Describe the life cycle of human malaria and how vector control may prevent transmission of the disease.

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Describe the life cycle of human malaria and how vector control may prevent transmission of the disease.

Malaria is a parasitic infectious disease which is commonly widespread in tropical and subtropical regions such as Sub-Saharan Africa, South-east Asia and South America. The protozoan parasites of the genus Plasmodium is responsible for this potentially life-threatening disease. There are five species of Plasmodium parasite that can infect humans, namely Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi. These parasites are transmitted by successively infecting human who is the intermediate host, and Female Anopheles mosquito which is the definitive host. This mosquito also serves as a biological vector of malaria parasite.

Exoerythrocytic Cycle

Plasmodiumlives in the gut and salivary glands of the femaleAnophelesmosquitoes. When an infected mosquito takes a blood meal, saliva that contains the parasites in its infectious sporozoite form is injected by proboscis into the human bloodstream.

The sporozoites circulate in the blood stream for 30-60 minutes and invade liver hepatocytes.

The sporozoites gain access to the hepatocytes by first invading and traversing a Kupffer cell (phagocytes that lines in liver capillaries). Sporozoites recognize proteoglycans expressed on the surface of Kupffer cells using their major surface proteins, the circumsporozoite protein (CSP) and the thrombospondin-related adhesive protein (TRAP). They then actively invade and safely traverse Kupffer cellsandinside a vacuole, which does not fuse with lysosomes, and exit the macrophages unharmed (Frevert, 2004).

After exiting the Kupffer cell, there is active invasion of a hepatocyte via an endothelial lining cell. The intrahepatocytic parasite undergo asexual reproduction that is referred as Exoerythrocytic Schizogony. They differentiate into schizonts or hypnozoites (latent forms of tissue stages), depending on whether the species of malaria parasite causes true relapses or not. The exoerythrocytic schizonts' growth is accompanied by nuclear division and an increase in cytoplasmic volume. No reaction is caused in the liver until the schizont bursts. At maturity a piece of cytoplasm joins with each nucleus to form daughter parasites—the merozoite—measuring about 1 um in diameter. The mature schizont and host cell then rupture, releasing thousands of uninucleate merozoites into the circulatory system.

It is estimated that eachPlasmodium falciparumsporozoite can have up to 40,000 merozoites. During this period of maturation, no illness is caused byPlasmodium(Khan and Lai, 1999).

In P. vivax and P. ovale some of the sporozoites do not immediately undergo asexual replication, but enter a dormant phase known as the hypnozoite. This hypnozoite can reactivate and undergo schizogony at a later time resulting in a relapse. Relapse refers to the reactivation of the infection via hypnozoites. Interestingly, strains isolated from temperate regions tend to exhibit a longer latent period between the primary infection and the first relapse than strains from tropical regions with continuous transmission. This suggests that the hypnozoite stage provides a means for the parasite to survive during periods in which mosquitoes are not available for transmission.

This exoerythrocytic or liver phase of the disease usually takes between 5 and 21 days, depending on the species ofplasmodium. However, inP vivaxandP ovaleinfections, maturation of liver-stage schizonts may be delayed for as long as 1 to 2 years. These quiescent liver-phase parasites are called hypnozoites.

Erythrocytic Cycle

Within 1-2 minutes, merozoitesreleased from the infected liver cells invade erythrocytes. The merozoites contain an apical complex including organelles which recognize specific surface receptor of the erythrocyte and actively invade the cell. The merozoite organelles induce invagination of the erythrocyte surface and the merozoite enters the erythrocyte via the invagination. The merozoite has an envelope consisting of an outer plasma membrane and two inner membranes and acquires a surface coat while in the plasma. On entering the erythrocyte it loses the two inner membranes and sheds the surface coat. After entry into the erythrocyte, the merozoite develops a vacuole and becomes a ring form. The parasite undergoes a trophic period followed by an asexual replication. The young trophozoite is often called aring formdue to its morphology in Geimsa-stained blood smears. As the parasite increases in size this 'ring' morphology disappears and it is called atrophozoite. During the trophic period the parasite ingests the host cell cytoplasm and breaks down the hemoglobin into consumable amino acids as nutrient source. A by-product of the hemoglobin digestion is the malarial pigment, or hemozoin. These yellow-brown to black pigment particles have been long recognized as a distinctive feature of blood-stage parasites.

The end of the trophic period is manifested by multiple rounds of nuclear division without cytokinesis producing an erythrocytic stage schizont. The mature schizont contains 8 to 36 merozoites, each 5 to 10 μm long. Erythrocytic schizogongy consists of 3-5 rounds (depending on species) of nuclear replication followed by a budding process. Late stage schizonts in which the individual merozoites become discernible are calledsegmenters. When the host erythrocyte and schizont rupture, the merozoites are released into the bloodstream. They invade new erythrocytes and initiate another round of schizogony. The blood-stage parasites within a host usually undergo a synchronous schizogony.

It is of note that blood stage parasites are responsible for the clinical symptoms of malaria (1). For example, lysis of the red blood cells is an important cause of malaria-associated anemia. In addition, if a significant number of infected cells rupture simultaneously, the resulting material in the bloodstream is thought to induce a malarial paroxysm (2). The simultaneous rupture of the infected erythrocytes and the concomitant release of antigens and waste products accounts for the intermittentfever paroxysmsassociated with malaria. However, P. falciparum often exhibits a continuous fever rather than the periodic paroxyms. P. falciparum also is responsible for more morbidity and mortality than the other species. This increase virulence is due in part to the higher levels of parasitemia associated with P. falciparum infections. Blood stage schizogony inP. falciparumdiffers from the other human malarial parasites in that trophozoite- and schizont-infected erythrocytes adhere to capillary endothelial cells and are not found in the peripheral circulation. This sequestration is associated withcerebral malaria.

After one or more cycles in the blood the sexual phase of the parasite begins. The nucleus becomes diploid in the macrogametocyte (female) and octoploid in the microgametocyte (male). The gametocytes are usually round (crescentic in one case), contain a single nucleus and scattered pigment; when mature they fill the host erythrocyte.

Sporogonic Cycle

As an alternative to asexual replicative cycle, the parasites can undergo a sexual cycle and terminally differentiate into eithermicrogametocyte or macrogametocyte. This is known as gametocytogenesis which occurs in the bloodstream of the human host. Commitment to the sexual stage occurs during the asexual erythrocytic cycle that immediately precedes gametocyte formations. The gametocytes are large parasites which fill up the erythrocyte. Daughter merozoites from this schizont will develop into either all asexual forms or all sexual forms. Gametocytes do not cause pathology in the human host and will disappear from the circulation if not taken up by a mosquito.

The sexual cycle is completed when a suitable species of mosquito bites the individuals in whose blood mature gametocytes are circulating. Gametogenesis, or the formation ofmicro-andmacrogametes, is induced when the gametocytes are ingested by a mosquito. After ingestion by the mosquito, macrogametocyte escapes from the erythrocyte and matures into a macrogamete in the lumen of the mid-gut of the mosquito; the nucleus undergoes reduction division. The microgametocyte undergoes a maturation process known asexflagellation. It undergoes internal organization, including spindle formation, and then emerges from the erythrocyte, and its nucleus undergoes a series of extraordinarily rapid divisions (Sinden, 1981) to form eight new nuclei. These eight nuclei then become associated with flagella that emerge from the body of the microgametocyte. This process takes about 10-20 minutes after blood is ingested by the mosquito. Critical factors involved in the induction of this gametogenesis are a decrease in temperature, a decrease in the dissolved carbon dioxide and the subsequent increase in pH to above 8.0. This somewhat mimics the environmental changes experienced by the gametocytes in that there will be a change to ambient temperature and the gut of the mosquito exhibits a pH of approximately 7.8 as compared to a pH of 7.4 for blood. In addition, a mosquito-derived exflagellation factor (MEF) has also been described and identified as xanthurenic acid, a metabolite from insects. Xanthurenic acid lowers the permissive pH for exflagellation to below 8.0 and is possibly a biological cue for the parasite to undergo gametogenesis(Billker et al, Nature 392:289,1998; Billker et al, Cell 117:503, 2004).

The highly mobile microgametes will seek out for a macrogamete, and the two nuclei fuse to give a diploid zygote. The zygote elongates over the next 12 hours and develops into anookinete within 12-24 hours. The ookinete is a motile invasive stage which will penetrate the gut epithelial cells and come to rest in the extracellular space between the gut epithelial cell layer and the basal lamina that covers the gut on the coelomic cavity side. The invasion process is similar to other apicomplexa except that the ookinete does not have rhoptries and does not form a parasitophorous vacuole after invading the host cell.

About two to three days after the infective blood meal, the ookinete have secreted a thin cyst wall developed into a haploid oocyst. The plasma membrane retracts from the capsule and invaginates into the oocyst cytoplasm (Thathy et al. 2002). Several cytoplasmic islands called the sporoblasts are formed in within oocyst. Sporoblast nuclei undergo numerous asexual multiplications (sporogony), producing thousands of sporozoites enclosed within the sporoblast membranes. As membranes rupture, sporozoites enter the cavity of the oocyst. After the mosquito ingests the gametocytes, upon maturation the oocyst ruptures and releases the sporozoites which cross the basal lamina into the hemocoel (body cavity) of the mosquito. This generally takes 10-28 days depending on the species of malaria parasite and temperature.

These sporozoites are motile and have an ability to specifically recognize the salivary glands. After finding the salivary glands the sporozoites will invade and transverse the salivary gland epithelial cells and come to lie within its lumen. These sporozoites will be expelled into the human host as the mosquito takes a blood meal, and thus reinitiate the infection in the host. Although the hemocoel and salivary gland sporozoites are morphologically similar, they are functionally distinct. Salivary gland sporozoites efficiently invade liver cells, but cannot re-invade the salivary glands, whereas the hemocoel sporozoites are inefficient at invading liver cells.

In order to fight malaria, vector control is a fundamental element of the existing global strategy to reduce malaria transmission. There are few vector control interventions that are proved to have successfully reduced the transmission of disease in malaria-prone countries. Two effective malaria vector control measures commonly used are Insecticide-treated nets(ITNs) and Indoor residual spraying (IRS).

Insecticide-treated nets(ITNs)

There are two types of mosquito nets: those that are not treated with insect killing chemicals, and those that are. ITNs are mosquito nets that are treated with insecticides. There are three primary functions of ITNs. First, they act as physical barriers providing protection to an individual by avoiding contact between the vector and the person. Second, ITNs kill the mosquitoes when they come in contact on the surface that is treated with insecticides. Third, they also act as chemical barrier due to the insecticide that may repel mosquitoes and prevent them from getting close to an individual under the net. These thereby reduce the human-vector contact and strengthen the protective effect of ITNs. The widespread usage of ITNs will reduce population of femaleAnophelesmosquito so even people who are not using ITNs will have less likelihood to get transmitted by malaria. This shows that ITN does not only provide personal protection to individuals, but it can also be a very useful vector control method for reducing malaria transmission for both individuals and communities.

Indoor residual spraying (IRS)

Indoor residual spraying is one of the main vector control measures for prevention of malaria transmission. IRS is an effective vector control because it is determined by theresting habitsof the malaria vectors. Female mosquitoes feed on host and lay their eggs around every three days. It takes about 10 days for parasite to fully develop inside a female mosquito, so they may have to feed three to four times before the parasite fully develops for transmission of disease.

Mosquitoes are at risk of coming into contact with the insecticide that will kill them when visiting a sprayed house to feed on people. They enter houses to take their blood meal mainly at night. After feeding, they fly short distance due to an increase of body weight which is more than twice of their unfed body weight. The female mosquitoes rest indoor are known as endophilic mosquitoes. They spend some time resting in undisturbed sites for two to three days until their eggs develop and are ready for laying. Mosquitoes are killed when come into contact with insecticide through their feet while resting on sprayed walls. Some insecticides also have repellent effect which irritate mosquitoes so they fly away without biting. However, IRS does not provide protection of free from mosquito bites.

Due to the resting and feeding habits of female mosquitoes, vector control programmes applied residual or long-lasting insecticides on the walls and ceilings of houses. In dry areas, mosquitoes prefer humid conditions so they will rest in rooms inside houses since it is more humid indoors. In tropical areas, exophilic mosquitoes may also rest outdoors on vegetation. However, even exophilic mosquitoes may fly into houses and rest indoors after blood meal. Mosquitoes will die within a few hours when they come into contact with the residualinsecticidesprayed on walls.

IRS reduces malaria transmission by, first, reducing the life span of femaleAnopheles mosquitoes, so that they cannot act as vector to transmit Plasmodium parasites from one person to another. Second, it reduces the density of the vector mosquitoes. Thirdly, IRS reduces human-vector contact as there is a decrease in number of mosquitoes entering the sprayed houses due to the repellant effect of some insecticides used in IRS.

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