**2. Plasmodium species causing human malaria**

#### **2.1 Diversity of human malaria parasites**

Malaria is caused by protozoan parasites that belongs to the genus Plasmodium. There are over 200 plasmodium species that have been proven to cause malaria. But human malaria is caused by only by five Plasmodium species, namely: - *Plasmodium falciparum (P. falciparum); Plasmodium vivax* (*P. vivax); Plasmodium malariae* (*P. malariae)*, *Plasmodium ovale* (*P. ovale)* and *Plasmodium knowlesi* (*P. knowlesi*) [6]. While the first four plasmodium species (*P. falciparum, P. vivax, P. malariae* and *P. ovale)* naturally cause malaria only in humans, *P. knowlesi* causes zoonotic malaria in South East Asia, that is naturally maintained in macaque monkeys. The malaria parasites differ in their epidemiology, virulance and drug resistance pattern. Of the five human malaria parasites, *P. vivax and P. falciparum* pose the greatest threat. *P. falciparum* is the most dangerous malaria parasite that is responsible for high morbidity and mortality [7, 8]. *P. falciparum* is the most prevalent human malaria parasite in Africa, that accounted for 99.7% of the estimated malaria cases in 2018 [9].

*Plasmodium* parasites belong to the order *Haemosporidia* [10]. The different Plasmodium species have different host range. For example, the host range of *P. relictum* is so broad, that can infect more than 100 different species of birds, that belong to different orders and families [11]. Whereas, the host range of *P. falciparum* is so narrow that only infects humans [12]. In contrast to mammalian malaria parasites, that are only transmitted by are mosquitoes of the genus *Anopheles*, *Plasmodium* species that infect birds are transmitted by a wide variety of mosquitoes including *Culex* and *Aedes* [13].

#### **2.2 The life cycle of malaria parasites**

The life cycle of human malaria parasites is generally the same [14]. The plasmodium life cycle involves two hosts (has two parts). In the first part, the parasite infects a vertebrate host such as human being and in the second part, the plasmodium parasite infects the mosquito vector.

The Plasmodium life cycle starts when sporozoites enter the blood of the vertebrate host following a bite by the mosquito vector [15]. Then, the sporozoites rapidly move to the liver and invade hepatocytes where they multiply asexually by a process called schizogony (exo-erythrocytic schizogony) and produce merozoites [16, 17]. The merozoites are released back into the blood and infect erythrocytes [18]. In only *P. ovale and P. vivax* infection, some of the merozoites in the liver may differentiate into a dormant stage (hypnozoite), which may recure again (cause relapse by invading blood stream) after some time in the future unless treated with primaquine. In the infected erythrocyte, each merozoite multiplies by schizogony (erythrocytic schizogony) to produce between 8 and 64 new merozoites, depending on the species of the plasmodium parasite [19]. The newly produced merozoites are

#### *Plasmodium Species and Drug Resistance DOI: http://dx.doi.org/10.5772/intechopen.98344*

released back to the blood, and continues its intraerythrocytic propagation cycle every 72 (*P. malariae*) hours; every 24 hours (*P. knowlesi*), and every 48 hours (*P. falciparum, P. ovale, P. vivax*). Some of the merozoites differentiate into male and female gametocytes for sexual reproduction [20, 21].

The second part of the plasmodium life cycle starts when the insect vector bites infected vertebrate host (such as infected person) and the insect ingests the blood containing gametocytes. The gametocyte completes its development in the lumen of the mosquito midgut and the male and the female gametes fuse to produce a zygote [22], which is the only stage with diploid chromosome (genome) [23].

Following fertilization, the zygote undergoes meiosis and differentiates into ookinete (motile form) that has a haploid genome [24]. Then ookinete penetrates the wall of the midgut of the mosquito and forms an oocyst [25]. In the oocyst, mitosis take place repeatedly, and numerous sporozoites are produced by sporogony [26, 27]. When the oocyst matures, it ruptures and releases sporozoites into the haemolymph. Then, the sporozoites migrate to the salivary glands, where they mature and acquire the capacity to infect vertebrate host cells [28]. This cycle (second part of the plasmodium parasite life cycle (from gametocytes to sporozoites) takes about 10–18 days.

#### **2.3** *Plasmodium falciparum*

*P. falciparum is* the deadliest Plasmodium species that causes human malaria [29]. According to the World Health Organization (WHO), *P. falciparum* accounted for nearly all malarial deaths (99.7%) in 2018, which caused an estimated 405,000 deaths [9]. With the exception of Europe, *P. falciparum* is found in all continents of the world. Before 1970s, *P. falciparum* malaria was common in Europe. But interventions which includes appropriate case management, insecticide spraying, and environmental engineering since the early 20th century resulted in complete eradication in the 1970s [30]. Unlike other malaria endemic countries in which non-falciparum malaria predominates, over 75% of malaria cases were due to *P. falciparum* in Sub-Saharan Africa [31], where 94% of malaria deaths occur [9].

The average incubation period of *P. falciparum* malaria is 11 days (ranging from 9 to 30 days) [32], which is the shortest among Plasmodium species. The sign and symptoms of uncomplicated malaria include fever, headache, nausea, vomiting, and diarrhea. If left untreated, *P. falciparum* malaria usually develops to sever malaria, which may bring about death. Children with severe malaria frequently develop severe anemia and or respiratory distress [33]. Multi-organ failure is common in adults with sever malaria. Acute respiratory distress occurs in 5–25% of adults and up to 29% of pregnant women [34].

The WHO recommends Artemisinin-based combination therapies (ACTs) as first-line treatment for uncomplicated *P. falciparum* malaria. The ACTs that are recommended by the WHO for the treatment of uncomplicated *P. falciparum* malaria include Artemether/lumefantrine, dihydroartemisinin/piperaquine, artesunate/amodiaquine, artesunate/mefloquine, and artesunate/sulfadoxinepyrimethamine [35]. The choice of ACT that be used in different parts of the world is different, that depends on the level of resistance to the constituents in the ACT. In a condition when first line therapy fails, the following alternative antimalarial drugs can be used as second-line treatment: - artesunate plus tetracycline or doxycycline or clindamycin, and quinine plus tetracycline or doxycycline or clindamycin which is given for seven days.

The recommended first-line treatment of uncomplicated *P. falciparum* malaria in pregnant women during the first trimester is quinine plus clindamycin for seven days [35]. The second line therapy for the treatment of uncomplicated *P. falciparum* malaria in pregnant women is artesunate plus clindamycin for 7 days. Atovaquone/ proguanil, or artemether/lumefantrine or quinine plus doxycycline or clindamycin are recommended for treatment of malaria in travelers returning to non-malaria endemic countries [35]. The recommended treatment for sever *P. falciparum* malaria in adults is intravenous (IV) or intramuscular (IM) artesunate. Quinine is also recommended as an alternative treatment of sever *P. falciparum* malaria if parenteral artesunate is not available [35]. Whereas, artesunate (IV or IM), quinine (IV or IM), and artemether IM are recommended for treatment of sever *P. falciparum* malaria in children, especially in malaria-endemic areas of Africa [35].

#### **2.4** *Plasmodium vivax*

*P. vivax* is the second important malaria parasite after *P. falciparum*, that causes significant morbidity*.* The parasite can cause severe disease and even death that is usually associated with splenomegaly [36, 37]. One of the important features that distinguishes *P. vivax* from *P*. *falicparum* is the occurrence of dormant stage in the liver (hypnozoites) that can be reactivated later in life.

The burden of *P. vivax* malaria differ from one region of the world to the other, which is mainly seen in central Asia (82%), the Americas (6%), Southeast Asia (9%), some parts of Africa (3%) [38, 39]. *P. vivax* has wider distribution than *P. falciparum*, which is associated with the dormant stage of *P. vivax* and the ability of *P. vivax* to survive and reproduce in the mosquito vector at lower temperatures and higher altitudes. In Africa, *P. vivax* is limited to parts of horn of Africa and Madagascar, unlike the other parts of Africa that is not affected by *P. vivax* infection due to the deficiency of Duffy antigen (which serves as receptor for the parasite) in the population [40]. It has been suggested that *P. vivax* originated in Africa*.* This is based on the fact that gorillas and wild chimpanzees in central Africa are naturally infected with plasmodium parasite that are closely related to the *P. vivax* that causes human malaria [41].

Usually, *P. vivax* causes mild disease, that causes fever, cough, abdominal pain and diarrhea. However, the parasite may cause serious conditions like respiratory distress. In pregnant women, *P. vivax* infection brings about low birth weight. In rare cases, complications might arise from *P. vivax* infection, which includes acute kidney failure, neurological abnormalities, hypoglycemia and low blood pressures, jaundice and coagulation defects [42]. Chloroquine is the drug of choice for the treatment of malaria that is caused by *P. vivax* [43]. However, in areas where the parasite has developed resistance for Chloroquine, such as Papua New Guinea, Korea, and India where chloroquine resistance has grown up to 20% resistance [44], chloroquine has been replaced by other drugs.

#### **2.5 Plasmodium** *ovale*

*P. ovale* is one of the five human malaria parasites. Unlike *P. falciparum* and *P. vivax, P. ovale* accounts very small proportion (5%) of the disease [45]. The species *P. ovale* is consisted of two subspecies, *P. ovale curtisi* and *P. ovale wallikeri* [46]. *P. ovale* is mainly found in Islands in western pacific and Sub-Saharan Africa [45, 47]*.* But the parasite also exists in Thailand [48], Vietnam [49] Guinea [50], Bangladesh [51], Cambodia [52] India, [53] and Myanmar [54]. The incubation period of *P. ovale* ranges from 12 to 20 days. The parasite causes very mild disease and it is less dangerous than *P. falciparum.* Like *P. vivax, P. ovale* has a dormant stage in the liver (hypnozoites) that can be reactivated later in life [45]. Chloroquine is the drug of choice for the treatment of malaria that is caused by *P. ovale* [55].
