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"Interactions of the malaria parasite and its mammalian host," by O. Silivie, et al, explores the relationship between the Plasmodium parasite and its host cells at the molecular level. The article highlights aspects of the Plasmodium's lifecycle while explaining the interactions between the various stages of Plasmodium with the different host cells, proteins, and other cellular structures it encounters at these different stages. Through the use of research and experiments, which will be discussed presently, the article addresses the questions of how Plasmodium has adjusted to life inside of the host and how it has enabled itself to so successfully persist and cause malaria in such a substantial amount of the human population.
The first interaction between Plasmodium and its host occurs when the parasite initially enters the mammal. As the proboscis of the Anopheles mosquito, the vector for Plasmodium, sinks into the skin of its victim while feeding, sporozoites are released. From the skin, sporozoites migrate quickly through cells, using three proteins in particular to accomplish this: (SPECT)-1, SPECT-2, and phospholipase. Other sporozoites drift in the dermis until they encounter a blood vessel leading to the circulatory system, which will eventually lead them to their target cells: heptatocytes inside of the liver. These sporozoites are able to enter heptatocytes via recognition between circumsporozoite proteins protruding from sporozoites and heparin sulfate proteoglycans, which are found on liver cells. Before this entry occurs, research has shown that plasmodium actually remains in the dermis for a defined phase; while the sporozoites are located here, the plasmodium is said to be in the skin stages.
As the parasite enters the liver stage (the stage where the plasmodium has invaded and began to develop inside of the liver) a specialized compartment forms called the parasitophorous vacuole (PV). The formation of the PV marks the transition from the sporozoite drifting or migrating in the hopes of entering a heptatocyte to what is called the productive invasive phase. Unfortunately, this transition is still elusive to the scientific community; however, previous experiments performed have revealed that parasites with mutated SPECT proteins are able to infect and form PVs in heptatocytes faster than normal parasites. This may expose the retardation consequences of the parasite's migration process. It also explains the distinct separation between migration and productive invasion and how migration needs to be terminated before the parasite can begin to form a PV, thus being able to actively infect and invade its host. In the liver, highly sulfated HSPGs allow productive invasion to take place by releasing signals that interact with the plasmodium, and sporozoite proteins P36 and P36p/P52 help to form the PV.
Inside of the PV, sporozoites divide and form a new structure called merozoites, which are contained in the membrane of the PV. Although research in the interactions between the merozoites and the heptatocytes at this stage has been stinted, it has been noted that the parasite has found ways to abuse the advantages of residing in the liver, thus promoting development. The circumsporozoite protein establishes conditions inside of the heptatocytes that allow growth and division to occur, while other proteins such as UIS, UIS4, Pb26p, and gene 3 are involved in inducing development in the Plasmodium as well. It has been hypothesized that UIS3 undergoes some sort of mechanism with liver-fatty acid binding proteins in which these proteins supply fatty acids to the parasite. Experiments indicate that parasites who do not undergo this interaction fail to develop properly during the liver stages.
After the merozoites are packaged in merosomes, the Plasmodium enters into the egress phase with the assistance of cystein proteins. A test done on rodents infected with Plasmodium yoelii showed that when the merozoites are released from the heptatocytes, they are released whole, a characteristic that inhibits phagocytosis and ensures that the parasite will enter the lungs and eventually the capillaries. Invasion of red blood cells, the next stage in the parasite's journey, occurs through the receptor-ligand binding of merozoite surface proteins and a ligand, called band 3, located on the surface of the red blood cell. The main entry pathway for Plasmodium falciparum involves the binding of erythrocyte binding antigens and Plasmodium falciparum reticulocyte-binding homologs. However, according to research done in Kenya, there are numerous modes of entry for Plasmodium aside from the conventional interactions. The study found that those who were previously infected with malaria produced antibodies that disallowed numerous of these pathways to ensue; this resistance seemed to increase with an increase in age.
Once inside of the erythrocyte, the parasite thrives by feeding on the hemoglobin located inside of these cells. Because erythrocytes lack secretory pathways and endocytic pathways, the plasmodium spreads proteins throughout red blood cells by employing a specific targeting sequence called Plasmodium export element. Through this mechanism, parasitic proteins move to the surface of the red blood cells. Due to the absence of specific systems in erythrocytes parasites normally use to establish infection and promote development, red blood cells can be used as an archetype for studying the growth of parasites in cells with marginal resources. Studies done on all of the proteins found in the erythrocytes of non-infected humans and mice revealed that the complex aging process of red blood cells exploits numerous proteins, and that with further insight into these proteins, soon the scientific community may understand how red blood cell host factors assist in the development of Plasmodium.
An important study on the composition of the PV membrane may also assist in understanding the interactions between red blood cells and the parasite. Early transcribed membrane proteins are proteins found on the PV membrane; some are predominantly found during the liver stages while others are predominantly present during the ring stages. These proteins form clumps and confine to a particular area within the membrane, signifying polarity at the sites of interaction between the parasite and the host.
Contracting severe malaria can cause numerous symptoms, one of the most dangerous being cerebral malaria. Research done on rodents infected with Plasmodium berghei has revealed that the link between the development of cerebral malaria in malaria-infected patients involves histamine-mediated signaling, chemokine receptors located in the brain, dendritic cells, T cells and the host complememt cascades. The downregulation of HO-1, an enzyme that decomposes heme, also has a connection with a decrease in the development of cerebral malaria. Rodents that had less of HO-1 eventually developed cerebral malaria, while the rodents with an upregulation of HO-1 did suffer from the illness. When HO-1 was removed from the test mice, they also acquired cerebral malaria. Like HO-1, CO has been linked to decreasing the chances of cerebral malaria; mice that were exposed to CO did not develop the disease. Further studies showed that the HO-1 and CO prevented entry pass the blood-brain barrier and inhibited actions characteristic of cerebral malaria, such as neuroinflammation. When CO binds to hemoglobin, it stops the production and release of free heme in the body (which can lead to cerebral malaria). Therefore, the role of HO-1 and CO in eliminating heme is key to decreasing the onset of cerebral malaria in patients.
. Because malaria is such a devastating disease worldwide, the research described in "Interactions of the malaria parasite and its mammalian host" is not only relevant but exceedingly important. The more the scientific community learns about the phases of Plasmodium within the host and its interactions with our own molecules and cells, the more likely a vaccine can be developed and distributed. Multiple times in the article the author describes how research in a particular arena has been inconclusive, and how a feasible vaccine may not be able to be constructed due to a lack of knowledge of how the parasite actually behaves or interacts with us. This realization of the current limitations of understanding and inhibiting malaria makes the knowledge we do have a very important building block. The analysis of the PV, PV membrane, CO, and the HO-1 protein all may seem small, but to me they were very insightful and interesting. The current knowledge of the PV and PV membrane should be exploited; scientists should find a way to destroy these structures and/or inhibit their synthesis and view how their absence affects the parasite. Hopefully, a vaccine can be designed soon to curtail malaria and save potentially millions of lives.