Synopsis: Interactions of the malaria parasite and its mammalian host. Malaria, a vector-borne infectious disease is caused when an Anopheles mosquito taking a blood meal injects Plasmodium sporozoites into the skin. It is extremely lethal and deadly killing millions of people across the globe, especially young children. After the intradermal sporozoites injection, the expansion of the parasite occurs in the liver with increasing parasitic population (termed as merozoites). The next stage is the erythrocyte invasion when infectious merozoite destroys and re-infects red blood cells. The disease is exclusively caused by the rapid asexual multiplication phase inside the red blood cells. More importantly, erythrocyte invasion occurs in seconds which follows several steps, each involving multiple receptor-ligand interactions. The article highlights some of the most recent insights into the parasite-host interactions with particular emphasis on their genetic basis.
Recent studies have established that after the mammalian host has been infected with Plasmodium sporozoites, the sporozoites remains in the skin for extended period of time until they encounter blood vessel to enter the circulatory system. Not all injected sporozoites make it to the blood circulation because some are eliminated by phagocytes while others entering the lymphatic circulation are degraded in the lymph nodes. During the transversal stage, three important proteins SPECT-1, SPECT-2 and phospholipase are crucial. Sporozoites lacking SPECT-1 and SPECT-2 are disabled to move through the skin and are degraded eventually. Amino et al. have suggested that some SPECT mutants even though do not transmigrate are capable of infecting cells more rapidly than normal sporozoite by forming parasitophorous vacuole (PV) in the host cells. This discovery suggests that migration may hinder infection and thus it needs to be switched off to allow entry by PV formation. A study suggests that two sporozoite proteins containing 6-cystein domains, P36 and P36p/P52, have been recognized to play a vital role in the formation of PV. Hence, such sporozoite proteins including many other uncharacterized sporozoite molecules can be a potential target for malaria vaccine.
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Following skin stages, the Plasmodium sporozoites enter the liver stages (LS) in which they multiply into thousands. A study demonstrates that parasiteââ‚¬â„¢s circum-sporozoite protein (CSP) plays a vital role in creating favorable conditions for the parasite to ensure survival in the hepatic cells. Also, two receptors parasitic protein receptor UIS3 and the liver ââ‚¬"fatty acid binding protein (L-FABP) seems to interact and the authors reveal that down regulation of L-FABP leads to a reduction of parasite development. It was suggested that lipid delivery is important for LS development and that the down regulation of lipoprotein receptor scavenger receptor type B class 1 (SR-B1) was shown to inhibit parasite growth in vitro. At the end of the liver stage, cystein proteases are thought to mediate the release of merozoites from the hepatocysts via the process of egress. A class of cystein proteases known as serine repeat antigens (SERAs) is upregulated during the release of merozoites from merosomes. Studying the process of egress of Plasmodium yoelii suggests that most merosomes exit the liver intact and that the membrane serves as a protective coat against Kupffer cells, the liver macrophages. After exiting the liver, merozoites are released in the lung capillaries where they reach bloodstream and trigger blood-stage infection. A recent study reveals that during maturation of liver and blood stage, the parasitic merozoite utilizes stage-specific parasite factors for invasion.
Merozoite entry into the erythrocytes is very lethal occurring in seconds and involving multiple receptor-ligand interactions. Due to the invasion and lysis of red blood cells (RBC), the blood-infection stage is a detectable stage with chills and fever. Initial attachment of merozoites occurs at any orientation mediated by merozoite surface proteins (MSPs). Also, transmembrane protein apical membrane antigen 1 (AMA-1) is involved in reorientation of the apical end of merozoites towards erythrocyte surface. After attachment, the merozoite penetration is influenced by two transmembrane proteins, erythrocyte binding antigens (EBAs) and Plasmodium falciparum reticulocyte-binding homologs (PfRh), forming PV in the host cells. The parasitic pathogen earns a major advantage as erythrocytes lack major histocompatibility complex (MHC) to display antigens on their surface. Hence, the pathogen can smoothly bypass the immune system even after invading RBCs. Following hemoglobin digestion to gain nutrients, the merozoites forms a ring stage by forming tubovesicular network (TVN). The incoming proteins for growth are regulated by Plasmodium export element (PEXEL) or host targeting (HT) signal. DNA replication precedes cell budding, a process called schizogony and the merozoites secrete exonemes to exit the host erythrocyte to invade the next. Research done in Kenya with the wild-type parasites indicates that they use alternative pathways to infect erythrocytes. This finding highlights the challenges that the vaccine should target all these alternating routes used by the pathogen.
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The experimental infection of mice with Plasmodium berghei ANKA has tried to provide the answers to the challenges mentioned above. The experiment has defined genetic components which regulate the development of cerebral malaria (CM). It is dictated that heme oxygenase-1 (HO-1), which degrades heme to CO and other by-products, decrease CM incidence in the infected mice with P.berghei. Increase in NO, which induces HO-1, was also shown to reduce CM incidence. Also, inhalation of CO gave protection to the mice against CM. CO binds to hemoglobin, preventing it from creating free heme which resulted in the development of CM in mice. It was also shown that NO follows the same mechanism as CO. Furthermore, the experiments showed that the down regulation of HO-1 and the deletion of Hmox1 lead to a complete nullification of the infection from the liver.
The article threw light on various biochemical pathways of the malarial pathogen and the parasite-host interactions. The important finding of the biological role of HO-1 during initial liver stage and blood-infection stage is fascinating. Such studies can open new doors to do advance research on more molecules like HO-1 which can be a potential target for vaccine productions and for understanding the biochemical pathway of the Plasmodium parasite. However, the importance of HO-1 molecule was concluded in mice and not in humans. Hence, the questions arise: how relevant is the HO-1 molecule for humans? Does it influence the liver-stage and the blood-infection stage in humans? Are there any other host factors that are crucial in ensuring the success of the Plasmodium-host interactions? Such prominent questions still remains unanswered and future research is crucial to understand the importance of the HO-1 and other host molecules.
The article is also ineffective in providing in-depth information of various pathways used by the parasite during the blood-infection stage. Moreover, even if we create a vaccine that hunts down a specific pathway or route of the parasite, it does not guarantee the halt of the infection. It presumably correlates to viruses. Viruses constantly mutate and thus creating vaccine for one does not necessarily guarantee the eradication as the same strain might have mutated creating a whole new pathway for infection. Thus, if we do not fully understand the many pathways that are used by Plasmodium, how can we create effective vaccine that can guarantee the eradication of the malarial disease? No wonder there are 1-3 million deaths per year due to malaria and the only plausible way to halt it is by understanding the multiple infective pathways of the parasite and create a vaccine that targets them all.