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Interactions of the Malaria Parasite and its Mammalian Host (Synopsis). Malaria is the most common infectious disease in the world, which is responsible for killing more children than any other single pathogen. This illness begins when a mammalian host has been bitten by a mosquito carrying the Plasmodium parasites. These microorganisms might be immobilized in the skin, where they are attacked by the body's immune system or travel to the liver. In the liver, these parasites multiply, rupture the infected liver cells and are released into the blood channels of the liver, at which point the symptoms of malaria develop in the infected individual. These parasites then infect, differentiate, and grow in the red blood cells, where they eventually break out of these cells to infect new erythrocytes. In order to successfully prevent this deadly disease, scientists must carefully examine the different developmental stages of these Plasmodium parasites as well as deeply investigate the interactions between the mammalian host and these parasites. Examining the role of the host's skin immune response, the mechanisms of the skin stage, liver stage and blood stage of these Plasmodium parasites, and understanding the onset and progression of the severe cases of malaria are some of the questions that must carefully studied in order to produce an effective prevention.
The first stage of malaria begins when an Anopheles mosquito injects Plasmodium sporozoites into the skin of the mammalian host. Inside the skin's cells, these parasites move in a random fashion, where they disturb the plasma membrane of the skin cells. (SPECT)-1, SPECT-2 and a phospholipase are some of the proteins that are essential for the random movement of these parasites in the skin. Plasmodium parasites that lack these crucial proteins are not able to mobilize. The skin may use different immunological responses to fight these parasites. Some of these sporozoites remain in the skin where they are attacked by phagocytes while other sporozoites are eliminated by the lymphatic circulation.
The sporozoites that will cause the symptoms of malaria will enter the blood circulation and travel to the liver, where they will invade and multiply inside hepatocytes. Upon reaching the liver cells, the sporozoites are covered with heparan sulfate proteoglycans (HSPGs) by the circumsporozoite protein (CSP). This protein plays a major role in enhancing the development of these parasites as well as downregulating the genes that express inflammatory response. The sporozoites then cross the sinusoidal cell layer of the liver cells, where they invade and produce the parasitophorous vacuole (PV) without disturbing the plasma membranes of the host cells. A study conducted by Torgler et al. has shown that migration of Plasmodium sporozoites through liver cells can trigger immune responses against these parasites. Thus, the sporozoites must switch from cell traversal to productive invasion mode, which leads to the formation of the PV. P36 and P36p/P52 are the two sporozoite proteins that are believed to have a major role in the production of the PV, although the exact mechanism of the role of these proteins is still unknown.
The next step includes the development of the Plasmodium sporozoites inside the PV membrane (PVM). Recent studies have indentified some of the essential proteins that are crucial in development of the Plasmodium sporozoites. UIS (upregulated in infective sporozoites) gene 3, UIS4, and Pb36p are the identified genes that encode for these proteins that are necessary in the development of these parasites. These studies have also shown that the parasites lacking these genes are not able to encode these essential proteins which results in these parasites not being able to survive and develop in the liver cells. In addition, other studies have shown interactions between UIS3 and the liver-fatty acid binding protein (L-FABP) in vitro, where downregulating L-FABP has resulted in reduction of the growth of the Plasmodium parasites. These studies indicate that lipid delivery is a crucial part of the development of the Plasmodium parasites.
After the development of the Plasmodium sporozoites, the multiplication stage of sporozoites into thousands of merozoites follows. The merozoites are contained within vesicles called merosomes. Through a process known as egress, the merozoites are released from the liver cells, assisted by cystein proteases. A study conducted using Plasmodium yoelii-infected rodents has shown that the merosomes leave the liver cells intact, which protects them from attack by Kupffer cells that are found in the liver cells. The symptoms of malaria are initiated when these merozoites eventually reach the lung capillaries, where they enter the bloodstream.
Plasmodium parasites are capable of invading the red blood cells rapidly within few seconds. Merozoite surface proteins assist in attachment process of the parasites to the red blood cells. There are also transmembrane proteins that are involved in reorientation of the merozoites towards the erythrocyte surface as well as in penetration of these parasites into the red blood cells. The erythrocyte binding antigens (EBAs) bind to specific receptors on the surface of the merozoites, resulting in efficient pathway of invasion. A study that was conducted in Kenya showed that the wild-type Plasmodium parasites use alternative pathways of invasion, which indicates the challenges scientists face in finding effective vaccines against this disease. Due to the fact that red blood cells lack intracellular organelles, the Plasmodium parasites are not able to obtain nutritional source from their host. Thus, the parasites must expand their surface area through formation of a tubovesicular network (TVN) and restrict their diet to digestion of hemoglobin that is abundantly found in red blood cells, which results in the formation of the malaria pigment called hemozoin. A study conducted by Spielmann et al. investigated the early transcribed membrane proteins (ETRAMPs) which reside inside the parasitophorous vacuole membrane (PVM). This study revealed that these proteins are expressed in the developmental ring stage of the Plasmodium parasites inside the red blood cells, while there are also other proteins expressed in the liver stage of the Plasmodium life cycle. In a growing phase known as the trophozoite, the merozoites asexually reproduce, multiply and expand inside the PVM. This is followed by the merozoites secreting exonemes that results in the egress of merozoites from the red blood cells. The free merozoites continue to attach to new red blood cells, in order to initiate a new erythrocytic cycle.
Symptoms of malaria range widely from benign to severe, although severe cases of this disease causes 1-3 million of deaths each year. Cerebral malaria (CM) has been studied in laboratories using mice that have been infected with Plasmodium berghei ANKA in order to understand the mechanism that causes the onset of this severe malaria. Although the onset and progression of cerebral malaria is not related to the CD36 receptor, these studies have revealed that the CD36 is the main receptor that plays a major role in the infection of the red blood cells by these parasites. Recent studies have indicated that other factors such as chemokine receptors in the brain and histamine-mediate signaling contribute to the development of cerebral malaria in Plasmodium berghei ANKA-infected mice. Other studies have shown that the upregulation of the host's enzyme known as the heme oxgenase-1 (HO-1) and the exposure to carbon monoxide (CO) suppresses the pathogenesis of cerebral malaria in these experimentally infected mice. It is believed that these results occur due to the fact that CO binds to hemoglobin, which prevents hemoglobin oxidation and the generation of free heme, a molecule which triggers the pathogenesis of cerebral malaria.
In conclusion, it is extremely important to carefully investigate and examine the different developmental stages of the Plasmodium parasites as well as to deeply understand the interactions between the mammalian host and these parasites in order to produce effective prevention methods against malaria. The studies discussed above examined the different mechanisms involved at different stages of the life cycle of the Plasmodium parasites. The skin stage, the liver stage and the blood stage of Plasmodium parasites as examined on these studies revealed the interaction between the mammalian host and these pathogens is crucial for the onset and progression of malaria. These studies further showed the various molecules, such as the receptors, surface proteins, transmembrane proteins, and enzymes that are involved for this interaction and in the life cycle of the Plasmodium parasites. I believe more research should be conducted in the different stages of the life cycle of these parasites in order to understand the exact mechanisms involved in the pathogenesis of malaria. I, specifically, believe the liver stage of Plasmodium parasites should be carefully investigated since the release of these parasites at this phase begins the symptoms of malaria. In my opinion, the molecules of the parasites that are involved in infecting the liver cells and red blood cells, such as the surface proteins, transmembrane proteins and enzymes should carefully be examined. I believe these studies could lead into effective methods that could block, destroy, or eliminate these molecules and ultimately prevent this deadly disease of malaria.