Human Pathogen Trypanosoma Brucei Biology Essay

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Trypanosomes are a group of kinetoplastid protozoa which are distinguished by having only a single flagellum, they are exclusively parasitic organisms which are found primarily in insects (Podlipaev, 2001). A few of these organisms such as T. brucei and T. cruzi have life cycles which involve a secondary host such as a human, and these species cause major diseases in humans (Simpson et al, 2006). The most important trypanosomal diseases are trypanosomiasis, African sleeping sickness and South American Chagas disease, caused by T. brucei and T. cruzi respectively.

Trypanosoma brucei requires several hosts in order to mature and reproduce. The primary host is mammalian, while the transmission vector is the Tsetse fly (Krafsur, 2009). The life cycle of Trypanosoma brucei is fairly simple. The tsetse flies feed on the blood of an infected mammal, where the immature parasites quickly evolve into the first stage of development, known as the procyclic stage. The procyclic larvae then travel to the midgut of the tsetse fly and mature into a trypomastigote (Fenn and Matthews, 2007). The trypomastigote then travels to the salivary glands of the fly, where chemicals trigger the development process again, changing the trypomastigote into an epimastigote, where it goes through further cell division and enters into the final stage of development, the metacyclic stage (Roditi et al, 2008). This is the stage where the parasite has become ready to infect a new host (Krafsur, 2009). The tsetse fly bites and transfers the metacyclic larvae into the new host. It is in the new primary hosts' bloodstream that T.brucei completes its development into an adult and begins the cycle over again. In order to survive in the hosts' bloodstream, T. brucei has developed an advanced defence mechanism. The glycoproteins that encase the parasite change approximately every 100 cell divisions. This occurs in order to stay one step ahead of the hosts' immune system allowing chronic infections to occur (Vassella et al, 2009).

The life cycle of Trypanosoma brucei is shown below in figure 1;

Figure 1

Early signs of infection include deep lesions where the parasite has damaged the capillaries in the skin, searching for larger blood vessels. Several days later the host will experience lymphatic discomfort as the lymph nodes begin to drain from infection. The host will begin to have headaches, fever and increased periods of fatigue. Several weeks to several years later, depending on the subspecies that is infecting the host, the parasite will begin to destroy organ tissues, most notably within the central nervous system (World Health Organisation). This disease is known as African sleeping sickness.

The treatment of this disease depends greatly on the stage at which the disease is at. The drugs used in the first stage of the disease are less toxic, easier to administer and more effective. The earlier the disease is identified and diagnosed, the better prospect of a cure. Treatment success in the second stage depends on a drug that can cross the blood-brain barrier in order to reach the parasite. These drugs are quite toxic and complicated to administer (World Health Organisation). Four drugs are registered for the treatment of sleeping sickness;

First stage treatments;

Pentamide

Suramin

Second stage treatments;

Melarsoprol

Eflomithine

However, it is important to remember that although treatments for T. brucei do exist, most infections occur in third world countries and so access to these life saving treatments is limited. Many people die from their infections without ever seeing a doctor or receiving any treatment at all.

Trypanosoma cruzi is a flagellated, insect-transmitted protozoa, living in the blood and tissues of infected mammalian hosts. The species is endemic to Central and South America and causes Chagas disease. The life cycle of T. cruzi involves multiple stages and life in a mammalian host and arthropod vector (Murray et al, 1998).

The T. cruzi life cycle begins with an arthropod vector, typically reduviid bugs, which are also called "kissing bugs" because they commonly bite mammalian hosts in the facial area. T. cruzi lives in the vectors salivary glands, in a form called an epimastigote, with a free flagellum but only a partial membrane. While in the salivary glands, the epimastigote transforms into a trypomastigote, with a free flagellum and a complete membrane. The trypomastigotes move to the blood, lymph and sometimes the central nervous system of the arthropod vector, and they are excreted into the faeces (Centers for Disease Control and Prevention).

The reduviid bugs then inject the trypomastigotes into the mammalian host by biting the host, burrowing into the skin and defecating into the wound (Laboratory Identification of Parasites of Public Health Concern). The T. cruzi trypomastigotes colonise in the mammalian host tissues and organs, losing their flagella and membranes. They encyst in the amastigote form, infecting cells, replicating by binary fission, destroying cells and releasing progeny. Most progeny are in the amastigote form, but some are trypomastigotes, living in the blood and lymph of the mammalian host. The trypomastigotes infect a reduviid bug when the bug feeds on the host and then transform back into epimastigotes in the midgut of the reduviid bug, repeating the life cycle (Murray et al, 1998).

The life cycle of Trypanosoma cruzi is shown below in figure 2;

Figure 2;

Trypanosoma cruzi causes Chagas disease in which the acute phase is usually asymptomatic, but can present with manifestations which include fever, anorexia, lymphadenopathy, mild hepatosplenomagaly and myocarditis. A nodular lesion or furuncle, usually called chagoma, can also appear at the site of inoculation. Most acute cases transform over a period of a few weeks or months into a symptomatic chronic form of the disease. The symptomatic chronic form may not occur for years or even decades after the initial infection. Its manifestations include cardiomypathy, pathologies of the digestive tract such as megaesophagus and megacolon, and weight loss. Chronic chagas disease and its complications can be fatal (Centers for Disease Control and Prevention).

There are currently two drugs, nifurtimox and benznidazole, which may be helpful in the acute stages of the infection. Both medications, however, have serious side effects limiting their use. Once the disease progresses to the chronic stage there is no known treatment (All about Chagas disease).

Energy Metabolism of T. brucei;

The energy metabolism of Trypanosoma brucei differs significantly from that of their hosts and changes drastically during their life cycle (Hellemond et al, 2005). In bloodstream-form organisms, substrate-level phosphorylation of glucose is sufficient to provide the energy needs of the parasite. The situation in procyclic-form trypanosomes is more complex (Besteiro et al, 2005).

African trypanosomes undergo a complex life cycle when they move from the bloodstream of their mammalian host to the blood-feeding insect vector, the tsetse fly. They encounter many different environments during their life cycle and respond to these by significant morphological and metabolic changes, including adaption of their energy metabolism. The long-slender bloodstream form of T. brucei has a very simple type of energy metabolism, as it is actively dependant of the degradation of glucose into pyruvate by glycolysis. Glucose is degraded to 3-phosphoglycerate inside the glycosomes and this intermediate is then further degraded in the cytosol to pyruvate, the excreted end product (Hellemond et al, 2005).

Transformation of bloodstream form T. brucei into procyclic stage is accompanied by striking changes in energy metabolism (Durieux et al, 1991 and Opperdoes, 1995). Upon transformation into the procyclic insect stage, the glycosomal metabolism is extended and part of the produced phosphoenolpyruvate is imported from the cytosol and subsequently converted into succinate via phosphoenolpyruvate carboxykinase, malate dehydrogenase, fumarase and a soluble glycosomal NADH:fumarate reductase (Besterio et al, 2002). In this procyclic insect stage, the end product of glycolysis, pyruvate, is not excreted but is further metabolised inside the mitochondrion in which it is mainly degraded to acetate. Acetate production occurs by acetate:succinate CoA-transferase and involves a succinate/succinyl-CoA cycle which generates extra ATP (Hellemond et al, 1998 and Glass et al, 2004). In addition to carbohydrate degradation, amino acids, mainly proline and threonine, are important substrates for the production of ATP in the procyclic insect-stage T. brucei (Evans, 1972 and Lamour et al, 2005).

Trypanosomatids possess a unique mitochondrion. In bloodstream forms this organelle has only a minor role in energy metabolism (Bienen et al, 1981). In procyclic forms, the mitochondrion is metabolically more active and contains many enzymes (Brown et al, 1973 and Michelotti and Hajduk, 1987). In the presence of glucose the production of ATP is likely to occur primarily by substrate-level phosphorylation, with key roles for cytosolic PGK and PYK and mitochondrial SCoAS (Priest and Hajduck, 1994 and Allemann and Schneider, 2000).

Arginine Kinase in Trypanosomes;

Arginine kinase is a phosphotransferase which catalyses the interconversion between phosphoargine and ATP. This enzyme is present in some invertebrates, including the trypanosomatids, and represents an analogous system to the creatine kinases in vertebrates (Fernandez et al, 2007).

Most of the research conducted on arginine kinase in trypanosomatids has been completed using T. cruzi and so the following information will be based upon this research.

The molecular and biochemical characteristics of arginine kinases have been reported by Perieira et al (Periera et al, 1999, 2000 and 2002), and it was established that a single-copy gene encodes for a functional arginine kinase in T. cruzi. The corresponding protein has 357 amino acids and a calculated molecular weight of 40kDa (Periera et al, 2000).

It has also been reported that the arginine kinase protein and the associated specific activity increases continuously along the parasite growth curve (Alonso et al, 2001). The arginine kinase expression pattern in epimastigote cells suggests a correlation between the enzyme activity and the nutrient availability or parasite density (Periera et al, 2003). It was also recently described by Perieira et al the existence of a relationship between arginine uptake, arginine kinase activity and the parasite stage and replication capability (Periera et al, 2002). Arginine kinase seems to play a critical role as a regulator of energetic reserves and cell growth. Taking into account that the more energy-demanding processes in the trypanosomatids are cell division, stage differentiation and environmental stress resistance, the role of arginine kinase activity in the cell energy requirements could be considered as a relevant unresolved issue (Periera et al, 2003).

The genome of T. brucei contains three different arginine kinase-encoding genes Tb09.160.4560, Tb09.160.4570 and Tb09.160.4590. The proteins encoded by the last two genes are more homologous to each other then to Tb09.160.4560. Until recently nothing was known about the subcellular localisation of the different arginine kinases. However, a recent experiment conducted by Colasante et al revealed the presence of two arginine kinases, Tb09.160.4560 and Tb09.160.457, in the bloodstream form glycosomes and each were distinguished from the other arginine kinases by a single unique peptide. Whether Tb09.160.4590 is present in the bloodstream form glycosome is still unclear, as a single unique peptide was not found for this arginine kinase. In the procyclic form glycosome, none of the mentioned arginine kinases could be detected through the experiment (Colasante et al, 2006).

The overall aim of this research project is to determine the localisation of arginine kinase within the Trypanosoma brucei parasite. It will be established if the enzymes are found within the glycosomes, mitochondria or another subcellular compartment such as flagellum within the parasite.

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