Transcript Med Mol Para

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