The Effect Of Leishmania Parasite Biology Essay

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Leishmania are protozoal parasite of the family of Trypanosomatidae responsible for Leishmaniasis. These are obligate parasites that are transmitted to the mammalian organism by a bite from a sandfly. In nature there are more than 700 species of sandflies of which roughly about 70 are known to be vectors of leishmaniasis (Lane, 1993). Based on were they are found, Leishmania can be divided into 2 different categories, those found in the Old world (Africa, Europe and Asia), and transmitted by sandflies of the Phlebotomine species. They comprise of L. major, L. tropica, L. infantum and L. donovani. Leishmania of the New world (Americas and Oceania) are transmitted to the mammalian host by the Luzomyia sandfly, these comprise of L.mexicana, L.Amzonesis, L.Breziliens, L. chagasi and a lot more. According to Azpura et al (2010), more than 20 species of Leishmania are able to cause the disease, however the main ones are those listed above as their biology and methods of infection have been studied.

Leishmaniasis is a disease that is caused by the Leishmania parasite and is endemic in more than 88 countries worldwide; the disease is more prevalent in hot regions i.e. the Sub-Saharan Africa, and other tropical and subtropical countries. According to the WHO, more than 12 million people are affected worldwide with another estimated of 350 millions being at risk of the contracting the disease, and this figure is rising due to globalisation and tourism, plus as well the increase of HIV in the recent years (Donovan et al, 2007).

Leishmaniasis can be subdivided into 3 different categories based on the symptoms and the parasite that cause them; cutaneous leishmaniasis (CL), mucocutaneous Leishmaniasis (ML) and visceral leishmaniasis (VL).

Cutaneous Leishmaniasis is caused by L. Mexicana, L tropica and L.major, it is characterised skin lesions, these lesions are normally self healing. It is estimated that globally there are about 1 to 1.5 million cases of cutaneous Leishmania each year (Reithinger, 2008).

The mucocuteneous leishmaniasis is characterised by degradation of mucosal membranes; this can lead to permanent disfigurement, this most notable nasal area, the pharynx and the mouth. It is caused by L. braziliensis (Snoog, 2008).

Visceral Leishmania is the most severe form the disease and is caused by L. infantum,L. chagasi and L. donovani, its characterised by fever, enlargement of important organs like the spleen and liver subsequently causing anaemia and weight loss. This has a high mortality rate with about 6000 cases every year (Azpura et al 2008).

Biology of Leishmania

Leishmania parasite exists in two main morphological forms during its life cycle; the promastigote form and amastigote form.

In the vector, Leishmania is found the promastigote form. Under a microscope, this can be seen as a flagellated, motile with an elongated body microoroganism. The promastigote form is found in the extracellular stage of the Leishmania life cycle. Promastigote are infested into the bloodstream when the sandfly feeds on its mammalian victim. The promastigote then undergoes changes intracellularly into amastigote.

The amastigote form of the parasite is found in the intracellular stage of the parasite in the mammalian cells after injection by the sandfly. The amastigote form is non motile, ovoid in shape and has no flagella. This is found in the intracellular stage of the parasitic life cycle.

In the sandfly, Leishmania undergoes a development metamorphose into seven different forms, these are known as subgenus. Early cellular transformations that take place in vivo have not been duly being studied, however in vitro observations have suggested that the transformations starts with the development of amastigotes into procyclic promastigotes (Bates, P.A., 1994), this process occurs between 24 to 48 hours. The procyclic promastigotes are the initial dividing form that increases the population of parasites in the gut of the sandfly. Procyclic promastigotes are short with a body length of 6-8µm, they have a very short flagellum and are not very motile. In vivo they are found the bloodmeal of the sandfly (Rogers, M.E. et al, 2002). Procyclic promastigotes also produce important surface molecules, most notably the lipophosphoglycan (LPG) that aid their survival in the sandfly and also aid their immune evasion (Descoteaux and Turco, 1999). The importance of these LPG was shown in genetically engineered mutant L. Major which was shown to not survive in the sandflies or even easily combated in the infection (Sacks et al, 2000).

The second most important transformation in Leishmania life cycle is the elongation of the procyclic promastigote into a 12-20µm nectomonad promastigote. This takes place 2-3 days after bloodfeeding from a mammalian host (Rogers et al, 2002). Nectomonad promastigotes are very motile and move towards the peritrophic matrix (PM), this protect them against chemicals in the gut of the sandfly (Walters et al, 1989).

The parasite however has to escape onto the epithelial cells in the guts of sandfly as although the PM initiates the protection of the promastigotes, their thickness can come as a hinderance to the development of the promastigotes (Lawyer et al., 1990).

After 3-7 days after bloodfeeding, the nectomonad undergoes another metamorphose into leptomonads promastigotes, these have shorter body length (8-9µm) (Gossage et al, 2003). These leptomonads can give rise to short promastigotes known as heptomonads, these attach themselves in the midgut of the sandfly but they mechanisms are not fully known (Bates and Rojers, 2004). The leptomonads produce a gel like substance that helps in the spread of infection; the promastigote secretory gel (PSG) (Rogers et al, 2002).

Leptomonads promastigotes differentiate into the metacyclic promastigotes. This is the major differentiation in the promastigotes cycle as it is ready to infect mammalian cells. Metacyclic promastigotes are narrow with 5-8µm cell body and are highly motile, a feature that allows them to migrate into the lumen of the midgut of the sandfly, where they can be transmitted into the bloodstream when the female sandfly is bloodfeeding on a mammalian host (Rogers et al, 2002).

These cells are non dividing cells in the sandfly, and are free swimming ready for infection, they also present features that allows them to evade the host immune system, for example the complement mediation (Sacks, 2002). In the mammalian host, the metacyclic promastigote differentiates into amastigote and loses the flagella changes shape in the mammalian cells.

Another subgenus associated with Leishmania is the Viannia subgenus. This has not been fully studied however it is presumed that cells undergo the same processes from promastigotes to amastigotes. It can also be said that the nectomonads in this case do not bind to the epithelium of the vectors; however they produce LPG like those of Leishmania subgenus (Pinto-da-Silva et al, 2002).

Immune system and control of Leishmania

The immune system is the ensemble of the cells and chemicals that protect the individual against any infection that they encounter. The innate response is the first point of control for Leishmania invasion of the immune system. Their study on Lieishmania Amazonesis, Aranha et al (2003) explained that Natural Killer (NK) cells play a key role in the control of Leishmania infections in the innate immune response. They found out that NK cells activated by the interleukin-2 (IL-2), lead to a reduction of viable parasites in vitro compared to a control group that wasn't exposed to the activated NK cells. The level of INF-γ were also elevated in the test group, this suggests that the NK cells play a key role in controlling early infection. It was found however that in cutaneous and visceral leishmaniasis, the control of the diseases is regulated by the activation of T cell, which induce the IL-12 driven Th1-type immune and the production of the interferon gamma (IFN-γ) by the CD4+T cells. The production of IFN-γ is important in combating intracellular parasites by promoting the activation of macrophage; this produces nitric oxide which kills the parasite (Alexander et al, 1999). Controlling Leishmania infection also depends on a group of intracellular proteins known as signal transducer and activator of transcription (STATs). There are 7 types of STATs, these are important in mediating the induction of the cytokines-responsive genes and the regulation of biological activity of cytokines (Wurster et al, 2000).

In the development of cell-mediated response to Leishmania, the coupling of IFN-γ and STAT1 is very important in controlling the disease. IFN-γ is a type II interferon secreted by activated T cells and NK cells; their activity depends upon the activation of STAT1 transcription factors. In response to IL-12 coupled with STAT4 signalling, the IFN-γ coupled with STAT1 is released inducing the activation of macrophages by inducing iNOS (inducible nitric Oxide synthase) expression and the production of NO, leading to the elimination of the parasite and Leishmania infections (Sacks and Noben-Trauth, 2002). A recent study by Barbi et al (2009) shows that STAT1 are important in CD4+T cells immune response in L.major infections by mediating the recruitment of T cells to the infection site. IFN-α/β with STAT2 have been shown to mediate the regulation of innate immune response in CL with L.major, they initiate the NO and the NOS2 (nitric oxide synthase 2), shown to play a role in the protection against intracellular parasites (Diefenbach, 1998).

Immune evasion by Leishmania

Immune evasion in Leishmania infections is the mechanisms used by the parasite to avoid the destruction by the immune system. In infections by L.Major, it was shown that L.Major promastigotes secrets substances that inhibit the migration of murine dendritic cells (DCs) in vitro and that the lipophosphoglycan (LPG) on the surface of L.major also inhibits the migration of langerhans cells in CL (Ponte-Sucre et al, 2001). This has been attributed to the glycoproteins gp63 and glycoinosytolphospholipids (GILPs) and LPG found the surface of different strains of the parasite. This happens due to changes that occur during DCs recruitment to the site of infection. The parasite changes the chemokine-chemokine receptor (CCR1, CCR2, CCR5 and CCR6) found on the DCs and consequently slowing the migration process. Other studies show that another mechanism used by Leishmania parasites is the inhibition of DC maturation; they do this by delaying the maturation of DC favouring the establishment of infections (Bennett et al, 2001).

On the other hand however it was that Leishmania infections depend upon their interactions with certain cytokines. It was shown that IL-4 and IL-13 with STAT6 favour the nonhealing forms of CL in mice (Tripathi et al, 2007). In mice, IL-4 was shown to be an inhibitor of IFN-γ-producing CD4+T cells an important mechanism in the Th1 immune response in Lieshmania infections (Tripathi et al, 2007). The mechanisms of interaction between the parasite and these cytokines is not known, however certain literatures suggest that the IL-13 and Il-4 promote parasitic survival and persistence by triggering macrophage to undergo alternative activation compared to their normal activation (Sacks and Noben-Trauth, 2002) this also prevent the development of Th1 responses. Another cytokine important in the development of leishamania is the IL-10 associated with STAT2, these are important in the inhibition of proinflammatory cytokines like IL-2, IL-1 and the TNF important in the Th-1 immune response in Leishmania. It was shown to be associated with the nonhealig forms of leishmaniasis bothi in animal and human (Tripathi et al, 2007).

Another important mechanism of immune evasion in Leishmania infections is the downregualtion of MHC proteins on the surface of macrophages. In experiments on mice it was shown that Leishmania infection lead to low expression of MHC-II on the surfaces of DCs (Muraille et al, 2003). This has been defined as a way for the parasite to inhibit the antigen presentation and also the inhibition of the T cells stimulation. However Ponte-Sucre et al (2001) found that in langerhans cells maturation, the LPG on the surface of the L.major upregulated the expression of MHC-II, but this was only during cell maturation. The effect of Leishmania on the expression of MHC-I is not fully understood, however it was shown that when the IFN-γ producing CD4+ cells is reduced, the presentation of Leishmania antigen by MHC-I is blocked (Roger and Titus, 2004).