**2. Nonhuman primate natural hosts of a large** *Plasmodium* **diversity**

Today, the diversity of *Plasmodium* parasites infecting primates is well documented. First studies based in morphological analysis have reported three species which infect African apes (*Plasmodium reichenowi*, *Plasmodium schwetzi*, and *Plasmodium rodhaini*), and some of these were found to resemble human parasites *Plasmodium malariae*, *Plasmodium vivax*, and *Plasmodium ovale* [7]. The development of molecular tools allowed for a re-examination of *Plasmodium* diversity [8–10]. Data collected over the past years have shown that NHPs are infected with large diversity of *Plasmodium* belonging to two subgenera (*Laverania* and *Plasmodium*) [11] (**Figure 2**).

### **2.1** *Laverania* **subgenus**

Among species classified into *Laverania* group, four species infect chimpanzees (*P. gaboni*, *P. billcollinsi*, *P. billbrayi*, and *P. reichenowi*), only three infect gorillas (*P. adleri*, *P. blacklocki*, and *P. praefalciparum*), and only one infect bonobo (*P. lomamiensis*) [8, 9, 12]. Therefore, *P. billbrayi* [10] is not accepted as a new species by some authors [6, 13] who reported that these isolates did not seem to be sufficiently distinct from *P. gaboni* to warrant a separate species designation [6]. However, this species was described only in *Pan troglodytes schweinfurthii* and hence is the reason why we believe that could be another species [10] (**Figure 2**). Moreover, Mapua and colleagues reported recently several lineages of these parasites among African apes [14].

To date, all studies on natural populations of apes (based on the analysis of fecal samples) have shown that no *Plasmodium* species from the *Laverania* subgenus is able to infect *in natura* both hosts (gorillas and chimpanzees) [8, 13], thus suggesting the existence of a strong host specificity due to genetic barrier [6, 15]. However, a recent study revealed that this genetic barrier is not completely impermeable [16]; moreover, in this study, authors reported that the exchanges between gorillas

**3**

**Figure 3.**

*Plasmodium species in these species [5].*

**Figure 2.**

*Origin of Two Most Virulent Agents of Human Malaria:* Plasmodium falciparum*…*

*The tree of relationship of primate Plasmodium with the currently known categories of hosts. Primate* 

*Distribution of the different subspecies of great apes in Africa and representation of the spread of the different* 

*Plasmodium is subdivided in two subgenera: Laverania and Plasmodium [11].*

*DOI: http://dx.doi.org/10.5772/intechopen.84481*

*Origin of Two Most Virulent Agents of Human Malaria:* Plasmodium falciparum*… DOI: http://dx.doi.org/10.5772/intechopen.84481*

**Figure 2.**

*Malaria*

**Figure 1.**

*P. falciparum* and *P. vivax*.

*Map of world malaria distribution.*

*Plasmodium*) [11] (**Figure 2**).

lineages of these parasites among African apes [14].

**2.1** *Laverania* **subgenus**

*responsible for this disease come from in humans*? This chapter is a synthesis of the available data on the origin of two most virulent agents of human malaria:

**2. Nonhuman primate natural hosts of a large** *Plasmodium* **diversity**

Today, the diversity of *Plasmodium* parasites infecting primates is well documented. First studies based in morphological analysis have reported three species which infect African apes (*Plasmodium reichenowi*, *Plasmodium schwetzi*, and *Plasmodium rodhaini*), and some of these were found to resemble human parasites *Plasmodium malariae*, *Plasmodium vivax*, and *Plasmodium ovale* [7]. The development of molecular tools allowed for a re-examination of *Plasmodium* diversity [8–10]. Data collected over the past years have shown that NHPs are infected with large diversity of *Plasmodium* belonging to two subgenera (*Laverania* and

Among species classified into *Laverania* group, four species infect chimpanzees (*P. gaboni*, *P. billcollinsi*, *P. billbrayi*, and *P. reichenowi*), only three infect gorillas (*P. adleri*, *P. blacklocki*, and *P. praefalciparum*), and only one infect bonobo (*P. lomamiensis*) [8, 9, 12]. Therefore, *P. billbrayi* [10] is not accepted as a new species by some authors [6, 13] who reported that these isolates did not seem to be sufficiently distinct from *P. gaboni* to warrant a separate species designation [6]. However, this species was described only in *Pan troglodytes schweinfurthii* and hence is the reason why we believe that could be another species [10] (**Figure 2**). Moreover, Mapua and colleagues reported recently several

To date, all studies on natural populations of apes (based on the analysis of fecal samples) have shown that no *Plasmodium* species from the *Laverania* subgenus is able to infect *in natura* both hosts (gorillas and chimpanzees) [8, 13], thus suggesting the existence of a strong host specificity due to genetic barrier [6, 15]. However, a recent study revealed that this genetic barrier is not completely impermeable [16]; moreover, in this study, authors reported that the exchanges between gorillas

**2**

*The tree of relationship of primate Plasmodium with the currently known categories of hosts. Primate Plasmodium is subdivided in two subgenera: Laverania and Plasmodium [11].*


#### **Figure 3.**

*Distribution of the different subspecies of great apes in Africa and representation of the spread of the different Plasmodium species in these species [5].*

and chimpanzees were possible in confined environments [16]. Second hypothesis was about the role played by potential vectors [17]. However, this hypothesis was refuted by a study which showed that vectors had no preference for hosts [18]. Thus, other ecological factors could play a potential role in host specificity. Furthermore the simians' species of this group seem to be geographically located in central Africa only (**Figure 3**).

#### **2.2** *Plasmodium* **subgenus**

Conversely, subgenus *Plasmodium* (non-*Laverania*) includes several species infecting a large variety of primates of varied origins [Africa, Asia (*catarrhines*), South America (*platyrrhines*) and Human] [11]. Two major facts concerning this group were the emergence of *P. knowlesi* in human population [19, 20] and the characterization of *P. vivax*-like in chimpanzees and gorillas [21, 22] which completely changed our consideration of this malaria parasite subgenus [23, 24].

In Africa NHPs, five species of this subgenus circulate among monkeys and great apes, two for monkeys (*P. gonderi* and *P*. sp. DAJ-2004 [called now *Plasmodium mandrilli* [25]]) and three for great apes (*P. vivax*-like, *P. malariae*-like, and *P. ovale*-like) [13, 16]. In African great apes, both hosts (chimpanzee and gorilla) are infected with these parasites (*P. vivax*-like, *P. malariae*-like, and *P. ovale*-like) (**Figures 3** and **4**). Thus, these *Plasmodium* species are not specific hosts, and it would be very interesting to establish the mechanisms which favor host switching for these parasites. Several species were reported as implicate in circulation of malaria parasites in central Africa [17, 18]. In African apes three *Anopheles* species (*An. moucheti*, *An. vinckei*, and *An. marshallii*) are known to allow the circulation of malaria parasites in forest environment [18].

Apart from African apes, Asian monkeys are also infected by many other species of *Plasmodium* (*P. cynomolgi*, *P. hylobati*, *P. knowlesi*, *P. coatneyi*, *P. fragile, P. fieldi*,

**5**

**3.1** *Plasmodium falciparum*

the conclusion of the authors.

*Origin of Two Most Virulent Agents of Human Malaria:* Plasmodium falciparum*…*

**3. Where do the malaria parasites that infect men come from?**

The understanding of origin of human malaria parasites has been the subject of numerous studies that have been based on the morphology, biology, and affiliation of parasites to their hosts [33]. However, recent development of molecular tools in diagnosis has made considerable progress in understanding the evolutionary history of malaria parasites. Indeed, the contribution of several new sequences by this new approach will clarify the debate on many theories developed on the subject [34]. Moreover, several of these parasites have been found to be associated with humans by lateral transfer from other vertebrate host species [35, 36]. We will present the probable origin of two most virulent *Plasmodium* species that infect human.

The debate on the origin of *P. falciparum* most spread in world (**Figure 5**) was opened with the study of Waters and his collaborators who proposed an avian origin of this parasite that is to say that the man would have recently acquired this parasite of a transfer from birds to humans [37]. Indeed, phylogenetic analyses based on the study of ribosomal RNA subunit (rRNA) sequences showed that *P. falciparum* formed a monophyletic group with *Plasmodium* spp. of birds (see **Figure 6**), hence

Three years after the first hypothesis on the origin of *P. falciparum*, Escalante and Ayala [38], in their study also based on 18S RNA, take into account for the first time *P. reichenowi*, an isolated parasite in a chimpanzee African (**Figure 7**). They will show that this parasite is the closest parent of *P. falciparum*; therefore, this observation allowed authors to conclude that *Plasmodium falciparum* origin was not a recent lateral transfer of this parasite of birds to humans [38, 39]. In this study, *P. falciparum* and *P. reichenowi* form a large group with primate parasites of the subgenus *Plasmodium* (*non-Laverania*), rodents, and birds [38, 40, 41] (**Figure 7**).

This will further fuel the debate on the origin of *P. falciparum*.

*P. simiovale*, and *P inui Plasmodium* spp. [26]) (**Figures 3** and **4**). Several other species of *Plasmodium* were observed among Asian apes by microscopic analyses, but no molecular evidence of the existence of these lineages are available (e.g., *P. pithecia* and *P. sandoshami*). These malaria parasites could infect many apes' hosts. Several studies reported of the different NHP species with same parasites [27] or many parasites which were found in one species of NHP, for example, four species of simian malaria parasites were characterized in the pig-tailed macaques (*Macaca nemestrina*) [28, 29]. In this part of the world, the situation of *P. knowlesi* gives a good example of the risk that these parasites could present to humans. Recently, the probable existence of three divergent subpopulations of *P. knowlesi* with the different origins was reported [30]. Finally, in South America some *Plasmodium* species were described as infecting NHPs. The species found in Southern American primates are *Plasmodium brasilianum* and *Plasmodium simium*, and these parasite species naturally infect monkeys from the Cebidae and Atelidae families [31] (**Figure 3**). However, *P. brasilianum* infects 11 species of monkeys (*Alouatta spp*, *Ateles spp*, *Brachyteles arachnoides*, *Cacajao calvus*, *Callicebus spp*, *Cebus spp, Chiropotes satanas*, *Lagothrix spp*, *Saimiri spp*, *Saguinus midas*, and *Pithecia pithecia*), while *Plasmodium simium* infects only 2 species (*Alouatta spp* and *Brachyteles arachnoides*). In recent studies, *P. simium* was found for the first time in capuchin monkeys from the Brazilian Atlantic Forest [32]. *P. brasilium* and *P. simium* are similar and indistinguishable from human *P. malariae* and *P. vivax.* These similarities occur at the morphological, genetic, and immunological levels [31, 32].

*DOI: http://dx.doi.org/10.5772/intechopen.84481*

**Figure 4.** *Phylogenetic tree of some Plasmodium species found in apes.*

*Origin of Two Most Virulent Agents of Human Malaria:* Plasmodium falciparum*… DOI: http://dx.doi.org/10.5772/intechopen.84481*

*P. simiovale*, and *P inui Plasmodium* spp. [26]) (**Figures 3** and **4**). Several other species of *Plasmodium* were observed among Asian apes by microscopic analyses, but no molecular evidence of the existence of these lineages are available (e.g., *P. pithecia* and *P. sandoshami*). These malaria parasites could infect many apes' hosts. Several studies reported of the different NHP species with same parasites [27] or many parasites which were found in one species of NHP, for example, four species of simian malaria parasites were characterized in the pig-tailed macaques (*Macaca nemestrina*) [28, 29]. In this part of the world, the situation of *P. knowlesi* gives a good example of the risk that these parasites could present to humans. Recently, the probable existence of three divergent subpopulations of *P. knowlesi* with the different origins was reported [30].

Finally, in South America some *Plasmodium* species were described as infecting NHPs. The species found in Southern American primates are *Plasmodium brasilianum* and *Plasmodium simium*, and these parasite species naturally infect monkeys from the Cebidae and Atelidae families [31] (**Figure 3**). However, *P. brasilianum* infects 11 species of monkeys (*Alouatta spp*, *Ateles spp*, *Brachyteles arachnoides*, *Cacajao calvus*, *Callicebus spp*, *Cebus spp, Chiropotes satanas*, *Lagothrix spp*, *Saimiri spp*, *Saguinus midas*, and *Pithecia pithecia*), while *Plasmodium simium* infects only 2 species (*Alouatta spp* and *Brachyteles arachnoides*). In recent studies, *P. simium* was found for the first time in capuchin monkeys from the Brazilian Atlantic Forest [32]. *P. brasilium* and *P. simium* are similar and indistinguishable from human *P. malariae* and *P. vivax.* These similarities occur at the morphological, genetic, and immunological levels [31, 32].

## **3. Where do the malaria parasites that infect men come from?**

The understanding of origin of human malaria parasites has been the subject of numerous studies that have been based on the morphology, biology, and affiliation of parasites to their hosts [33]. However, recent development of molecular tools in diagnosis has made considerable progress in understanding the evolutionary history of malaria parasites. Indeed, the contribution of several new sequences by this new approach will clarify the debate on many theories developed on the subject [34]. Moreover, several of these parasites have been found to be associated with humans by lateral transfer from other vertebrate host species [35, 36]. We will present the probable origin of two most virulent *Plasmodium* species that infect human.

#### **3.1** *Plasmodium falciparum*

The debate on the origin of *P. falciparum* most spread in world (**Figure 5**) was opened with the study of Waters and his collaborators who proposed an avian origin of this parasite that is to say that the man would have recently acquired this parasite of a transfer from birds to humans [37]. Indeed, phylogenetic analyses based on the study of ribosomal RNA subunit (rRNA) sequences showed that *P. falciparum* formed a monophyletic group with *Plasmodium* spp. of birds (see **Figure 6**), hence the conclusion of the authors.

Three years after the first hypothesis on the origin of *P. falciparum*, Escalante and Ayala [38], in their study also based on 18S RNA, take into account for the first time *P. reichenowi*, an isolated parasite in a chimpanzee African (**Figure 7**). They will show that this parasite is the closest parent of *P. falciparum*; therefore, this observation allowed authors to conclude that *Plasmodium falciparum* origin was not a recent lateral transfer of this parasite of birds to humans [38, 39]. In this study, *P. falciparum* and *P. reichenowi* form a large group with primate parasites of the subgenus *Plasmodium* (*non-Laverania*), rodents, and birds [38, 40, 41] (**Figure 7**). This will further fuel the debate on the origin of *P. falciparum*.

*Malaria*

central Africa only (**Figure 3**).

**2.2** *Plasmodium* **subgenus**

and chimpanzees were possible in confined environments [16]. Second hypothesis was about the role played by potential vectors [17]. However, this hypothesis was refuted by a study which showed that vectors had no preference for hosts [18]. Thus, other ecological factors could play a potential role in host specificity. Furthermore the simians' species of this group seem to be geographically located in

Conversely, subgenus *Plasmodium* (non-*Laverania*) includes several species infecting a large variety of primates of varied origins [Africa, Asia (*catarrhines*), South America (*platyrrhines*) and Human] [11]. Two major facts concerning this group were the emergence of *P. knowlesi* in human population [19, 20] and the characterization of *P. vivax*-like in chimpanzees and gorillas [21, 22] which completely

In Africa NHPs, five species of this subgenus circulate among monkeys and great

Apart from African apes, Asian monkeys are also infected by many other species of *Plasmodium* (*P. cynomolgi*, *P. hylobati*, *P. knowlesi*, *P. coatneyi*, *P. fragile, P. fieldi*,

apes, two for monkeys (*P. gonderi* and *P*. sp. DAJ-2004 [called now *Plasmodium mandrilli* [25]]) and three for great apes (*P. vivax*-like, *P. malariae*-like, and *P. ovale*-like) [13, 16]. In African great apes, both hosts (chimpanzee and gorilla) are infected with these parasites (*P. vivax*-like, *P. malariae*-like, and *P. ovale*-like) (**Figures 3** and **4**). Thus, these *Plasmodium* species are not specific hosts, and it would be very interesting to establish the mechanisms which favor host switching for these parasites. Several species were reported as implicate in circulation of malaria parasites in central Africa [17, 18]. In African apes three *Anopheles* species (*An. moucheti*, *An. vinckei*, and *An. marshallii*) are known to allow the circulation of

changed our consideration of this malaria parasite subgenus [23, 24].

**4**

**Figure 4.**

*Phylogenetic tree of some Plasmodium species found in apes.*

malaria parasites in forest environment [18].

**Figure 5.** *Distribution of Plasmodium falciparum in the world [42].*

#### **Figure 6.**

*Phylogenetic tree of malaria parasites obtained by Waters and colleagues [37].*

The disputes surround the probable origin of *P. falciparum*, whether it comes from birds or rodents, will be raging. Authors as Prugnolle et al. believe that the problems or weaknesses of many studies were based essentially on two aspects [5]: firstly the low number of plasmodial species and sequences integrated in these analyses and secondly the limited number of molecular markers used for the development of phylogenies. Despite all this controversy, *P. falciparum* will be considered to have an African origin [43–45].

The year 2009 will completely change our understanding of the evolutionary history of *P. falciparum*, because prior to this year, only one species (*P. reichenowi*) was known to be closer to *P. falciparum*. After the discovery of *Plasmodium gaboni* parasite that infects chimpanzees [46], several other sequences from African great apes will definitively bring elements of answers to question on the origin of this parasite.

Indeed, in 2010, Prugnolle and colleagues will highlight for the first time *P. falciparum*-like in gorillas and several other lineages. These studies will prove that the *Laverania* group that includes *P. falciparum* has a great diversity of species that circulate in African primates [9]. This will make it possible to show that the origin

**7**

**Figure 7.**

**Figure 8.**

*are grouped as Plasmodium spp.) [38].*

that which infects humans [11, 13].

*Plasmodium parasites infecting African apes (Holmes 2010).*

species is not a natural reservoir for this parasite [48].

*Origin of Two Most Virulent Agents of Human Malaria:* Plasmodium falciparum*…*

of *P. falciparum* is not found in birds or rodents but in the gorillas that have recently transmitted it to humans via anophobic zoo-anthropophilic mosquito [17, 18]. *P. falciparum*-like of gorillas will be named *P. praefalciparum* to distinguish it from

*Origin of human Plasmodium falciparum. This phylogenetic tree illustrates the remarkable diversity of* 

*Two ML phylogenetic trees obtained by grouping 11 Plasmodium species as indicated (the six unlisted species* 

In 2011, the hypothesis of a gorilla origin of *P. falciparum* seems to be weakened

Today, after numerous studies that analyzed more than 5000 samples of wild and captives apes [8–10, 12, 13, 16, 21, 22, 47] (**Figure 8**), it appears that gorillas are

by the discovery of *P. praefalciparum* in a small African monkey (*Cercopithecus nictitans*) [47]. This study also will reveal the existence of at least two types of *P. praefalciparum*: 1 and 2. *P. praefalciparum*-1 infects gorillas and monkeys (*C. nictitans*), and *P. praefalciparum*-2 infects only gorillas [11]. Other studies will focus on African monkeys, but will not find *P. praefalciparum* [48]. Thus, we believe that the hypothesis of *Plasmodium falciparum* from monkeys is not solid and that *C. nictitans*

*DOI: http://dx.doi.org/10.5772/intechopen.84481*

*Origin of Two Most Virulent Agents of Human Malaria:* Plasmodium falciparum*… DOI: http://dx.doi.org/10.5772/intechopen.84481*

**Figure 7.**

*Malaria*

**Figure 5.**

*Distribution of Plasmodium falciparum in the world [42].*

**6**

parasite.

**Figure 6.**

to have an African origin [43–45].

The disputes surround the probable origin of *P. falciparum*, whether it comes from birds or rodents, will be raging. Authors as Prugnolle et al. believe that the problems or weaknesses of many studies were based essentially on two aspects [5]: firstly the low number of plasmodial species and sequences integrated in these analyses and secondly the limited number of molecular markers used for the development of phylogenies. Despite all this controversy, *P. falciparum* will be considered

*Phylogenetic tree of malaria parasites obtained by Waters and colleagues [37].*

The year 2009 will completely change our understanding of the evolutionary history of *P. falciparum*, because prior to this year, only one species (*P. reichenowi*) was known to be closer to *P. falciparum*. After the discovery of *Plasmodium gaboni* parasite that infects chimpanzees [46], several other sequences from African great apes will definitively bring elements of answers to question on the origin of this

Indeed, in 2010, Prugnolle and colleagues will highlight for the first time *P. falciparum*-like in gorillas and several other lineages. These studies will prove that the *Laverania* group that includes *P. falciparum* has a great diversity of species that circulate in African primates [9]. This will make it possible to show that the origin

*Two ML phylogenetic trees obtained by grouping 11 Plasmodium species as indicated (the six unlisted species are grouped as Plasmodium spp.) [38].*

#### **Figure 8.**

*Origin of human Plasmodium falciparum. This phylogenetic tree illustrates the remarkable diversity of Plasmodium parasites infecting African apes (Holmes 2010).*

of *P. falciparum* is not found in birds or rodents but in the gorillas that have recently transmitted it to humans via anophobic zoo-anthropophilic mosquito [17, 18]. *P. falciparum*-like of gorillas will be named *P. praefalciparum* to distinguish it from that which infects humans [11, 13].

In 2011, the hypothesis of a gorilla origin of *P. falciparum* seems to be weakened by the discovery of *P. praefalciparum* in a small African monkey (*Cercopithecus nictitans*) [47]. This study also will reveal the existence of at least two types of *P. praefalciparum*: 1 and 2. *P. praefalciparum*-1 infects gorillas and monkeys (*C. nictitans*), and *P. praefalciparum*-2 infects only gorillas [11]. Other studies will focus on African monkeys, but will not find *P. praefalciparum* [48]. Thus, we believe that the hypothesis of *Plasmodium falciparum* from monkeys is not solid and that *C. nictitans* species is not a natural reservoir for this parasite [48].

Today, after numerous studies that analyzed more than 5000 samples of wild and captives apes [8–10, 12, 13, 16, 21, 22, 47] (**Figure 8**), it appears that gorillas are the reservoir for the *P. praefalciparum*, even though several hypotheses concerning the origin of *P. falciparum* have been proposed for primates [10, 47].

The hypothesis according to which *Plasmodium falciparum* would come from gorillas seems to be the most plausible at the moment. Indeed, several *P. praefalciparum* sequences had been found from numerous wild-living gorillas in different areas [8, 13]. Loy and colleagues suggested that this parasite strain that was able to cross the host species barrier by carried one or more highly unusual mutations that conferred him an ability to colonize humans [49]. This theory comes to the fact that recent studies in human populations living close to the wild apes did not reveal the presence of parasites of great apes belonging to *Laverania* subgenus in humans [50, 51]. Thus, then it would seem that *P. falciparum* comes from African gorillas according to available data at the moment.

#### **3.2 Origin of** *Plasmodium vivax*

*Plasmodium vivax* is particularly prevalent in Asia, Southeast Asia, South America, and the Western Pacific region [52] (**Figure 9**). Already the first studies on malaria of the great apes had revealed the presence of parasites resembling *P. vivax* [53, 54]. Despite its first observations, the question on the origin of *P. vivax* remained uncertain for several years. Concerning this interesting question of the *P. vivax* origin, several hypotheses have been proposed in recent years.

The first hypotheses about the origin of *P. vivax* had suggested that it originated in Southeast Asia [24, 49]. These hypotheses were based on the fact that *P. vivax* shares morphological and biological traits with several macaque parasites and that *Plasmodium* simian's species are abundant in this Asian region [36]. This hypothesis was supported by the phylogenetic analyses that placed *P. vivax* among the *Plasmodium* spp. of Asian monkeys with like closest parent, *Plasmodium cynomolgi*, which infects macaques in Asia [40, 55]. The consensus view has thus been that *P. vivax* emerged in southeastern Asia following the cross-species transmission of a macaque parasite [23, 56, 57].

In addition to the first hypothesis, another hypothesis will articulate around of the negative Duffy receptor and would suggest African origin of *P. vivax* [58, 59]. Indeed, the presence of negative Duffy blood group in central and West African populations was correlated with the absence of *P. vivax*. This character would confer resistance to *P. vivax* infection, which suggested that this mutation arose in response to prolonged selection pressure from *P. vivax* [60]. Currently, Duffy antigen is the

**9**

*Origin of Two Most Virulent Agents of Human Malaria:* Plasmodium falciparum*…*

only receptor known to be used by parasite to invade the red blood cell. Thus, it has been proposed that *P. vivax* co-evolved with African populations for longer than

*The diagram presents a possible two-step scenario for the transfer and establishment of ape malarias in humans. Sylvatic anopheline vectors were transmitting malaria between apes; in the first step, one (or more) bridge vector(s) would also transfer infective Plasmodium parasites to humans. In a second step, humanadapted Plasmodium parasites adapted to domesticated mosquito vector species that share the same ecological* 

However, the recent studies using the development of molecular tools allow to have a clear view on the origin of this parasite. These studies have shown that chimpanzees and gorillas from central and West Africa harbor a large diversity of *P. vivax*-like parasites [10, 21, 22, 62]. This discovery accentuates the African origin of *Plasmodium vivax* and reveals that African great apes are potential sylvatic reservoir of *P. vivax* [21, 22]. However, elucidation of the origin of *P. vivax* in African apes needed complementary studies of wild-living populations across central Africa [22]. Also, Prugnolle et al. have shown that *P. vivax*-like found among African great apes form a distinct and much more diverse genetic group than that of human parasites [21]. In this study authors revealed also an older origin of the African simian lineages and the fact that these lineages are able to infect the Caucasian population today [21] (**Figure 10**). Thus, the discovery of *P. vivax* in large numbers of chimpanzees and gorillas provides compelling evidence for an African, rather than an Asian, origin of human *P. vivax*. Today, an interesting question would be to understand how this passage of apes to man had been done. To this question, in view of current data and analyses, we agree to say, instead, it is much more likely that extant human *P. vivax* could represent a lineage that survived after spreading out of Africa [21, 64, 65], because this theory could explain the fact that we observed today a reduced diversity of the human parasites which would result from an out-of-Africa bottleneck, such as

**4. Malaria like a zoonotic disease: the running toward new environments** 

It is true that many *Plasmodium* parasites circulating in African NHPs could produce symptoms of this disease in apes [67]. However, no *Plasmodium* species particularly parasites belonging to *Laverania* subgenus has been found to infect human to date. Studies conducted in rural population in central Africa (Cameroon and Gabon) have shown that *Laverania* parasites were absent of human populations living in villages that are in very close proximity to wild forest [50, 51] and even

*DOI: http://dx.doi.org/10.5772/intechopen.84481*

with other human populations [24, 61].

**Figure 10.**

*niche with humans [63].*

observed in *P. falciparum* [45, 66].

**is a wont for** *Plasmodium*

**Figure 9.** *The spatial distribution of Plasmodium vivax in the world [52].*

*Origin of Two Most Virulent Agents of Human Malaria:* Plasmodium falciparum*… DOI: http://dx.doi.org/10.5772/intechopen.84481*

**Figure 10.**

*Malaria*

**3.2 Origin of** *Plasmodium vivax*

macaque parasite [23, 56, 57].

the reservoir for the *P. praefalciparum*, even though several hypotheses concerning

The hypothesis according to which *Plasmodium falciparum* would come from gorillas seems to be the most plausible at the moment. Indeed, several *P. praefalciparum* sequences had been found from numerous wild-living gorillas in different areas [8, 13]. Loy and colleagues suggested that this parasite strain that was able to cross the host species barrier by carried one or more highly unusual mutations that conferred him an ability to colonize humans [49]. This theory comes to the fact that recent studies in human populations living close to the wild apes did not reveal the presence of parasites of great apes belonging to *Laverania* subgenus in humans [50, 51]. Thus, then it would seem that *P. falciparum* comes from African gorillas according to available data at the moment.

*Plasmodium vivax* is particularly prevalent in Asia, Southeast Asia, South America, and the Western Pacific region [52] (**Figure 9**). Already the first studies on malaria of the great apes had revealed the presence of parasites resembling *P. vivax* [53, 54]. Despite its first observations, the question on the origin of *P. vivax* remained uncertain for several years. Concerning this interesting question of the

The first hypotheses about the origin of *P. vivax* had suggested that it originated in Southeast Asia [24, 49]. These hypotheses were based on the fact that *P. vivax* shares morphological and biological traits with several macaque parasites and that *Plasmodium* simian's species are abundant in this Asian region [36]. This hypothesis was supported by the phylogenetic analyses that placed *P. vivax* among the *Plasmodium* spp. of Asian monkeys with like closest parent, *Plasmodium cynomolgi*, which infects macaques in Asia [40, 55]. The consensus view has thus been that *P. vivax* emerged in southeastern Asia following the cross-species transmission of a

In addition to the first hypothesis, another hypothesis will articulate around of the negative Duffy receptor and would suggest African origin of *P. vivax* [58, 59]. Indeed, the presence of negative Duffy blood group in central and West African populations was correlated with the absence of *P. vivax*. This character would confer resistance to *P. vivax* infection, which suggested that this mutation arose in response to prolonged selection pressure from *P. vivax* [60]. Currently, Duffy antigen is the

*P. vivax* origin, several hypotheses have been proposed in recent years.

the origin of *P. falciparum* have been proposed for primates [10, 47].

**8**

**Figure 9.**

*The spatial distribution of Plasmodium vivax in the world [52].*

*The diagram presents a possible two-step scenario for the transfer and establishment of ape malarias in humans. Sylvatic anopheline vectors were transmitting malaria between apes; in the first step, one (or more) bridge vector(s) would also transfer infective Plasmodium parasites to humans. In a second step, humanadapted Plasmodium parasites adapted to domesticated mosquito vector species that share the same ecological niche with humans [63].*

only receptor known to be used by parasite to invade the red blood cell. Thus, it has been proposed that *P. vivax* co-evolved with African populations for longer than with other human populations [24, 61].

However, the recent studies using the development of molecular tools allow to have a clear view on the origin of this parasite. These studies have shown that chimpanzees and gorillas from central and West Africa harbor a large diversity of *P. vivax*-like parasites [10, 21, 22, 62]. This discovery accentuates the African origin of *Plasmodium vivax* and reveals that African great apes are potential sylvatic reservoir of *P. vivax* [21, 22]. However, elucidation of the origin of *P. vivax* in African apes needed complementary studies of wild-living populations across central Africa [22].

Also, Prugnolle et al. have shown that *P. vivax*-like found among African great apes form a distinct and much more diverse genetic group than that of human parasites [21]. In this study authors revealed also an older origin of the African simian lineages and the fact that these lineages are able to infect the Caucasian population today [21] (**Figure 10**). Thus, the discovery of *P. vivax* in large numbers of chimpanzees and gorillas provides compelling evidence for an African, rather than an Asian, origin of human *P. vivax*.

Today, an interesting question would be to understand how this passage of apes to man had been done. To this question, in view of current data and analyses, we agree to say, instead, it is much more likely that extant human *P. vivax* could represent a lineage that survived after spreading out of Africa [21, 64, 65], because this theory could explain the fact that we observed today a reduced diversity of the human parasites which would result from an out-of-Africa bottleneck, such as observed in *P. falciparum* [45, 66].

### **4. Malaria like a zoonotic disease: the running toward new environments is a wont for** *Plasmodium*

It is true that many *Plasmodium* parasites circulating in African NHPs could produce symptoms of this disease in apes [67]. However, no *Plasmodium* species particularly parasites belonging to *Laverania* subgenus has been found to infect human to date. Studies conducted in rural population in central Africa (Cameroon and Gabon) have shown that *Laverania* parasites were absent of human populations living in villages that are in very close proximity to wild forest [50, 51] and even

those working in very close contact with NHPs [16]. On the other hand, several studies reported that *P. falciparum* is able to infect African apes, for example, Bonobos, chimpanzees [10, 26], and recently the mandrills [16]. The question is *why these transfers are rare or why the ancestral parent of P. falciparum (P. praefalciparum) appear incapable of infecting humans today*. Loy et al. suggest that gorilla parasite strain that was able to cross the host species barrier must have carried one or more highly unusual mutations that enable it to colonize humans [49]. But, supplementary studies would be necessary to support this hypothesis.

In contrast, many parasites of *Plasmodium* subgenus were reported to infect humans. The major case known is *P. knowlesi* that infects NHPs in south Asia and now is considered as the fifth *Plasmodium* species that infects human and cause malaria in southern Asian population [19]. Other cases of natural or accidental infections of humans with simians *Plasmodium* were reported in literature. Indeed, a total of seven species of monkey malaria have been reported via mosquitoes (*P. cynomolgi*, *P. brasilianum*, *P. eylesi*, *P. knowlesi*, *P. inui*, *P. schwetzi*, and *P. simium*) [11, 68, 69]. Recently, ape *P. vivax* has been found to cause clinical malaria in Caucasians who stayed during some days in African forest [21]. Thus, parasites of *Plasmodium* subgenus are apparently able to cross the species barrier to humans. So the emergence of these parasites should be monitored in areas where an influx of contact between humans and NHPs increases with anthropization, which destroys ape habitat and favors contact. In view of the rare faction of monkeys and the increase of the human population, it is feared that human infection of simians *Plasmodium* will become more frequent which could lead to humans becoming simians' major host [70].

## **5. Prevention**

The potential for zoonosis is influenced by human habitation and behavior as well as the adaptive capabilities of parasites and vectors. Indeed, the existence of potential sylvatic reservoirs of *P. vivax* and *P. falciparum* in Africa could compromise malaria control and eradication efforts. Actually, there is lack of knowledge about the real extent of malaria zoonosis. Thus, this aspect of zoonosis malaria parasites must be taken into account by the public health authorities responsible for the fight against malaria. African structures health need to put appropriate strategies of prevention against zoonotic malaria parasites that could be developed. However, they must be based on good data of research on diagnosis and treatment of zoonotic malaria. Moreover, all people living in the locality or monkeys are known to grass a large variety of malaria parasite, which must take their precaution when they venture into forest environment, in order to avoid mosquito bites.
