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m? Leishmaniasis is a disease resulting from infection by protozoa of the genus Leishmania

(family 

 and can affect man and several other species of mammals.
m? he parasites are transmitted by the bite of infected female phlebotomine sanflies.
m? aromastigotes very similar to those found in the fly can be grown in appropriate culture
media.
m? Ypon inoculation to warm-blooded animals, promastigotes are phagocytized by skin
macrophages, wherein they transform into aflagellar ovoid bodies known as  
m? cmmune recovery from "   infection is thought to involve intracellular killing of
the parasite as a result of macrophage activation.
m? Ôononuclear phagocytes thus function both as host cells required for survival of the
infecting agent and as the effectors arm of successful immune response.

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m? Leishmaniasis is a disease caused by infection of the Leishmania parasite.

m? he parasite is transmitted through the bite of an infected sand fly.
m? here are two common forms of the disease, one that causes skin sores and another that
infects the organs, including the spleen, liver and bone marrow.
m? ct is estimated by the Centers for Disease Control that there are about 2 million new cases of
leishmaniasis in the world each year. Ôost cases occur in Ôexico, Central America, South
American and some parts of Asia, the Ôiddle East, Africa and southern Europe. here are 21
species of the parasite that cause infection in people.

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m? he life cycle of the disease begins when an infected female sand fly bites a person.
m? ]emale sand flies must have blood for the development of their eggs, so it is common for
them to seek a human to supply this meal. When the bite occurs, the sand fly injects the
promastigotes, or the infective stage of the Leishmania parasite, into the person.

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m? hrough binary fission, reproduction starts to take place and the infection spreads.
m? cn the form of the disease that infects internal organs, the parasite then begins infection there
and enters into the circulation system of their host.




m? At this point, if a sand fly chooses the infected human as the source of a blood meal, it will
again ingest the parasite.
m? Within the sand fly's body, the parasite -- now in its promastigote stage again -- will
reproduce. he parasite will stay inside the sand fly for four to 25 days.

 



m? As the parasite protozoa reproduce within the sand fly, they migrate toward the insect's
pharynx, creating a blockage in its esophagus.
m? When the sand fly gets ready to feed, it cleans out its esophagus -- containing the
promastigotes -- by injecting the leishmaniae into the skin of the person or animal from which
it is preparing to feed.
m? he life cycle of leishmaniasis is now full circle.





m? £ringing the life cycle to an end through treatment depends upon what form of the disease has
occurred. ]or the disease that infects the skin, topical paromycin is often used.
m? cf the lesions caused by the disease are more invasive, sodium stibogluconate, meglumine
antimoniate or pentamidine may be prescribed. cn the form of the disease known as mucosal,
pentavalent antimony is often prescribed over a four-week course. ]or the leishmaniasis
 disease that infects organs, pentavalent antimony compound is the most common treatment
protocol.

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m? Serum from many animal species displays potent lytic activity against Leishmania
promastigotes, due to complement activation by the alternate pathyway.
m? ct may therefore be speculated that survival of the parasite within animal hosts depends
on its capacity to become intracellular.
m? cnterestingly, no specific organelle that might facilitate cell invasion has been detected at
the ultra structural level, and leishmanias appear to rely entirely on the phagocytic
activity of macrophages to reach a safe intracellular location.
m? Attachment to the macrophage membrane is prerequisite to phagocytosis.

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m? he parasitophorous vacuole undergoes fusion with secondary lysososmes. cn their

amastigote form, leishmanias suffer no harm form this situation; indeed, they have been
shown to multiply within phagolysosomes.
m? aro-mastigotes may be more susceptible to intracellular destruction, and it has been
suggested that survival in phagolysososmes may depend on the capacity of
promastiogites to transform rapidly to amastiogtes.
m? heir location within phagoysosmes rednders the para-sites potentially susceptible to the
toxic activity of lyso-somotropic agents, such as certain amino-acid esters.
m? hese are trapped in host cells by protonation; they then presumbably accumulate in the
lysosomal compartment of the parasite itself, where their hydrolysis would occur, leading
to osmotic swelling of the organelle and to rapid parasite disruption.

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 m? ransformation from the promastigote (insect-adapted to the amastigote (mammal-
adapted developmental stage and adaptation to the intracellular life entail major
metabolic changes.
m? he respiration rate and glucose catabolism are strongly decreased in amastigotes
compared to promastigotes, correlating with lower activity of several glycolytic enzymes.
m? Concomitantly, nonesterified fatty acids becomes a predominant energy sources.
m? he biochemical mechanisms that induce such modifications remain speculative.
m? A causal relationship between HSa synthesis and the ac-quisition by the parasite of the
morphological and metabolic characteristics of the intracellular life remains, however, to
be established.



 

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m? ahagocytosis of "   promastigotes has been shown to induce in macrophages a

strong metabolic burst and the production of active derivatives of oxygen [54], and
resistance to such toxic agents must be prerequisite to intracellular survival.
m? "   parasites contain a novel reducing agent, trypanothione [29], which may help
to detoxify oxygen metabolites.
m? As regards resistance to "
 hydrolases, it has been suggested that Leishmania
parasites might inhibit such enzymes, perhaps by shedding polyanionic substances
capable of complexing the positively charged hydrolases or binding calcium ions.
m? Conflicting observations have been published, however, that demonstrate unimpaired, or
ever enhanced 
 enzyme activity following ingestion of "  .

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m? A critical question is whether the nature of the ligqand-receptor interaction that precedes
phagocytosis has a role in the successful infection of macrophages.
m? cnfectivity of cultured pro-mastigotes is strongly dependent on the growth phase in vitro
(logarithmic vs. stationary of the microorganism, and it correlates with the increased
expression of a surface glycoprotein presumed to be gp 63 and of a high molecular-
weight glycolipd structurally re-lated to La .
 m? ct is noteworthy that, in addition to its postu-lated capacity to dampen macrophage
respiratory burst, La also appears to function as an acceptor of C3 cleaveage products.

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m? Ôacrophages are involved in both the inductive and the effectors phases the immune
response.
m? Similarly, -cell mitogenic stimulation and interleukin-2 production by spleen cells from
L. major-infected susceptible mice are de-pressed by macrophage-mediated mechanism,
perhaps as a result of excessive prostaglandin synthesis.
m? Seclusion of parasites within phagolysosomes raises the question of the mechanisms of
presentation of parasite antigens by host macrophages to the immune systems.
m? aarasite constituents appear to be both released from infected macrophages and
displayed on the macrophages surface.
m? Ôembrane-bound "   antigen has also been demonstrated on infected
macrophages in vitro.

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m? Human and murine macrophages can be activated to kill "   parasites in vitro by
exposure to lym-phokin-rech preparations.
m? Such as supernatant fluids from mitogen- or antigen-stimulated lymphoid cell cultures.
m? he c]
-Ȗ mediated mechanism of macrophage activation is presumably critical to the
process of recovery from infection.
m? cn mice, depending on the genetic constitution of the host, infection by " 
 
parasites leads to a self-resolving disease or to a progressive disease.
m? ct has been suggested that -cell (CD4+ subsets produced in each instance are different.

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m? Earlier studies of the infection of mice from different strains by L. donovani suggested
that initial host susceptibility (or lack of it to the parasite is controlled by a single gene,
termed " of which two alleles exist (" in ³acutely resistant´ animals, " in
 susceptible ones. ct was further demonstrated that Lsh gene exercisedits activity through
macrophages.
m? A particularly interesting question is what features of the"  -parasite interaction
have a decisive role in determining the overall susceptibility of the host to infection.
m? Ôore precisely, what are the mechanisms controlled by the " gene that render
macrophages permissive or not to the parasite.
m? iven the wealth of knowledge accumulated in recent years in the field of macrophage-
parasite interaction.