The relationship between Malaria and the human body serves as an excellent model to further explore the complexity of protists. Malaria remains one of the better studied pathologies on which a vast amount of experimental studies have been performed and published. The extensive information in the scientific community on malaria provides a glimpse into the world of protists and into our own evolution.
Malaria is injected into the dermis of the skin by the Anopheles mosquito. The sporozoite must contain sporozoite protein essential for cell traversal (SPECT)1-2 in order to successfully transverse the dermis and enter the blood supply. Sporozoites lacking these proteins are quickly immobilized and become the subject of an immune response. Sporozoites remaining in the dermis may also drain into the lymph nodes furthering the immune response. The sporozoites that enter circulation move rapidly to the liver where they transverse the sinusoidal spaces through kupffer cells.
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Upon entering the hepatocytes sporozoites switch from to a migration phase to a productive invasion phase. The productive invasion phase is marked by the sporozoite transversing several hepatocytes before forming a parasitophorous vacuole (PV). The time for the PV to form as well as the number of hepatocytes the sporozoite transverses is directionally proportional to the time needed to allow for different gene expression. These genes resulting in the switch from phases are thought to be activated through many different mechasims upon transmigrating across the hepatocytes. Chemical products within the liver cells themselves such as uracil derivatives are believed to play a role in activation. Heparan sulfate proteoglycans (HSPGs) present on liver cells contain a high level of sulfate that triggers activation as well. HSPGs are also involved in the initial binding of the sporozoite to hepatocytes. The sporozoite transverses several liver cells before activation is complete. At this time the sporozoite will begin displaying adhesive proteins on the outer membrane which will bind to a final hepatocyte causing an invagination of the plasma membrane and PV formation.
Another important feature of Malaria is survival within the liver cell. A number of proteins must be expressed in order for the sporozoite to survive. UIS (upregulated in infective sporozoites) gene 3 regulates lipid delivery by interacting with liver-fatty acid binding protein (L-FABP). L-FABP docks to UIS and delivers fatty acids to the sporozoite in vitro. Another protein Cystein protease CSP is believed to cause merozoite release from hepatocytes after the developmental phase is complete. The merozoites are still protected from the immune system by being encased in merosomes. Merosome are formed by merezoites budding off the liver and are covered by the plasma membrane of the host liver cells which helps avoid recognition by the immune system. These findings are based on in vitrio experimentation and intravital microscopy of P. yoelii in rodents.
The next stage of infection involves the red blood cells. This stage is also associated with the hemmoragic signs and symptoms of malaria including fever and chills. Merozoite surface proteins (MSPs) are coded by The Plasmodium falciparum reticulocyte-binding homologs (PfRh) found in malaria and are expressed on the surface of the merezoites. These proteins bind to the erythrocyte binding antigens (EBAs) found on the surface of erythrocytes. In vitro studies with inhibitory antibodies showed that apical membrane antigen 1 (AMA-1) orients the apical end of the merezoite to face the surface of the erythrocyte preceding injection into the red blood cell.
Following entry into the red blood cell, the merezoite digests and uses hemoglobin as a food source as well as altering the composition of the erethroycte plasma membrane. Plasmodium export element (PEXEL) forms the gateway though which virulence factor proteins are inserted into the plasma membrane. The study performed by Chang illustrated N-acetylation site with classical cleavage. This fact is of great importance as it shows the vast majority of viral antigens expressed on the surface of the erethroycte all have the same basic core fragment to which different chemical building blocks are added. This means malaria is able to display a wide range of adaptability by continually altering the chemical composition of virulence proteins based on the same core fragment. This in turn means different proteins are able to be expressed on the surface of the erethrocyte. Varying protein expression at the site of plasma membrane presents the immune system of the host with a difficult challenge as new antibodies now must be generated against the new virulence factors being expressed.
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Malaria infection is not just confined to the bloodstream and may also affect the brain. This form is known as cerebral malaria and has been extensively studied in rodents using Plasmodium berghei. The experiments in vitrio conducted by various laboratories suggest that heme oxygenase-1 (HO-1) plays a major role in host susceptibility to malaria. Hmox-1 is the gene that codes for heme oxygenase-1 and disruption causes an increased risk of malaria in the host. This is because CO is one of the breakdown products of the catabolism of free heme and helps prevent disruption of the blood brain barrier and harmful effects to the blood vessels of the brain. These consequences are avoided because CO binds to hemoglobin preventing its oxidation to free heme which has been shown to carry an increased risk for developing cerebral malaria. This also leads to a decreased risk of an inflammatory response in neural tissues with less damage to the brain itself. The mechanism of action in preventing disruption of the blood brain barrier is two-fold. Free heme, a molecule with increased risk for cerebral malaria, is catabolized generating CO as one of the products which in turn binds to hemoglobin and prevents its oxidation and the development of free heme thereby stopping the cycle.
Protists are one of the most amazing organisms that exist on our planet today. From the time the protist first enters the body, many different pathways are at work culminating in infection. The number of complex molecular steps show protists to be highly differentiated and the next step in the world of evolution. To summarize, gene expression is the key feature in all stages of the malaria life cycle and directly responsible for protist success as an agent of disease. Gene expression regulates which proteins are synthesized during the different phases of the malaria life cycle and correspond to the organismâ€™s virulence.
I was highly impressed by the efficiency of malaria as an agent of disease. Adaptability was the theme that continued to stand out when reading the article and is what I consider to be the most important factor in determing the virulence of an organism. The ability to alter gene expression and produce many different proteins clearly sets protists and malaria in a different category from other organisms and in my opinion furthers our understanding of our own world to a great extent.