**2. The parasite life cycle**

All types of malaria parasite have a similar and complex life cycle (**Figure 1**). The main part of the complexity related with the life cycle of *Plasmodium* is due to the parasite's capability to (a) modifiy its cellular and molecular make up, which is under control by a genome with more than 5,000 genes, and (b) developed in intra-cellular and extra-cellular niches in both mosquito and mammalian host [42]. The life cycle of every *Plasmodium* species infecting humans is distinguished by an exogenous sexual phase (sporogony), in which replication takes place in many *Anopheles* mosquito species, and an endogenous asexual phase (schizogony), which occurs in the vertebrate hosts. The sexual cycle is taken place in the gut and abdominal wall of some species of female mosquito, whereas the asexual cycle that causes the disease symptoms is taken place in the liver and RBCs of the humans [16]. The life cycle within the mosquito takes approximately 8 to 35 days, after which the parasite becomes infective. When the mosquito bites the skin, the sporozoite (motile infectious form of the parasite) will be injected in to human's dermis and then searchs a blood vessel to feed from it. The insect discharges different vasodilators to raise the possibility of finding a vessel. It also salivates into our blood to avoid blood clotting. The destiny of these sporozoites is not clearly illustrated; however they can take one to two hour to exit from the dermis. The trap-like protein of the sporozoites plays a role to exit the dermis (using gliding motility) and enters to the blood-stream. Those sporozoites remained in the skin could be killed and drained by the lymphatics, where a host immune response is activated. After 30 to 60 minutes of the injection, the thread-like shaped sporozoites will be transported to the liver through the vascular system. One single sporozoite in one hepatocyte multiplies into tens of thousands of exoerythrocytic merozoites [6, 43].

#### **Figure 1.**

*Life cycle of malaria parasites [40]. The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites . After this initial replication in the liver (exo-erythrocytic schizogony ), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony ). Merozoites infect red blood cells . The ring stage trophozoites mature into schizonts, which rupture releasing merozoites. Some parasites differentiate into sexual erythrocytic stages (gametocytes) . The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal . The parasites' multiplication in the mosquito is known as the sporogonic cycle . While in the mosquito's stomach, the microgametes penetrate the macrogametes generating zygotes . The zygotes in turn become motile and elongated (ookinetes) which invade the midgut wall of the mosquito where they develop into oocysts . The oocysts grow, rupture, and release sporozoites , which make their way to the mosquito's salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle [41].*

Within 7 to 12 days, the sporozoites develop into schizonts and then grow up to thirty thousand merozoites, which burst the liver cells [44]. Alternatively, some of the sporozoite of *vivax* and *ovale* species turn into hypnozoites (dormant form) in the liver for months/years and can cause relapsed malaria [4, 45]. Unusually, the reappearance of *falciparum* malaria was observed in patient's years after departure of an endemic area. This indicates that *falciparum* has a dormant stage although occurs occassionally [46–49]. Then, the asexual erythrocytic cycle begins and the merozoites start invading red blood cell to consume hemoglobin for their growth. The parasites then multiply 10 times every 2 days, destroying RBCs and infecting new cells throughout the body. Inside the host red blood cell, the *Plasmodium* continues its maturity from the early ring stage to late trophozoite. Then, following mitotic divisions, the trophozoite undergoes to the schizont stage, which consists 6–32 merozoites depending on the *Plasmodium* species [50, 51].

The period from acquiring infection through mosquito bite and the first appearance of the trophozoites in RBCs is called "prepatent period". This constant time is the characteristic of every species. It lasts 9 days in falciparum, 11 up to 13 days in vivax, 10 up to 14 days in ovale, 15 days in malariae and 9 up to 12 days in knowlesi*.*

#### *Malaria: Introductory Concepts, Resistance Issues and Current Medicines DOI: http://dx.doi.org/10.5772/intechopen.98725*

When the blood schizont bursts, the discharged merozoites maintain the life cycle through invading the neighbor red blood cells until it is brought under control. The rupture of schizonts is accompanied by the manifestation of the malaria febrile paroxysm typically lasting 8–12 h ("Golgi cycle") and characterized by 3 stages. The first stage (cold stage) is manifested by the quick rise of the temperature together with chills (sensation of the extreme cold). The patient desires to cover with the blankets. The second stage (hot stage) is with the temperature peak (may rises to 41°C), skin vasodilatation, myalgia and very severe headache. Patients feel too burning hot and cast their clothes. During the third stage (sweating stage), the patients have profuse sweating and their fever become drops. Then after, the patients may go to sleep due to tiredness. The typical (classical) symptoms which are stated above may not be appeared in some patients [40, 52]. Cyclical fevers are classically occurs soon before or during lysis of RBC (schizonts rupture). This happens every 48 h in tertian malaria (*vivax*, *ovale* and *falciparum*), and every 72 h in *malariae* infection (quartan *malaria*). At the time of this repetitive cycle, some merozoites differentiate into male and female sexual stages, which are called erythrocytic gametocytes (the only stages transmitted to the mosquito vector) with one nucleus and then cleared by drugs or the immune system, or awaiting the arrival of a blood-seeking *Anopheles* mosquito [6, 50].

The time required for the maturation of gametocytes (do not cause disease) are prominently different among different *Plasmodium* species. *P. falciparum* gametocytes require 8 up to 10 days for development into 5 morphologically different phases or stages (I–V) but *vivax* gametocytes take 48 h for maturity and disappear from blood within three days of sexual phase. In *falciparum*, the first identifiable stages of gametocytes are round compact forms having hemozoin. This stage (stage I) and the subsequent growth steps (stage 2–4) are principally absent from the vascular system, but sequestered in deep tissue in which they grow into mature sausage-shaped stage 5 gametocytes and reappeared in the blood and infective for mosquitoes. In diffrent to *falciparum*, matured *vivax* gametocytes are large and round, filling up almost the whole stippled red blood cell with a prominent nucleus. Because of their rapid maturation than *falciparum*, *vivax* gametocytes become exist in vascular system within a week subsequent to inoculation by mosquito and prior to parasite detection by light microscopy. This creates a major challenge in strategies of *vivax* elimination, as infected persons may be infectious prior to parasite detection using microscopy [53].

When a mosquito takes up erythrocytic gametocytes at the time of blood meal, the gametocytes migrate to the mosquito gut. At the midgut of mosquito, matured gametocytes egress from the host cell and differentiate into male and female gametes. The triggering factors for this differentiation are a fall in temperature, raise in pH and increase in xanthurenic acid concentration. Afterward, undergo fertilization (gametogenesis) - the flagellated forms of microgametes/male gametocytes formed by exflagellation penetrate/fertilize the macrogametes/female gametocytes to form a diploid zygote. The zygote develops into motile ookinetes, which penetrate the mosquito midgut and develop into round oocysts. The oocyst development is the longest developmental phase (takes three up to thirty days) and the only extracellular portion of the *Plasmodium* life cycle. The *falciparum* oocysts mature over a period of 11 to 16 days before releasing the infectious sporozoites (**Figure 1**). The sporozoites vigorously get away from the oocyst and only twenty five percent of those released from oocyst travel via the hemocoelomic fluid to the acinal cells of salivary glands, where following residence for a day, they turn into highly infective stage. They are permanently programmed for their trip in the vertebrate host because they totally lost their capability to invade salivary glands again. The chance of a mosquito for acquiring an infection at the time of blood meal is depend on

various human, *Plasmodium* and mosquito factors. The maturity of gametocytes in human host is fundamental to the continuation of malaria transmission and represents a potential bottleneck in the life cycle of malaria parasites. Knowing the biology of gametocyte maturity and the human infectious reservoir at both the individual and population level is therefore essential to ablate disease transmission nonetheless, it is remained ambiguous [52, 53].
