Describe Leishmaniasis - its vector, epidemiology
Leishmania is a genus containing over 20 species that are pathogenic for humans.
Vector –> It is transmitted by the small biting sandfly – two species of which transmit Leishmania: Phlebotomus in the eastern hemisphere (Africa, Europe and Asia) and Lutzomyia in western hemisphere (South and Central America).
- Only the females take blood meals.
- Larvae inhabit moist places with much organic matter (animal burrows, termite hills, tree holes, leaf litter etc) as larvae feed on dead organic matter.
Responsible for Leishmaniasis –> endemic in tropical regions throughout the world and is an emerging disease as number of reported cases are increasing.
- Affects 12 million people in 88 countries.
- Leishmaniasis can range in its manifestations, from a self-limiting cutaneous lesion to a disseminated mucocutaneous disease to a visceral disease.
Describe Leishmania’s life cycle
– During a blood meal, metacyclic promastigotes (present in the anterior portion of the gut and pharynx of the sandfly) are transferred to the blood of human.
In human
- the promastigotes are phagocytosed by macrophages – the parasite cannot actively invade host cells.
- Several receptors are thought to mediate the uptake of the parasite: complement receptor 1 (CR1) and 3 (CR3) and ligands on promastigotes: C3 complement and a parasite surface protein gp63.
- The parasite-containing phagosome fuses with the lysosome to form a phagolysosome inside the macrophage.
- Leishmania is resistant to the acidic pH.
- -The promastigotes are converted to amastigotes by losing their flagellum. The amastigotes will divide by binary fission and fill up the phagolysosome until the cell bursts and amastigotes can enter more macrophages and repeat cycles of division.
In the sandfly
- During a blood meal, the sandfly will take up amastigotes which will convert to extracellular promastigotes which will replicate in the midgut of the fly.
- They then migrate to the mouthparts and will convert to metacyclic promastigotes which are infectious to mammals.
What are the strategies Leishmania has developed to evade the immune response
– Leishmania attracts complement molecules so that it is engulfed by macrophages however it is not killed since it can resist the acidic pH –> it can ‘hide’ in macrophages.
– C3b binds to Leishmania in order to opsonize it but instead the parasite will express the gp63 protease that will convert it into iC3b which makes it more attractive to macrophages.
– It manipulates macrophages to release cytokines that will induce production of helper T cells which don’t have an effect on the parasite and inhibit CTL production.
– Leishmania is also protected from digestion in the phagolysome by its coat of LPG (lipophosphoglycan) which also affects macrophages microbial activity.
What are the different manifestations of Leishmaniasis?
Cutaneous Leishmaniasis
- Most common manifestation of the disease, characterized by benign self-healing lesions at site of infection that are generally painless.
- Can also cause skin wounds along lymphatic ducts if the parasite has infected there.
- The lesions are often ulcerated and can take weeks or months to heal.
Mucosal cutaneous Leishmaniasis
- A small proportion of cutaneous patients (5%) will develop MCL.
- This is when the infected macrophages spread via the blood or lymph to the mucosae of the nose and mouth.
- The macrophages will cause the rapid and extensive erosion of the cartilaginous tissues of the nose and palate.
- This disease will continue to progress if left untreated and can lead to severe pathology from secondary infections and deformity.
- Mainly caused by L. braziliensis in South America.
Diffuse cutaneous Leishmaniasis
- Characterized by disseminated nodular lesions all over the body that resembles leprosy. The lesions are scaly and contain high numbers of amastigotes.
- It doesn’t heal spontaneously and is difficult to treat.
- Caused by L. aethiopica in Kenya/Ethiopia and L. amazonensis in central America.
Visceral Leishmaniasis
- Most serious form of the disease and is fatal in up to 90% of untreated cases.
- Kala-azar, meaning black sickness in Hindi, is widely known name for disease due to darkening of forehead and hands that is sometimes seen.
- It’s generalized infection of spleen, liver and bone marrow and lymph nodes. Characterized by enlargement if these organs and muscle wasting.
- Caused by L.infantum and L.donovani.
What are the methods of treatment for Leishmaniasis
– A limited number of drugs are available, with most having toxicity and requiring long duration of therapy. Usually cutaneous form doesn’t require treatment.
– Most common treatment is pentavelent antimonials which are first line of treatment and are generally effective. However they have severe side effects - damaged veins, pancreatitis, hepatitis, myalgias, fatigue and cardiac problems. There’s emerging drug resistance.
– An alternative is liposomal amphotericin B – effective against visceral Leishmaniasis but also with severe side effects. Drug of last resort due to being expensive.
– An oral drug miltefosine has been approved for use in India – effective against VL, less toxic than other two and will be cheaper since hospitalization won’t be required. However effectiveness is species and location dependent.
How can parasite travel against the flow of blood in the sandfly in order to be transmitted to human?
The problem – parasites develop in the midgut and must exit through the food channel in the proboscis against the flow of blood.
- However infection will cause the cardia valve to be damaged (parasite enzymes digest chitin) so that valve is left open during the blood meal and blood moves back into the mouthparts.
- This will cause the promastigotes to be expelled to bite wound as the fly regurgitates content of their midgut.
What are the strategies the parasite has evolved to ensure transmission and to evade the immune response?
Transmission
- Infection will also cause increased feeding –> Sandflies generally probe 1-2 times to find blood, and take a full blood meal in less than 10 minutes.
- -Infected sandflies probe 3 or more times, and take little or no blood in 15 minutes.
Immunosuppressive
– Some components of vector’s saliva is expelled into bite wound and will have immunosuppressive actions against lymphocytes to increase infectivity of parasite.
– E.g. the peptide Maxadilan (MAX) – involved in inducing vasodilation and immunmodulation:-
• inhibits T-cell activation,
• stimulates the production of cytokines that favor a type 2 T-cell response - not effective against parasite.
• inhibits the production of molecules that de-activate macrophages (e.g. TNF-a and NO) since macrophages are necessary for their infection.
–> Vaccination against Maxadilan has shown to inhibit Leishmania infection.
