Leishmaniasis: A Study of the Disease, Its Progression, and Its Effects on Macrophages and the Immune System

Leishmaniasis:

A Study of the Disease, its Progression, and its Effects on Macrophages and the Immune System

Leishmaniasis is a debilitating disease that is found in parts of Africa, the Middle East, and South and Central America. The disease is a caused by a heteroxenous parasite known as Leishmania. The leishmania parasites spend the first part of their life cycle in the gut of a sand fly. Once transmitted to the mammalian tissues, the leishmania is known as an amistigote (1). Amistigotes are sometimes known as Leishmania-Donovan (L-D) bodies. The most common hosts of the leishmania parasite are mammals, but over a dozen species have been found in lizards. The species that are found in lizards are now placed in the subgenus Sauroleishmania (2). The most common mammals that become infected with the leishmania parasite are humans and dogs. The disease is considered a zoonotic threat with wild mammals acting as the reservoir (1). The life cycle of the disease is shown in Figure 1.

Figure 1. Life Cycle of Leishmania. www.dpd.cdc.gov/DPDx/html/Leishmaniasis.htm

It is believed the disease started in Africa, with the slave trade to the west through the Middle East and Asia caused it spread to those areas. Air travel creates the possibility of moving the disease very rapidly. According to the Army Medical Surveillance Activity office more than 2,500 soldiers have contracted Leishmaniasis while serving in Iraq and Afghanistan. It is estimated that about 15 million people are infected worldwide, with 400,000 new cases annually, in 67 countries (3). The figure is probably under representing the actual number of cases, however. Parts of the world where the disease is common do not have adequate health care networks and records are hard to come by. Also, in Africa, many patients who contract leishmaniasis die very quickly because of a weakened immune system from AIDS. Many of these patients are never diagnosed and recorded (4).

Leishmaniasis is a very odd disease among parasites in that actually lives in the very cells that usually work to destroy infections from bacteria, parasites, and other foreign invaders. The leishmania parasite lives in the macrophage cell, and more accurately, lives in the phagolysosome that normally is the compartment that ingests foreign particles. The disease also takes on a variety of clinical manifestations, which range from a skin lesion to a fatal visceral takeover. Sometimes that disease can even respond to treatment, and then reappear in a different manner. It is one of the unique mysteries of parasitology and hematology alike.

To fully understand the complexity of this single celled parasite known as Leishmania you must look into how the disease is contracted as well as how it proliferates. The parasite is passed around by route of a vector, or intermediate host, known as a sand fly. There are over 600 species of sand flies divided into five genera. The genera consist of Phlebotomus, Sergentomyia, Lutzomyia, Brumptomyia, and Warileya. The sand flies suck the blood of an infected host, either a human or a reservoir animal like a dog and ingest the amistigote form which was mentioned earlier in the paper. The amasitgotes are passed into the hindgut of the sand fly and transform into a form known as the procyclic promastigote and replicate by binary fission. Binary fission is a form of asexual reproduction used by all prokaryotes. The promasitgotes take about eight days to fully develop by metamorphosis. After developing into metacyclic promastigotes they are injected when the sand fly takes its next blood meal from a mammal. Transmission can also occur by crushing the infected sand fly into the skin or mucous membrane, so it does no good to swat the sand fly when it lands on you. The amistigote ranges from 2.5 to 5 micrometers wide and can be even smaller than that. At this size they are one of the smallest nucleated cells known to man.

The species of Leishmania are impossible to distinguish based on morphology. They can be distinguished clinically, biologically, and serologically; but even those characteristics cannot always be definitive. They can change clinical manisfestions and immunodiagnostics may give false positives for several species of Leishmania and sometimes even for species of Trypanosoma. Leishmania differ in their biochemical properties, notably in their membrane components. Some evidence points to the virulence of Leishmania being based on membrane bound lipophosphoglycans, but not always. Leishmania major lost virulence when the genes that control synthesis of lipophosphoglycans was knocked out, but this was not the case with Leishmania mexicana (5). Strains and species of Leishmania are characterized biochemically. Isoenzymes, buoyant density of DNA, RFLP, RAPD analysis, and gene sequencing have all been used to identify have been used to differentiate the various species of the parasite (6). It is very confusing to tell what type of Leishmania is referred to in some old literature on the creatures. Some researchers refer to several species while other refer to one species with different features.

It is also very difficult to identify Leishmania forms in the sand fly. This is a problem because identification of parasites in their vector is important to controlling the disease. Controlling the disease cannot focus on just on species of vector and you must not try to eliminate a species morphologically similar to the one that affects humans, but does not actually do so. Modern biochemical methods such as hybridization of kDNA have helped with this problem (7). The best test is the polymerase chain reaction that is used to amplify kDNA (8,9,10). These tools can be used to help identify varying species of L donovani which is responsible for the disfiguring post-kala-azar (11).

Treatment of Leishmania is a very complicated thing. There are very many types of treatment, many of which are toxic. Trivalent antimonials used to be the only drugs available, but were very dangerous for the patient. Pentvalent antimonials have been used the most in recent years, but is also very toxic. Pentostam is the pentvalent antimonial that is available in the United States through the Centers for Disease Control. Several species of Leishmania are believed to have become resistant to the drug (12). Relapse and post-kala-azar dermal leishmanoid can follow insufficient treatment with the drugs.

Many new treatments involve attaching drugs to liposomes or colloidal particles so that macrophages will eat them. The idea is that the drugs will

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