Leishmaniasis is a vector borne protozoan infection that causes a wide range of infections from cutaneous infections to in some cases fatalities (Pavli and Maltezou, 2010). It is listed amongst the 6 most important tropical diseases by the World Health Organisation. It is approximately endemic in 88 countries, putting an estimated 330 million people at risk (Neghina and Neghina, 2010). An estimated 500,000 cases are reported worldwide each year with around 50,000 dying from the disease (Gorski and Wiercinska-Drapalo, 2009). A sharp increase has been observed over the last decade. This increase in the disease has been associated with international tourism, military operations and an increase of immigration from endemic countries. The two main types of leishmaniasis are cutaneous and visceral. The cutaneous form is mostly associated with South America and the more fatal visceral form is commonly seen in popular Mediterranean destinations (Pavli and Maltezou, 2010). Leishmaniasis is caused by a hemoflagellate, Leishmania spp. This parasite is transmitted by infected female phleobotomine sandflys when blood feeding. The parasite goes through different stages in order for the infection to occur. The first form of the protozoa is a promastigote which forms residues inside the midgut of infected female sand flies. When the female sand fly takes a blood meal, promastigotes are regurgitated into the pool of blood and enter the host. A rapid response is initiated by phagocytic cells at the site of infection. The macrophages take up the promastigotes by phagocytosis where they then differentiate into a different form of protozoa called amastigotes. These remain in the cell and replicate until the cell lyses releasing the parasites into neighbouring cells. This cycle continues as the sand fly can bite an infected host again, taking up the infected macrophages and amastigotes, the amastigotes then transform back into the promastigote form in the sand flies midgut (Mosser and Miles, 2000). Leishmanial infections in humans can manifest into different forms of the disease depending on the species of parasite. The four types of leishmaniasis are cutaneous leishmaniasis (CL), mucocutaneous leishmaniasis (MCL), diffused cutaneous leishmaniasis (DCL) and visceral leishmaniasis (VL). 90% of cutaneous cases are seen in Afghanistan, Saudi Arabia, Algeria, Brazil, Iran, Iraq, Syria and Sudan (Singh and Sivakumar, 2004). Cutaneous leishmaniasis is most commonly caused by the protozoa, Leishmania tropica. It has an incubation period of two to eight weeks. It begins as an erythematous papule on the sand flies bite site. This papule will then increase in size to become a nodule, which ulcerates and crusts over. This ulcer is usually large and painless unless a secondary infection has occurred. Leishmaniasis lesions tend to heal within a few months but in some cases the lesions can remain for years. The cutaneous form of leishmaniasis can become disseminated, this is the diffuse cutaneous leishmaniasis form of the disease. This is seen most commonly in immunosuppressed patients such as people with human immunodeficiency virus (HIV). Another is the mucocutaneous form being most prevalent in Latin America. This can occur straight after an initial cutaneous infection. This usually begins in the nose or palate, causing lesions to destroy mucosa and sometimes cartilage. This can cause disfigurement, pulmonary aspiration and even death (Markle and Makhoul, 2004). 90% of visceral cases are seen in India and Sudan. Visceral leishmaniasis is characterized by a prolonged fever, anaemia, loss of appetite, weight loss and hepatosplenomgaly (simultaneous enlargement of liver and spleen). If this form of leishmaniasis is left untreated the patient's skin becomes darkened and due to the weight loss, anaemia and systemic impairment, the patient will die (Singh and Sivakumar, 2004). But in order for the disease to be caught, the parasite must survive host immune responses. It does this through a variety of different chemicals and methods.
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Many virulence factors have been identified for the infection process, some of these chemicals include lipophosphoglycan, A2, cysteine protease (cp) and gp63 (Matlashewski, 2001). Lipophosphoglycan is a glycosylphosphatidylinositol anchored polysaccharide that is found on the leishmania surface coat. It has many roles that are important in the infectious stages of the disease. It helps the parasite survive by evading complement ad oxidants. It also acts as a major adhesion product for attachment to macrophages and enables the deactivation of macrophage signalling pathways (Spath et al, 2000). Another important chemical in leishmania survival is cysteine protease. Cysteine protease is important for leishmania infection, development, replication and metabolism of parasitic stages. Its activity has been associated with survival of the leishmania mexicana parasite and seen as a modulator of the host's immune system. Cysteine protease allows for leishmania survival inside macrophages by the mechanism of gene disruption and antisense mRNA expression (Mundodi et al, 2005). Gp63 is a 63 kDa molecule that is the most abundant protein on promastigotes surfaces. Gp63 has shown properties related to the fibronectin glycoprotein which is used for cell adhesion. Leishmania expressing gp63 on its cell surface have shown adhesion to human macrophages, which is one stage in the life cycle of the Leishmaniasis parasite. Gp63 is used as a defence mechanism against host immune responses. It allows the parasite to survive on cell surfaces and provides resistance to complement mediated lysis (Brittingham, 1999). Virulence factors can cause problems for the host, but the human body has many immune responses in place to fight the parasitic infection.
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The hosts immune response to the leishmaniasis infection is cell mediated, and onset of symptoms depend on whether the immune response is a Th1 or Th2 response. A Th1 response can cause infection and a Th2 response can cause the diseases progression, any of these responses can occur even from the same parasitic epitope. Even though the parasite causes a primary innate response by macrophage proliferation the disease control is determined by the adaptive immune system. An innate response involves toll like receptors (TLRs) and complement receptors (CRs), which detect the initial infection to induce an inflammatory and antimicrobial response. Toll like receptors on dendritic cells (DCs) can trigger an antigen specific adaptive response by presenting the antigen to CD4 + cells. This can stimulate T cell differentiation into INF-γ Th1 cells or IL-4 Th2 cells. Also toll like receptors are activated by microbial lipoproteins which intern activate IL-12 and nitric oxide which can induce host cell apoptosis. Macrophages are activated by IL-12 and tumour necrosis factor (TNF). One tumour necrosis factor is called LIGHT and enhances inflammation and T cell mediated immunity, also it is important for IL-12 production by dendritic cells (Ezra, Ochoa and Craft, 2010). The production of INF-γ will also control the intracellular death of amastigotes inside macrophages or upon the parasites release from host cells. Another method of intracellular killing is down to macrophages being killed by cytotoxic T lymphocytes (CTL) and FasL - mediated macrophage apoptosis (Roberts, 2005). But in many cases addition treatment is need to fully cure the disease and destroy all presence of any parasite in the body.
When treating leishmaniasis some considerations need to be taken into account. The type of treatment depends on the form of leishmaniasis, etiology and geographic location of the infection (Lee and Hsai, 2010). When treating cutaneous leishmaniasis, antimonials are used which help heal lesions faster, prevent relapse, dissemination, the mucosal form and transmission. It is important to treat lesions as soon as possible as they can worsen. Lesions can become larger, get infected and move to other parts of the body. Pentavelant antimony works by the inhibition of adenosine triphosphate synthesis. The main antimonial used is sodium stibogluconate which is also called pentostam. These antimonials have many side effects including aching, arthralgia, fatigue, gastrointestinal upset, elevation of amylase, lipase, leukopenia and anaemia. Signs of healing should be seen after 20 days of treatment. The mucosal form of the disease takes longer to heal as it is more difficult to cure (Markle and Makhoul, 2004). For advanced forms of the mucosal form amphotericin B deoxycholate is the first line of therapy. When treating visceral leishmaniasis, secondary problems such as pneumonia and diarrhea can occur due to infections and bleeding. So firstly antibiotics are needed to treat these infectious conditions. To treat initial visceral leishmaniasis, pentavelant antimonials are usually effective except areas where resistance to this drug can occur, for example India. In the treatment of mucosal leishmaniasis, amphotericin B deoxycholate is used, but a new drug has been derived from this using liposomal formulations. A trail has shown the liposomal amphotericin B to be more effective and cheaper (Lee and Hsai, 2010). Although the treatment of leishmaniasis is effective in some cases prevention of the disease in the first place can be beneficial.
There is currently no vaccination for Leishmaniasis so no way of successfully preventing getting the infection. A vaccine is in development which uses killed promastigotes and bacille Calmette - Guérin vaccine. This vaccine is being tested in Iran, Sudan and Ecuador. The most effective way of preventing from a leishmaniasis infection is by avoiding initial transmission from phleobotomine sandflys. In recent years this has become more difficult due to sandfly migration from their tropical environment to more urban areas. Travellers should ensure they wear insecticides in endemic areas and residents in these areas should spray their houses to reduce the population of phleobotomine sandflys. Fine weave nets should be placed around beds to prevent bites at night. Also rodent reservoirs of disease should be sprayed with insecticides to prevent the parasites transmission. A study was carried out in Venezuela has shown the effectiveness of using nets. Fine gauze nets were placed in windows to reduce sandfly population in urban areas. The incidence of cutaneous leishmaniasis in this study had dropped to zero after a 12 month period (Markle and Makhoul, 2004).
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