Pondering Plasmodium: Revealing the Parasites Driving Human Malaria and Their Core Biology in Context of Antimalarial Medications

Abstract

Malaria is one of the most severe infectious diseases, imposing significant clinical and financial burdens, particularly in underdeveloped regions, and hindering socioeconomic development. The disease is caused by unicellular protozoan parasites of the genus Plasmodium, which infect not only humans but also various animals, including birds, mammals, and reptiles. Among over 200 recognized Plasmodium species, five—P. falciparum, P. vivax, P. malariae, P. ovale, and P. knowlesi—pose serious risks to human health. The first four are specific to humans, while P. knowlesi, primarily found in macaque monkeys, is responsible for zoonotic malaria in Southeast Asia. Malaria transmission relies on an intermediate insect vector, typically Anopheles mosquitoes, which act as both carriers and final hosts, facilitating the sexual reproduction of the parasite. This dependence on anopheline mosquitoes underscores the complex ecological dynamics influencing malaria epidemiology. Plasmodium species exhibit significant genetic plasticity, enabling rapid adaptation to external pressures such as changes in host specificity and the evolution of treatment resistance. This chapter explores the biology of human-infecting Plasmodium species and the significant threats they pose to humanity, highlighting their complex interactions with hosts and vectors.

1. Introduction

The history of malaria extends from its prehistoric origin as a The history of malaria spans from its origins in primates in Africa to its impact on humans from the 1800s through the twenty-first century; malaria has remained a serious health threat, permanently altering the lives of people living in endemic areas [1]. This persistent scourge is caused by parasitic protozoa of the species Plasmodium. Malaria has exerted constant pressure on human populations in impacted areas, shaping their evolutionary trajectory, and allowing for the formation and selection of unique genetic adaptations. Notably, there is some protection against malaria from genetic illnesses, such as sickle-cell disease and thalassemia, which are common in areas where malaria is endemic. Similar to this, communities in Central and West Africa have a high incidence of Duffy-negative blood type [2], which confers a particular resistance against infection by the Plasmodium parasite P. vivax [3, 4]. According to estimates, this genetic feature first appeared about 42,000 years ago [5]. The prevalence of Plasmodium falciparum malaria has decreased over time, while Plasmodium vivax malaria has increased in certain regions, particularly in sub-Saharan Africa [6]. The complex interactions between malaria’s unrelenting drive and human genetics are highlighted by such evolutionary dynamics. Even with the availability of efficient antimalarials and measures, such as insecticide-treated bed nets (ITNs), malaria still plagues many parts of the world, especially developing nations where P. falciparum is the greatest concern. Financial limitations have impeded the ongoing fight against malaria, making it more difficult to execute comprehensive control programs. Acknowledging the gravity of the issue, the United Nations made the eradication of malaria a central goal in the 2000 Millennium Development Goals. Global investments in the fight against malaria increased over time, and by 2009, they had surpassed $2 billion. This increased financing has resulted in notable improvement, as evidenced by the notable declines in malaria-related mortality that have been observed globally, mainly in Africa [7, 8]. With numerous countries reaching the milestone of successive years with zero indigenous cases and receiving certification from the WHO as malaria-free zones, the number of countries reporting fewer than 1000 indigenous malaria cases has significantly increased as a result of the coordinated efforts [8, 9, 10]. The Plasmodium species that cause human malaria have similar life cycles, are susceptible to some antimalarial medications, and depend on particular insect vectors for transmission. Primarily, P. vivax malaria has distinct difficulties since there are episodes of relapse following the therapy; nevertheless, this can be successfully addressed by using medications, such as primaquine [11, 12, 13]. Even though zoonotic malaria cases are uncommon, the fact that P. knowlesi has become a major human infection highlights the possible danger that comes from Plasmodium species that inherently infect nonhuman primates [14, 15, 16]. Concerns have been expressed about P. knowlesi instances found in humans in Malaysia, especially in areas where malaria from other human-infective species has all but disappeared [17, 18, 19]. Similar to this, it has been determined that certain Plasmodium species, including P. cynomolgi and P. inui, that are carried by nonhuman primates may be susceptible to zoonotic transmission [20, 21, 22]. This emphasizes the importance of ongoing surveillance and investigation into newly developing infectious illnesses. The complexity of malaria epidemiology and the need for an all-encompassing approach to disease surveillance [23, 24, 25] and control is further highlighted by zoonotic malaria cases that have been documented in South America and are caused by organisms that are closely related to P. vivax and P. malariae [26, 27, 28, 29, 30].

2. Malaria and Plasmodium biology

2.1 Life cycle of Plasmodium

Every Plasmodium species has a similar life cycle that consists of two key stages: the transfer of the parasite from a vertebrate host to an insect vector [31]. Anopheles mosquitoes are the primary vector of transmission for humans among the five species that infect them. On the other hand, species of Plasmodium that infect birds and reptiles spread their infection through different genera of mosquitoes or other insects that feed on blood [32, 33, 34]. The life cycle begins when sporozoites—produced by the insect vector—enter the vertebrate host’s circulation after a mosquito bite, as shown in Figure 1 [35, 36]. The life cycle of Plasmodium falciparum begins when sporozoites from the salivary gland of a mosquito enter the human host’s circulation after a mosquito bite. The sporozoites mature in the liver and then infect hepatocytes, where they undergo asexual multiplication in a process called exo-erythrocytic schizogony [37, 38, 39]. This stage is crucial in the parasite’s life cycle, as it allows for the continuous infection and replication of the parasite within the host. The resulting merozoites are liberated and proceed to invade red blood cells, initiating a pivotal stage in the parasite’s life cycle known as erythrocytic schizogony. During the intraerythrocytic phase, spanning from 24 to 72 hours, contingent upon the specific species, merozoites proliferate within red blood cells, perpetuating the cycle of infection by invading fresh erythrocytes [40, 41]. The onset of sexual reproduction occurs as particular merozoites differentiate into gametocytes, initiating the next phase of the parasite’s life cycle [42, 43].

Figure 1.

Life cycle of Plasmodium.

Different species differentiate their gametocytes differently. For example, P. falciparum needs multiple intraerythrocytic cycles to begin gametocytogenesis, but P. vivax makes gametocytes continually [44, 45]. Gametocytes in the midgut of mosquitoes undergo differentiation into macrogametes and microgametes after ingesting contaminated blood [46, 47]. After these gametes fuse, a zygote is created, which goes through meiosis to become an ookinete, a motile form. After penetrating the mosquito’s midgut wall, the ookinete emerges as an oocyst on the exterior [48, 49, 50]. Sporogony takes place inside the oocyst, producing a large number of sporozoites. As the oocyst rips open during maturity, sporozoites are released into the hemolymph of the mosquito and go to the salivary glands [51, 52, 53]. The transmission cycle is completed when infected mosquitoes inject sporozoites into vertebrate hosts during successive blood meals [54, 55]. Apart from the nucleus, two unique organelles found in Plasmodium cells are the mitochondrion and the apicoplast, each of which has its own genetic material [56, 57, 58]. Research shows that mitochondrial DNA from the female gamete is inherited uniparentally, emphasizing the role of the macrogamete in the transmission of organelles [59, 60]. These discoveries broaden our knowledge of Plasmodium biology by illuminating important facets of the parasite’s life cycle and inheritance mechanisms [61, 62].

2.2 Recurrence of malaria and the hypnozoite

Vivax malaria is a chronic hazard because it can return, frequently presenting as recrudescence or relapse, even after parasites appear to have been removed from the patient’s system [63]. A little pool of parasites that avoid detection and carry on multiplying in the host’s bloodstream is the source of recrudescence [64, 65]. On the other hand, relapse is brought on by dormant hypnozoites, which are cryptic cells found in the liver. Interestingly, hypnozoites never originate from circulating merozoites in the bloodstream; instead, they only ever arise from sporozoites. P. vivax is unique among human malaria parasites in the fact that it may generate hypnozoites, which can cause relapses even after antimalarial medication, such as quinine or chloroquine [66, 67]. Interestingly, research indicates that the genotype of parasites responsible for relapses could be different from those during the original acute episode. This could be because the host is infected by several sporozoite genotypes or because extrinsic cues, such as concurrent infections, activate particular hypnozoites [67, 68]. Although P. ovale has long been suspected of developing hypnozoites, a lack of sufficient clinical and experimental evidence has led to a recent review that casts doubt on this idea. On the other hand, neither P. falciparum nor P. malariae are linked to the creation of hypnozoites, although they can linger in the bloodstream of the host for long stretches of time, sometimes even without exhibiting any symptoms [69, 70]. Cases of chronic infections that linger for years highlight how host immunity and parasite development must coexist in a delicate equilibrium. The fact that certain P. vivax recurrences may originate from non-hypnozoite sources, despite the fact that hypnozoites are well-established in P. vivax malaria, highlights the complexity of malaria recurrence mechanisms. Interestingly, studies of P. vivax recurrence in neurosyphilis patients getting blood from malaria patients point to non-hypnozoite alternate routes for recurrence, that adds to our understanding of the mysterious recurrence patterns of malaria [71, 72].

2.3 Gametocytes

The haploid genome of Plasmodium parasites is preserved during their growth in vertebrate hosts. Surprisingly, a cloned lineage of Plasmodium that started from a single cell can produce both male and female gametocytes, indicating that chromosomal elements are probably not the only variables influencing gametocyte sex determination [73, 74]. The details of this mechanism are still being investigated, but mounting data suggests that some environmental factors may facilitate the spread of parasites. Asexual intraerythrocytic development is the primary target of artemisinin and chloroquine, two antimalarial medications; however, gametocytes of Plasmodium species that infect people are resistant to both drugs [75, 76, 77]. As a result, gametocytes continue to exist in the circulation and may spread malaria to other individuals, even after asexual parasites are eliminated as a result of therapy with these antimalarials [77, 78]. According to research, P. falciparum gametocytes can survive for weeks after asexual blood-stage parasites are eliminated, and some cells can survive for up to 2 months. The existence of asymptomatic infections, host immunity, and treatment techniques all have an impact on the clearance rates and infectivity reduction of gametocytes [79, 80, 81]. In order to stop the parasite from spreading further, it is crucial to treat both symptomatic malaria patients and asymptomatic carriers with gametocytocidal medication [82, 83]. This is because people who harbor asymptomatic infections may carry significant quantities of gametocytes.

2.4 Asymptomatic carriers

Due to acquired immunity, a sizable fraction of the populace in malaria-endemic areas carries Plasmodium parasites but does not exhibit any symptoms [84, 85]. Frequently, more sensitivity procedures, such as molecular detection by PCR and LAMP or ultrasensitive versions of RDTs, are required for correct diagnosis because traditional diagnostic methods, such as microscopy or rapid detection tests (RDTs), fail to identify parasites in these asymptomatic carriers [86, 87, 88]. Even though asymptomatic carriers have the potential to spread infectious gametocytes to mosquitoes, with low gametocyte levels, their influence on local malaria transmission is usually negligible. But as their immunity weakens, as when they move to malaria-free areas where immunity is not maintained, their propensity to spread the disease increases [89, 90]. As a result, carriers who do not exhibit symptoms may unintentionally aid in the spread of malaria by means of organ or blood transplants [91, 92]. In the globalized world of today, where economic growth and transportation have led to a greater movement, managing asymptomatic carriers becomes critical. In addition, the increase in the number of refugees from malaria-endemic areas plagued by conflict highlights how critical it is to identify and treat asymptomatic carriers [93, 94, 95]. Similar to symptomatic malaria patients, these carriers must be properly identified and cared for in order to stop the illness from spreading or re-emerging in areas that are malaria-free. Thus, to maintain malaria control efforts and prevent future outbreaks in susceptible groups, comprehensive interventions aimed at asymptomatic carriers are crucial [95].

2.5 Apicoplast and plant-like metabolism

Within the superphylum Alveolata, the genus Plasmodium is related to creatures, such as dinoflagellates and ciliates [96]. It is a member of the varied group of protozoans known as apicomplexa. Almost all apicomplexans, including all species of Plasmodium, are obligatory parasites that include an apicoplast—a non-photosynthetic and vestigial plastid—inside their cells [97, 98, 99]. Encased in four layers of membrane, this secondary plastid has the smallest known plastid genome, a minute genome [100, 101]. Remarkably, recent findings have revealed remarkable apicomplexan species known as chromerids, which have photosynthetic plastids that allow for phototrophic growth without the assistance of other organisms [102, 103, 104]. The apicoplasts of parasitic apicomplexans, including Plasmodium, are not photosynthetic in contrast to their photosynthetic counterparts. Most of the gene products encoded in the organellar genome are linked to transcription or translation [105, 106, 107]. When genetic information became available, the presence of a non-photosynthetic plastid in parasitic apicomplexans—which had previously been perplexing—became more evident [108, 109]. It became clear that the Plasmodium apicoplast is involved in key metabolic processes that are similar to those in plants, including as the manufacture of haem, type II fatty acids, and isoprenoid compounds [109, 110, 111]. The apicoplast-derived pathways are essential for Plasmodium survival and are especially important at specific phases of development, such as in mosquitoes and the liver [112, 113, 114]. Interestingly, though, research has revealed that Plasmodium may thrive in culture even in the absence of the apicoplast if it is given enough of the essential precursor chemical isopentenyl pyrophosphate (IPP). The only source of IPP in Plasmodium is the plant-like methylerythritol phosphate (MEP) pathway found in the apicoplast, which is vital to the parasite’s survival [115, 116, 117]. Targeting the apicoplast metabolism has therapeutic potential, as demonstrated by the notable antimalarial effect of the medication fosmidomycin against P. falciparum, which targets the enzyme of the MEP pathway [118, 119, 120]. In contrast, certain apicomplexan species—such as Gregarina and Cryptosporidium—completely lack the apicoplast, while others—such as P. falciparum and T. gondii—cannot survive without it [121, 122, 123]. Species without the organelles usually lack the genes encoding the enzymes needed in plant-like metabolism within the apicoplast [124, 125]. Species of cryptosporidium that lack an apicoplast have a large number of putative amino acid transporters, indicating a different method of obtaining necessary metabolites from the host [126, 127]. Consequently, the complicated relationship between host-parasite interactions and apicoplast-dependent metabolism highlights the essential function of this organelle in the survival and pathophysiology of Plasmodium and other apicomplexan parasites [128, 129, 130].

2.6 Antimalarial drugs and resistance

Traditional medicine has been using a variety of plant compounds to treat malaria since ancient times. The South American quina-quina tree’s bark, which contains the antimalarial drug quinine, was found and used to cure malaria in the seventeenth century [131]. The 1930s witnessed the development of therapeutically effective synthetic antimalarials, such as chloroquine, as a result of centuries-long efforts to synthesize pure chemicals with antimalarial characteristics [132]. A natural substance that has long been utilized in China; artemisinin was discovered to have strong antimalarial properties in 1972. Currently used in clinical settings, antimalarial medications fall into five structural classes, each with unique modes of action. These classes include endoperoxides (like derivatives of artemisinin), 4-aminoquinolines (like chloroquine), aryl-amino alcohols (like quinine, mefloquine), naphthoquinones (like atovaquone), antifolates (like pyrimethamine, proguanil, sulfadoxine), and 8-aminoquinolines (like primaquine, tafenoquine). These medications target a number of metabolic pathways that are essential to the parasite’s survival, including mitochondrial oxidoreduction, pyrimidine biosynthesis, and hemoglobin detoxification. The parasites that cause human malaria, especially P. falciparum, have grown resistant to each class of medication over time, despite the fact that these treatments are effective [133]. Point mutations in target transporters or enzymes frequently cause this resistance, making the medications useless. Moreover, medication resistance may also be exacerbated by processes, such as gene amplification or modifications to regulatory networks [134, 135]. Furthermore, resistance strains’ deficiencies in DNA mismatch repair enable a higher pace of genetic alterations, which may help parasites endure strong pharmacological pressure [133, 136, 137]. Small genetic alterations that lead to treatment resistance are also made easier by the high A + T content of the Plasmodium species’ genome [138, 139, 140]. Thus, creating successful malaria prevention methods requires an understanding of the mechanisms underlying antimalarial drug resistance.

2.7 Host specificity

The natural host range of Plasmodium exhibits both narrow and large ranges, contingent upon the species. For example, although African apes and humans are closely related phylogenetically, P. falciparum, which only infects humans, does not affect them [141]. On the other hand, P. relictum affects more than 100 bird species globally, belonging to different families and orders [142]. Plasmodium species are traditionally divided into discrete subgenera according to their morphology, vertebrate hosts, and vectors. Every subgenus of Plasmodium appears to be monophyletic, despite the genus itself appearing to be polyphyletic. The three subgenera into which most mammalian Plasmodium species fall are Laverania, Plasmodium, and Vinckeia; apes are infected by Laverania, monkeys by Plasmodium, and rodents by Vinckeia [143, 144]. Mammalian malaria parasites are mainly spread by anopheline mosquitoes, in contrast to avian Plasmodium species, which are spread by a wide variety of mosquitoes, such as Culex and Aedes. Some non-anopheline mosquitoes, however, are capable of supporting a little amount of parasite growth [145]. For example, P. falciparum gametocytes in non-anopheline mosquitoes may develop into ookinetes, but they die before oocysts form. The environment, feeding habits, and host choice of different Anopheles species vary, which affects the dynamics of Plasmodium species’ transmission and host specificity [146]. The subgenus Laverania’s P. falciparum, which is the most common human Plasmodium species, can infect chimpanzees by laboratory adaptation, but it primarily infects humans. Only infecting gorillas, P. praefalciparum is phylogenetically related to P. falciparum. Strong host specificity is exhibited by species in the subgenus Laverania, which is probably controlled by gene families, such as stevor and Rh5, which are involved in host-parasite interactions. However, other species of Plasmodium found in the subgenus Plasmodium, such as P. vivax and P. malariae, exhibit a higher capacity for host change [147, 148]. For instance, isolates similar to P. vivax from Gabonese mosquitoes grouped together with P. simium, indicating a tendency for host flipping. In a similar vein, P. brasilianum, another zoonotic species that infects humans as well as simian hosts, most likely originated from P. malariae [149, 150]. Despite these findings, nothing is known about the mechanisms that allow Plasmodium subgenus hosts to swap hosts.

3. Conclusion

Malaria, which is brought on by Plasmodium, has plagued people throughout history. Malaria is now curable due to the development of both synthetic and natural antimalarial medications [151, 152]. When combined with insecticide-based mosquito control strategies, the use of synthetic antimalarials, such as artemisinin and chloroquine, has dramatically decreased the worldwide malaria load in comparison to earlier periods. Nevertheless, hundreds of thousands of people die from malaria every year. Drug-resistant parasite development and transmission is a major obstacle to controlling malaria [153, 154]. To tackle this problem, scientists are looking for new antimalarial substances that have different targets from those of current medications. By combining these novel inhibitors with existing antimalarials, the likelihood of parasite resistance can be reduced. Inhibitors directed toward the parasite’s metabolic pathways, such as plants, for example, exhibit potential. The ease with which Plasmodium can spread from endemic to non-endemic areas as a result of greater human movement is another barrier [155, 156, 157]. Although areas free of malaria are growing, imported malaria still poses a serious hazard to public health in many nations. Asymptomatic carriers may inadvertently start malaria epidemics in areas where the disease is not common by contracting the disease spontaneously or through organ and blood transplantation. Plasmodium species that infect humans have evolved to share certain traits that allow them to do so. Even while the number of human malaria species in existence is currently restricted, more Plasmodium species may spontaneously become human infectious, which could result in fresh outbreaks of zoonotic malaria [158, 159]. Depending on the proximity between humans and nonhuman primates—which is determined by local development—the probability of interspecies transmission may differ. Different mosquito hosts can also be adapted to by Plasmodium species. Avian malaria parasites can grow in non-anopheline mosquitoes, in contrast to mammalian Plasmodium [160, 161]. This raises the possibility that mammalian Plasmodium may develop immunity against non-anopheline mosquitoes and use them as vectors. Some kinds of non-anopheline mosquitoes are able to survive in a variety of settings, including cities, and if they spread malaria, they might pose a threat to the entire world [162, 163]. Effective malaria management measures require a thorough understanding of parasite biology due to the constant interplay between humans and Plasmodium. The realization of a healthier global society can be aided by the use of this information.