicana L. venezuelensis L. amazonensis http://www.emedicine.com/DERM/topic219.htm Med Mol Para15 Leishmaniasis L. tropica L. braziliensis Recidivans Cutaneous Leishmaniasis http://www.emedicine.com/DERM/topic219.htm Med Mol Para16 Leishmaniasis L. major L. aethiopica L. mexicana L. guyanensis L. amazonensis L. braziliensis L. panamensis Mucocutaneous Leishmaniasis Med Mol Para Leishmaniasis L. donovani L. tropica L. infantum L. infantum Visceral Leishmaniasis Med Mol Para18 Leishmaniasis Amazon India Med Mol Para Leishmaniasis Afghan Med Mol Para20 Leishmaniasis Afghan Med Mol Para Leishmaniasis Nepal Med Mol Para22 Symptoms • • • • • Symptoms of cutaneous leishmaniasis : Breathing difficulty Skin sores, which may become a skin ulcer that heals very slowly Stuffy nose, runny nose, and nosebleeds Swallowing difficulty Ulcers and wearing away (erosion) in the mouth, tongue, gums, lips, nose, and inner nose • • • • • • • • • • Systemic visceral infection in children usually begins suddenly with: Cough diarrhea Children Fever Vomiting Abdominal discomfort Fever that lasts for weeks; may come and go in cycles Night sweats Scaly, gray, dark, ashen skin Thinning hair Weight loss ADULTS Med Mol Para23 Diagnosis • Direct visualization of amastigotes by hematological staining doing tissue biopsy. • Enzyme linked Immunosorbent assay (ELISA). • Antigen coated dipsticks. • Direct agglutination test. • Leishmania specific PCR assay. • Indirect Immunofluorescent antibody test. • Complete blood count. Med Mol Para24 Treatment Antifungal Med Mol Para25 Treatment • • • • • Miltefosine First oral drug against leishmaniasis. http://www.youtube.com/watch?v=yr-01IPiz0g Originally developed for cancer. Used in the case of visceral and cutaneous leishmaniasis. Also target HIV infected macrophages. Inhibit PI3K/AKT pathways. Med Mol Para26 Vaccine • No successful vaccine. • There are several first generation and second generation vaccines which are under clinical trial. • 1st gen: use whole molecular organism • 2nd gen: recombinant protein grown in bacteria; purified; then, take vaccine of that purified vaccine. • LACK antigen (Leishmania homologue of receptor for activated C kinase). • LEISH-F1+MPL-SE Vaccine (Second generation vaccine) was in clinical trial for its safety and immunogenicity (2011). Presently under clinical development. • Infectious Disease Research Institute launched two phase-1 clinical trial of vaccine against visceral Leishmaniasis. Med Mol Para27 Preventions • Vector control intervention. • Insecticidal treated nets. • Indoor residual spraying. • Screening windows. • Wearing insect repellents. • Wearing protective clothing. Med Mol Para28