PBPrimate BiologyPBPrimate Biol.2363-4715Copernicus PublicationsGöttingen, Germany10.5194/pb-4-47-2017Wild African great apes as natural hosts of malaria parasites: current
knowledge and research perspectivesDe NysHélène Mariehelene.de-nys@ird.frLöhrichThereseWuDorisCalvignac-SpencerSébastienLeendertzFabian HubertusProject group Epidemiology of Highly Pathogenic Microorganisms, Robert Koch Institute, Berlin, Germanycurrent address: UMI 233, Institut de Recherche pour le Développement (IRD), INSERM U1175, and University of Montpellier, Montpellier, FranceHélène Marie De Nys (helene.de-nys@ird.fr)14March201741475926December201620February201724February2017This work is licensed under a Creative Commons Attribution 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/This article is available from https://pb.copernicus.org/articles/4/47/2017/pb-4-47-2017.htmlThe full text article is available as a PDF file from https://pb.copernicus.org/articles/4/47/2017/pb-4-47-2017.pdf
Humans and African great apes (AGAs) are naturally infected with several
species of closely related malaria parasites. The need to understand the
origins of human malaria as well as the risk of zoonotic transmissions and
emergence of new malaria strains in human populations has markedly encouraged
research on great ape Plasmodium parasites. Progress in the use of
non-invasive methods has rendered investigations into wild ape populations
possible. Present knowledge is mainly focused on parasite diversity and
phylogeny, with still large gaps to fill on malaria parasite ecology.
Understanding what malaria infection means in terms of great ape health is
also an important, but challenging avenue of research and has been subject to
relatively few research efforts so far. This paper reviews current knowledge
on African great ape malaria and identifies gaps and future research
perspectives.
Introduction
African great apes (AGAs) have been known to naturally host malaria parasites since
the early 1920s, when researchers first described various
Plasmodium species infecting chimpanzees (Pan troglodytes) and gorillas (Gorilla spp.), which are closely related
to those infecting humans (Reichenow, 1920). To this day, it
remains difficult to date the actual origins of the malaria parasites which
infect humans (Sharp et al., 2013) as well as their
emergence in human populations. However, the expansion of P. falciparum for instance, the most virulent Plasmodium parasite
(White, 2003), is believed to have started in Africa at least
thousands or even tens of thousands of years ago (Carter
and Mendis, 2002; Rich et al., 2009; Tanabe et al., 2010; Volkman et al.,
2001) and to have played a significant role in recent human evolution
(Carter and Mendis, 2002). Malaria is currently
geographically widespread and constitutes a heavy burden for human public
health (WHO, 2015). Malaria in great apes, our closest
evolutionary relatives, has thus increasingly been subject to research as
this leads to a better understanding of human malaria and the
significance and implications of malaria parasite infection for great ape
population health.
Research on AGA malaria parasites was initially limited to the study of
captive and laboratory individuals (Bray,
1960; Contacos et al., 1970; Garnham et al., 1956; Rodhain and Dellaert,
1943; Rodhain, 1936, 1940; Schwetz, 1934). However, the development of
molecular diagnostic tools and, later on, the ability to use non-invasive
samples, i.e. the discovery that malaria parasite genetic material can be
found in faecal samples of primates (Prugnolle et al., 2010),
opened up opportunities for further research in wild ape populations. This
allowed for more accurate identifications, the discovery of additional
Plasmodium species in chimpanzees and gorillas, and the study of
their phylogenetic relationships (Kaiser et
al., 2010; Liu et al., 2010, 2014). Most of the current knowledge concerns
malaria parasite diversity, host specificity and evolutionary history. There
is still relatively little understanding of the epidemiology, ecology and
biology of great ape malaria, but with increasing efforts being made in
recent years to investigate these aspects. Here, we review up-to-date
knowledge about the natural history of malaria parasite infection in wild
AGAs, highlight the gaps in the knowledge and conclude with some perspectives for
further investigation.
Parasite diversity, distribution and prevalence in African great
apes
Malaria parasites naturally infecting AGAs were initially described in the
1920s by Reichenow (Reichenow, 1920) and then studied further and
experimented on by various researchers such as Blacklock and Adler (Adler,
1923; Blacklock and Adler, 1922), Schwetz (Schwetz, 1934), Rodhain (Rodhain
and Dellaert, 1943; Rodhain, 1936, 1940), Brumpt (Brumpt, 1939), Garnham
(Garnham et al., 1956), Bray (Bray, 1958a, 1960) and Contacos (Contacos et
al., 1970). Based on morphological features, three distinct
Plasmodium species, considered similar to the human parasites, were
identified in West and Central Africa: P. falciparum-like and
P. ovale- or vivax-like parasites in chimpanzees and
gorillas and P. malariae-like parasites in chimpanzees (Reichenow,
1920). These three species
were subsequently named P. reichenowi (P. falciparum-like
parasites) (Blacklock and Adler, 1922), P. schwetzi (P. ovale or vivax-like parasites) (Brumpt, 1939) and P. rodhaini (P. malariae-like parasites) (Brumpt, 1939). P. falciparum and P. reichenowi, considered relatively distinct from
other known Plasmodium species, were grouped separately under the
Laverania subgenus (Bray, 1958b).
Distribution of Plasmodium species detected in wild
chimpanzees and gorillas. Plasmodium species symbols placed on the
geographical range of chimpanzee subspecies (a) and gorilla
species and subspecies (b) indicate that the assigned
Plasmodium species was, to this date, detected in at least one
sample of the relevant great ape species and subspecies. Positions of the
Plasmodium symbols do not represent specific field site locations.
From 2009 onwards, with the increased use of molecular diagnostic tools
(deoxyribonucleic acid, DNA, amplification and genome sequencing) and, later
on, the development of non-invasive methods to detect malaria infection
through the amplification of parasite DNA from faecal samples, large-scale
studies on malaria parasites infecting wild great apes flourished. These studies led
to the description of a higher diversity of parasites than previously
thought and gave clearer insight into prevalence rates and the possible
origins and evolutionary history of malaria infection in humans. To date, at
least six Plasmodium species have been shown to be endemic in
wild-living chimpanzees: three Laverania species –
P. reichenowi (Boundenga et al., 2015; Kaiser et
al., 2010; Liu et al., 2010, 2016; Prugnolle et al., 2010; Rich et al.,
2009) and two newly discovered Laverania species, P. gaboni (Boundenga et al., 2015; Kaiser et al., 2010; Liu et al., 2010, 2016;
Prugnolle et al., 2010; Rich et al., 2009) and P. billcollinsi
(Boundenga et al., 2015; Krief et al., 2010; Liu et al., 2010, 2016); and
three non-Laverania species – P. ovale- (Kaiser et al., 2010;
Liu et al., 2010), vivax- (Kaiser et al., 2010; Liu et al., 2010,
2014) and malariae-like (Kaiser et al., 2010; Liu et al., 2010)
parasites (putative nomenclature was proposed by Rayner et al., 2011, and used in
the present review). All four chimpanzee subspecies are naturally infected
with all known chimpanzee Laverania parasites and with at least one
of the non-Laverania parasites (Fig. 1a). Western lowland gorillas
(Gorilla gorilla gorilla) also naturally harbour three parasite
species belonging to the Laverania subgenus, i.e. P. praefalciparum, P. adleri and P. blacklocki (Liu et al.,
2010, 2016; Prugnolle et al., 2010), and two non-Laverania species,
i.e. P. vivax- (Liu et al., 2014) and ovale-like parasites
(Mapua et al., 2015) (Fig. 1b). A P. praefalciparum, or
falciparum-like, sequence (an undistinguishable sequence) was
also detected in Cross River gorillas (Gorilla gorilla diehli)
(Prugnolle et al., 2010), and P. vivax-like parasites were detected in eastern
lowland gorillas (G. b. graueri) (Liu et al., 2014). Despite
significant search efforts (861 samples tested by Liu et al., 2010, 2014),
natural infections of wild-living bonobos (Pan paniscus) have not
been reported so far (Fig. 1).
Before large-scale screenings on wild great ape populations were carried
out, the natural prevalence of malaria parasites in some chimpanzee and
gorilla populations was suspected to be high given the frequent detection
in sporadic blood or tissue samples (Kaiser et al., 2010;
Rich et al., 2009) as well as in faecal samples (Krief
et al., 2010; Prugnolle et al., 2010) from wild-living chimpanzees (all four
subspecies) and western gorillas. This was confirmed when prevalence levels
of Plasmodium spp. infection in wild apes were estimated using
detection rates from larger sets of faecal samples. Parasites were clearly
found to be endemic in the four chimpanzee subspecies and in lowland
gorillas (G. g. gorilla and G. b. graueri), with, according to
different studies, estimated prevalence levels ranging from 32 % to
48 % for P. t. ellioti, P. t. troglodytes, P. t. schweinfurthii and G. g. gorilla, in which faecal detection rates were corrected
for the sensitivity of the diagnostic test, sample degradation and redundant
sampling (Liu et al., 2010);
15.42 % for P. t. troglodytes and 21.28 % for G. g. gorilla faecal detection rates (Boundenga et al., 2015); and 33 % for
P. t. verus, in which the point prevalence rate was based on the proportion of
positive individuals tested by faecal detection (De Nys et al.,
2013, 2014). The vast majority of parasites harboured by AGAs belong to the
Laverania clade with non-Laverania strains rarely
found (Boundenga
et al., 2015; Kaiser et al., 2010; Liu et al., 2010; De Nys et al., 2013,
2014). The specific prevalence rates of P. vivax-like parasites in
chimpanzees (P. t. troglodytes and P. t. schweinfurthii) and
lowland gorillas (G. g. gorilla and G. b. graueri) seem to
range from 4 to 8 %, close to the infection rates in endemic human
populations (Liu et al., 2014). Co-infection with
two or more Plasmodium parasite species is prevalent (Krief
et al., 2010; Liu et al., 2010), e.g. present in 55 % of positive chimpanzee samples
tested by Liu et al., (2010). Bear in mind that these prevalence
rates are likely to represent underestimates due to the lower sensitivity of
faecal testing compared to blood testing (Liu
et al., 2010, 2014). In some chimpanzee and gorilla communities, no
malaria parasites were detected so far (Boundenga
et al., 2015; Liu et al., 2010, 2014), which could be the result of the
relatively low sensitivity of faecal detection combined with the small sample
size (Liu et al., 2014). Additionally, low
prevalence or absence of malaria parasites in certain communities could also
be explained by environmental factors – for example, factors that lead to a scarcity
of efficient vectors or demographic factors such as variations in host
density.
Until the discovery of other Laverania parasites, P. reichenowi was known as the closest relative of P. falciparum (Escalante
and Ayala, 1994; Escalante et al., 1995). Consequently, it was the first
great ape Plasmodium species to be molecularly characterised. A
number of phylogenetic analyses have led to various hypotheses on the origin
of the human P. falciparum: (1) one is the co-speciation hypothesis, in which the two Plasmodium species diverged from a
common ancestor at the same time as the chimpanzee and human lineages
diverged, about 6 to 10 million years ago (Escalante
and Ayala, 1994; Escalante et al., 1995; Hayakawa et al., 2008; Hughes and
Verra, 2010); and (2) another is the hypothesis of a more recent chimpanzee origin
through a single host transfer of P. reichenowi from chimpanzee to
human. The latter theory was supported by the low genetic polymorphism of
P. falciparum which was fully included into the broader genetic diversity of
malaria parasite lineages, which the authors collectively considered as
forming the species P. reichenowi (Prugnolle
et al., 2010; Rich et al., 2009). However, recent broad-scale
investigations based on the detection of malaria parasite DNA
(mitochondrial, nuclear and apicoplast sequences) in faecal samples of wild
AGA populations resulted in the genetic characterisation of a wide array of
other Plasmodium species. This showed that the entire diversity of
human-derived P. falciparum sequences is encompassed by the gorilla
P. praefalciparum clade (Liu et
al., 2010; Sundararaman et al., 2013) and led to the substantial indication
that P. falciparum originated from a relatively recent zoonotic
transmission of P. praefalciparum from gorillas to humans (Liu et al., 2010).
As far as non-Laverania parasites are concerned, many questions
remain on their evolutionary origins and the phylogenetic relationships between the parasites hosted by
non-human primates (NHPs) and those hosted by humans. Phylogenetic analyses initially suggested that
P. vivax originated in Asia from an ancestral macaque
Plasmodium species (Escalante
et al., 2005; Mu et al., 2005). P. simium, a New World monkey
parasite, has also been designated as a potential ancestor of P. vivax given their high genetic similarity, which is suggestive of a recent
host transfer between New World monkeys and humans, although the direction
of this cross-species transmission remains uncertain (Escalante
et al., 2005; Tazi and Ayala, 2011). Finally, the near fixation of the
Duffy-negative phenotype in Sub-Saharan human populations, which confers
resistance against P. vivax, supports the hypothesis of an African
origin of this parasite with positive selection of the Duffy negativity
through long-term exposure (Carter, 2003). The P. vivax
strains found in captive AGAs are genetically distinct from those circulating
in humans (Prugnolle et al., 2013). They include
the monophyletic lineage formed by the human P. vivax parasites
in their diversity, but they lack host specificity amongst the AGAs they
infect, i.e. P. t. troglodytes, P. t. ellioti, P. t. schweinfurthii, G. g. gorilla and G. b. graueri (Liu
et al., 2014). This supports the idea that the human P. vivax
developed from within a Plasmodium species which also infected
African apes and that all present human P. vivax parasites
originated from an ancestor which spread out of Africa (Liu et al., 2014). For P. malariae- and
ovale-like parasites, larger-scale investigations of infections
in wild NHPs together with phylogenetic analyses are still needed to clarify
the evolutionary relationship of these parasites with human strains.
Transmission of AGA malaria parasitesVectors
It is well established that mosquitoes are responsible for the transmission of
malaria between humans. These malaria vectors belong to the
Anopheles genus (An.), of which approximately 40 species
(out of 430) are thought to be competent for malaria parasite transmission
(CDC, 2012). They have been studied extensively and mapped in
detail (Sinka
et al., 2010). The ecology of mosquito species, including habitat and host
preferences, varies and determines their importance as a vector in given
habitats (Sinka
et al., 2010). For instance, An. gambiae is considered as one of
the most efficient vectors in open landscapes in Sub-Saharan Africa (Coetzee,
2004; Sinka et al., 2010). Additionally, An. moucheti, also
highly anthropophilic, is entirely restricted to forested habitats and
considered a significant vector of human malaria in this type of environment (Sinka
et al., 2010).
Until very recently, not a single vector responsible for AGA malaria parasite
transmission had been identified. Early experiments had shown the
susceptibility of some known human malaria vector species to P. reichenowi (Blacklock and Adler, 1922; Collins et al., 1986), with a notable
exception being An. gambiae. Bray (1958a) had managed to infect An. gambiae with the formerly
called P. schwetzi; however, the low levels of sporozoites in the
salivary glands had suggested that these were not the natural vectors.
Another experiment succeeded in infecting humans with P. schwetzi
via Anopheles balabacensis bites (Contacos et al., 1970).
It is mainly since the discovery of the gorilla origin of P. falciparum that the question of AGA malaria vectors has been increasingly raised
due to the concern for future zoonotic transfers of malaria
parasites from NHPs to humans and thus the importance of identifying species
that can act as bridges (Verhulst et al., 2012). At the
present time, several studies have thus specifically searched for mosquito
species responsible for the transmission of malaria parasites between
chimpanzees or gorillas in their natural habitat. The first study tested
female Anopheles (N=100) captured at chimpanzee (P. t. schweinfurthii) natural nesting and feeding sites in Uganda, but it did not
detect any Plasmodium parasites (Krief et al., 2012). The failure of detection
might, however, have been linked to the small number of specimens tested. A
second study, which screened a larger number of female Anopheles (N=1070) captured in areas hosting AGA populations in Gabon, found DNA
from P. praefalciparum in one An. moucheti and from
P. vivax-like parasites in one An. moucheti and one
An. vinckei (Paupy et al.,
2013). Finally, the analysis of 2415 female Anopheles captured in the same
areas in Gabon led to the discovery of both chimpanzee and gorilla
Laverania and non-Laverania parasites in An. vinckei, An. moucheti and An. marshallii (Makanga et al., 2016), with the highest
prevalence rate in An. vinckei (N=35). The detection of sporozoites
in their salivary glands confirmed their role in natural transmission. These
mosquito species appeared to be non-host-specific (they were shown to feed
on humans and to carry malaria parasites from rodents, bats and antelopes)
and were thus unlikely to be responsible for the host specificity of
Laverania parasites.
It is important to note that the prevalence rates of different mosquito species
might differ between geographical sites, suggesting a variability of vectors
depending on the
investigated sites.
For example, mosquito trappings
performed in and around the forest of the Taï National Park (TNP) in
Côte d'Ivoire to study the distribution of mosquito genera in habitats
varying from human settlements to a primary forest only identified one single
Anopheles in the primary forest (at a camp site), whereas they were
abundant in the neighbouring villages (Junglen
et al., 2009). Mosquitoes of the Uranotaenia genus, however,
were dominant in the primary forest but rarely found in other areas.
This suggests that the malaria vectors responsible for the transmission
of malaria parasites in the resident chimpanzee population differ from those
transmitting parasites in humans and in other AGA populations. Obviously,
other mosquito genera and other dipterans should not be excluded as
possible vectors. Biting midges (genus Culicoides), for example,
transmit Hepatocystis spp., which are bat and monkey malaria
parasites (Blanquart and Gascuel,
2011), and are known to be abundant in the TNP (personal observation).
Interspecies transmission
Since the discovery of AGA malaria parasites, the marked similarities they
share with those infecting humans have raised the question of whether
the exchange of these parasites between AGAs and humans could occur,
experimentally and/or naturally.
Early experiments involving captive chimpanzees and humans (volunteers
and/or neurological patients for former therapeutic purposes) demonstrated
that, for some strains, the infection of humans with chimpanzee parasites, or
vice versa, is possible. This was the case for the chimpanzee-borne
P. rodhaini (probably a P. malariae-like strain) (Bray,
1963; Rodhain and Dellaert, 1943; Rodhain, 1940), the human-borne
P. malariae (Bray, 1960, 1963; Garnham et al., 1956),
the chimpanzee-borne P. schwetzi (probably P. ovale- or
vivax-like strains) (Bray, 1963; Coatney, 1968; Contacos et al.,
1970; Rodhain and Dellaert, 1955) and the human-borne P. vivax
(Bray, 1963; Garnham et al., 1956; Rodhain, 1939). In contrast, attempts to
transfer the Laverania species P. reichenowi from
chimpanzees to humans failed (Blacklock and Adler, 1922; Rodhain, 1939). The
marked host specificity of P. reichenowi might be due to the human
loss of the common primate Sia (sialic acid) N-glycolylneuraminic acid, which is the
preferred target of P. reichenowi for erythrocyte binding, as
opposed to P. falciparum, which prefers the precursor of the
N-glycolylneuraminic acid, the Sia N-acetylneuraminic acid (Martin et al.,
2005). In addition, the transfer of P. falciparum to chimpanzees only seemed
possible in splenectomised individuals, or limited to the liver or
to a very low parasitaemia in intact individuals (Bray, 1963; Taylor et al.,
1985).
For certain human malaria parasites, natural (non-experimental) transmission
to AGAs seems to occur. De facto, early experimental attempts at infecting
chimpanzees with P. falciparum gave poor results, but captive
bonobos (Krief et al.,
2010) and chimpanzees (Duval
et al., 2010; Ngoubangoye et al., 2016) living in areas of high human
P. falciparum endemicity have been found to be infected with these
parasites. These infections were probably acquired from humans (Rayner et al., 2011). There is, however, no
information on the viability of such infections and thus the potential for
vector-based transmission between apes. Similarly, P. malariae,
which has never been detected in wild bonobos so far, was found in captive
individuals (Krief et
al., 2010), and a P. ovale strain, identical to the human
P. ovale variant type, was found in a captive chimpanzee (Duval et al., 2009).
As for natural zoonotic transmission of AGA parasites to humans, it appears
from the phylogenetic relationships between known malaria parasites that,
historically, ape Plasmodium (P. praefalciparum) have
managed to naturally cross the species barrier at least once (Liu et al.,
2010). This, together with some of the old experimental results reported
above, instinctively leads to the assumption that natural zoonotic transfers
of AGA malaria parasites might still occur, leading to new host switches or
just to regular transmission events in the same manner that a P. knowlesi infection in humans originates from regular zoonotic transfer
events from Southeast Asian macaques (Lee et al., 2011; Sharp et al., 2013).
Interestingly, the AGA malaria parasite vectors found by
Makanga et al. (2016) are mosquito species
that also seem to feed on other mammalian species, including humans. They
could thus, in theory, act as vectors for interspecies transmissions. Studies
led in Cameroon (Sundararaman et al., 2013) and Gabon (Délicat-Loembet et
al., 2015) searched for evidence of zoonotic transfers of ape
Laverania species by testing large numbers of human blood samples
(N=1402 and N=4281) from people living in the vicinity of chimpanzee
and gorilla populations with high Laverania prevalence rates. No ape
parasites (Laverania or non-Laverania) were detected in
these samples, implying that zoonotic transfers might be rare events.
There is, however, current evidence that cross-species transmission from
wild apes to humans of the non-Laverania species P. vivax
is ongoing. Since wild chimpanzees in West and Central Africa were confirmed
hosts of P. vivax-like strains, it was hypothesised that wild apes
could act as a natural reservoir (Rayner et
al., 2011), thereby explaining the occasional infection of travellers
despite the low prevalence of P. vivax in the human populations of
these regions (Broderick
et al., 2015; Culleton et al., 2008; Gautret et al., 2001; Mühlberger et
al., 2004; Skarbinski et al., 2006). Moreover, a P. vivax-like
parasite isolated from a traveller coming back from a Central African forest
was recently shown to cluster with the AGA isolates outside of the human
lineage, confirming the occurrence of cross-species transmissions (Liu et al., 2014; Prugnolle et
al., 2013). This is supported by the fact that P. vivax-like
parasite DNA was found in an anthropophilic mosquito species,
Anopheles moucheti (Paupy et
al., 2013). Given the close resemblance to their human counterparts and
past experimental findings, it is likely that, similarly to P. vivax, zoonotic transfers of P. ovale- and malariae-like
parasites from chimpanzees also take place. It would be useful to
characterise more of these parasites in order to search for evidence of such
transmissions (Sundararaman et al., 2013).
Transmission of host-specific parasites between different AGA genera has
only, so far, been observed in captivity, where great ape species cohabit
closely, e.g. transmission of Laverania parasites from chimpanzees
to gorillas and vice versa (Ngoubangoye
et al., 2016). Cross-species transmission between AGAs and other NHPs sharing
their habitat is probably exceptional. So far, the only published finding
showing such potential is that of P. praefalciparum detected in a single
captive greater spot-nosed monkey, Cercopithecus nictitans (Prugnolle et al., 2011). Yet, during a
subsequent study which tested blood from a significant number of wild
spot-nosed monkeys (N=292), only Hepatocystis spp. and one
Plasmodium sp. previously described in birds and lizards were
found (Ayouba et al., 2012). P. vivax has
also specifically been searched for in blood samples (N=998) from 16 Old
World monkey species; however, with the exception of Hepatocystis
spp., no malaria parasites were found (Liu et al.,
2014). Similar results were obtained after screening specimens from six
monkey species from Uganda (N=102) (Thurber et al., 2013) and
from three monkey species in the TNP, Côte d'Ivoire (N=38) (S. Calvignac-Spencer, personal communication, 2015). Hepatocystis represents
one of the numerous genera of malaria parasites, just like the genus
Plasmodium, which seems to be paraphyletic to Hepatocystis
(Martinsen et al., 2008). Hepatocystis parasites comply with a broad pattern of host-specificity, with distinct lineages
that specialise on monkeys and bats (Ayouba et al., 2012; Schaer et
al., 2013). So far, there is no published evidence of transmission of NHP
malaria parasites such as Hepatocystis spp. to AGAs. Moreover,
amongst 30 chimpanzee carcasses from the TNP (Côte d'Ivoire) that were
tested for malaria parasites, no Hepatocystis spp. were found (S. Calvignac-Spencer, personal communication, 2015). Interestingly, however, a liver
sample from one of these chimpanzees tested positive for a saurian
Plasmodium parasite.
Extrinsic and intrinsic determinants of Plasmodium infection
Extrinsic factors, such as environmental factors (habitat type and climate),
group size and host density as well as possibly behavioural factors, such
as sleeping site choice, most likely influence the exposure to malaria
parasites and thus the frequency of infections in specific AGA communities.
However, only very few studies so far have investigated their effects, which
remain largely unknown.
The influence of monthly rainfall on the probability of Plasmodium
detection in chimpanzee and gorilla faecal samples was tested in a single
study so far, but no significant effect was found (Boundenga et al., 2015). Yet, it was
shown that rainfall can affect Plasmodium parasite prevalence in
the vectors of AGA malaria parasites, with increased prevalence and thus
exposure during the rainy season (Makanga et
al., 2016). Prevalence in mosquitoes was also shown to vary with canopy
height, with higher rates at mid-height compared to ground and canopy level.
There is very limited information on the effects of host group size and
sleeping site, mainly drawn from studies on New World primates. In contrast
to the encounter-dilution effect, which predicts a decreased risk of
exposure to an infected vector with increasing group size (Krebs et al.,
2014; Mooring and Hart, 1992), malaria prevalence in New World primates was
found to increase with average sleeping group size, suggesting that malaria
might be a significant cost associated with larger group sizes (Davies et al., 1991; Nunn and
Eckhard, 2005). However, data on primate malaria and group size
are still too scarce to draw any firm conclusions. Sleeping site selection in
these primates also seems to play a role in malaria infection rates by
reducing the risk of attack by the vector (Nunn and
Eckhard, 2005). In chimpanzees, two studies looked at malaria and sleeping
sites indirectly by capturing mosquitoes at natural nest sites. While one
study failed to detect any patterns of association between the choice of nest site
and mosquito densities (Koops et al., 2012),
the second study found patterns compatible with mosquito avoidance
(Krief et al., 2012). Chimpanzees seemed to
choose nest sites in drier and higher places compared to their feeding
sites, and these sites were indeed characterised by lower densities of
Anopheles mosquitoes. Mosquitoes were also less abundant in sites
with more nests (Krief et al., 2012).
Moreover, an experimental study showed that tree species preferred by
chimpanzees for nest building might be selected due to their repulsive
properties against flying arthropods (Samson et al.,
2013).
As for intrinsic determinants of malaria infection in AGAs, based on data
from human malaria, one would expect factors such as age, pregnancy status,
co-infections, immune status and genetics to influence susceptibility
to infection as well as levels of parasitaemia and the expression of clinical
malaria.
As a matter of fact, patterns strikingly similar to those found in human
populations from malaria endemic areas have been observed in wild AGAs.
Faecal detection rates of Plasmodium infection were found to be
higher in younger individuals of P. t. verus (De Nys et al., 2013) and G. g. gorilla
(Mapua et al., 2015) as well as in pregnant
females of P. t. verus (De
Nys et al., 2014).
This probably reflects changes in the frequency of new
infections and/or in parasite densities induced by variation in
susceptibility to these parasites due to age and pregnancy status.
These fluctuations in susceptibility might be the result of immune
protection acquired in adults through constant exposure to the parasites
(Doolan et al., 2009) and, during pregnancy, a
combination of immunological and hormonal changes, together with the ability
of P. falciparum-infected erythrocytes to sequester in the placenta
(Rogerson et al., 2007). However, variations in the exposure
to the vectors and, thus, to malaria parasites might also occur and play a
role in these observed patterns. It was, for instance, demonstrated in
humans that pregnant women are more attractive to Anopheles
mosquitoes compared to non-pregnant women, probably for physiological
reasons, e.g. increased exhaled breath and abdominal temperature (Ansell
et al., 2002; Lindsay et al., 2000). Additionally, possible
behavioural changes, such as nesting habits, that could lead to increased
exposure to the vectors should be considered.
In addition, it would be judicious to keep in mind that in a given host, malaria
parasites are part of a parasite community, whereas we use the term parasite
in its broad ecological sense, designating micro- and macroparasites
(Faure, 2014). This implies that, just
like in an ecosystem, multiple and complex interactions between these
parasites and with their host (i.e. their environment) take place;
this can also partly dictate the presence of parasite species or their
densities in a specific host, as opposed to a single host–parasite
relationship (Pedersen
and Fenton, 2007; Rynkiewicz et al., 2015), and perhaps explain (at least
partially) the patterns of malaria parasite detection observed in AGAs. As an
illustration, Telfer et al. (2010) actually demonstrated, for the
first time in a natural population of field vole (Microtus agrestis), that co-infection with
several microparasites explains more of the variation in the risk of infection
compared to other factors such as host condition, e.g. age, and exposure
risk, e.g. season (Telfer et al., 2010).
Co-infection interactions can take place via competition for shared
resources, e.g. nutrients, physical site of infection, or the immune system
of the host, e.g. cross-reactivity or immunosuppressant pathogens such as HIV (Graham,
2008; Pedersen and Fenton, 2007; Rynkiewicz et al., 2015). Resource-mediated
parasite interactions would be likely to occur between malaria parasites and
other haemoparasite species which target the same cells, like erythrocytes.
For instance, Babesia microti infection in
Microtus agrestis negatively affects host susceptibility to
Bartonella spp. infection and vice versa (Telfer et al., 2010). Likewise, a
negative association between Plasmodium spp. and Babesia
spp. has been recently observed in wild Malagasy primates
(Propithecus verreauxi), where high Babesia spp. infection
levels in younger individuals also seem to confer protection against
Plasmodium spp. infections, possibly via shared resource
competition (Springer et al., 2015). Inhibition of
Plasmodium cynomolgi infection by Babesia microti was also
previously described in experimental rhesus macaques (van
Duivenvoorde et al., 2010; Voorberg-vd Wel et al., 2008). In humans, there
is evidence of a pathological interaction between the immunosuppressant HIV
virus and Plasmodium, with HIV-seropositive people being at
increased risk of Plasmodium infection and the development of clinical
malaria (Patnaik
et al., 2005; Whitworth et al., 2000). Malaria parasites and various
helminth species have also been shown to interact in humans, with either an
antagonistic or beneficial relationship, possibly mediated by cross-reactive
immune responses (Faure, 2014). In order
to fully understand the patterns of malaria infection in AGAs, it would thus
be necessary to also explore and take into account co-infections with
parasites that are likely to interact.
Genetic factors may additionally play a role in conferring a certain degree
of resistance to infection by malaria parasites or clinical disease. Genetic
regulation of the immune response by certain alleles encoding the major
histocompatibility complexes I and II, several interleukins, the CD40 ligand,
the nitric oxide synthase, and interferon α and γ receptors
has been associated with protection against severe malaria in humans (Hill
et al., 1991; Kwiatkowski, 2005). Mutations leading to variants of
erythrocyte characteristics also provide protection against parasite
invasion – for example, the Duffy negativity for P. vivax; glycophorin A,
B and C deficiency for P. falciparum; and haemoglobin E
(β-globin gene mutation) – or confer protection against clinical
malaria, such as haemoglobin S (sickle haemoglobin) and C
(both β-globin gene mutations), glucose-6-phosphate dehydrogenase
(G6PD) deficiency and α+-thalassemia (defective production of
α globin) (Kwiatkowski, 2005; Williams, 2006). To date, there is very
little information available for AGAs. The diversity of the G6PD and β-globin genes has been examined in chimpanzees, but so far no mutations
appear to have been selected for malarial resistance (MacFie et al., 2009;
Verrelli et al., 2006). Moreover, Liu et al. (2014) sequenced samples from
134 AGAs but did not find any Duffy-negative phenotypes.
Pathogenicity of malaria parasites in African great apes
None of the published studies have focused on the consequences of malaria
infection on wild great apes' health so far, and the information collected from
experimental or captive conditions is rather limited. Observations made
during early experiments on the clinical course of malaria in captive
chimpanzees, i.e. mainly the lack of noticeable illness behaviour during
various infections with human and possibly chimpanzee strains, led Rodhain (1936, 1940) to believe that, in natural conditions, chimpanzees do not
suffer significantly from malaria and that they can be subject to
asymptomatic chronic infections lasting several months. On one occasion, he
reported a double inoculation with P. falciparum and P. vivax in a young individual, which had induced a febrile state with loss of
appetite but only mildly (Rodhain, 1936). The only
indications on the duration of infections also come from early
experimental studies. The infections seemed to be able to last for at least several
months, with periods as long as 5 months recorded for P. reichenowi
and P. schwetzi (Garnham et al., 1956)
and over 1 year for P. malariae (Rodhain, 1940).
Reports from sanctuaries or other facilities hosting captive individuals are
rare and variable. In Japan, two captive chimpanzees were found to be
chronically infected with P. malariae, without showing any evidence
of illness for 30 years (Hayakawa et al.,
2009). P. falciparum infection of captive bonobos in the Democratic
Republic of the Congo were also not associated with apparent clinical signs or
increased body temperature (Krief et al., 2010).
Moreover, a young chimpanzee newly transferred to a sanctuary after
6 years of captivity in an urban setting developed severe anaemia and
hyperthermia concomitant with a high P. reichenowi parasitaemia
(Herbert et al., 2015). The latter case would suggest
that infection with certain malaria parasites can, under certain
circumstances, be detrimental for chimpanzees' health. However,
extrapolating these observations to the wild is difficult as stress related
to captivity could also influence the effect of such infections. Moreover,
whether individuals were initially naïve to the Plasmodium
strains they were diagnosed with (whether human or chimpanzee derived) is
generally undetermined (strains novel to a chimpanzee's immune system would
be more likely to cause illness). One publication also reported the death of
a 1-year-old captive chimpanzee infected with P. reichenowi; however,
given the extremely poor and stressful conditions this individual was kept
in, whether malaria effectively played a significant role in the fatal
outcome is questionable (Tarello, 2005).
In contrast, pathogenicity has never been demonstrated in AGAs living in
natural conditions so far. The general impression given by the above-mentioned
elements, as well as by the absence or rarity of reported
malaria-like clinical signs or death associated with infection in
individuals observed on a sometimes daily basis (wild habituated or captive
individuals) (e.g. Kaiser et al., 2010), is that wild-living chimpanzees are
mostly undisturbed by malaria infections, or that at least the clinical
impact and related discomfort are generally mild enough to be invisible to
observers' eyes when not specifically searched for. Also, as pointed out by
Rayner et al. (2011), the very high prevalence rates of malaria parasite
infections observed in numerous wild chimpanzee and gorilla populations
indicate that severe outcomes are probably rather rare.
As young and pregnant chimpanzees seem to be more susceptible to malaria
infection, it is possible that they are also more prone to suffer from the
biological consequences of infection and to develop clinical malaria, as
seen in humans (Doolan et al., 2009). Healthy and
non-pregnant adults probably benefit from a certain degree of acquired
clinical immunity, but it would be reasonable to think that malaria
infection would start having some level of detrimental effect when the
host's ability to control parasite density is diminished. Higher levels of
blood parasitaemia are likely to at least induce higher degrees of anaemia
(Kotepui et al., 2015; Oni
and Oguntibeju, 2006), which in turn could cause morbidity or even
mortality. Anaemia is actually recognised as one of the major causes of
morbidity and mortality related to malaria in young children and pregnant
women (Ekvall et al., 2001). Moreover, in humans,
malaria during pregnancy can have deleterious consequences for the
pregnancy's
outcome and the infant's health (Desai et
al., 2007; Guyatt and Snow, 2001). Deleterious effects on pregnancy outcome
and/or infant health would mean a general impact on population reproductive
success and fitness, thereby shaping population dynamics.
Further investigation of the relationship between malaria parasites and
chimpanzees in natural conditions is important to understand the
significance of malaria infection for wild great ape populations' health,
and it can serve as a model to understand the host–parasite relationship in human
populations, where malaria is believed to have acted as an important driver
of recent evolution (Carter
and Mendis, 2002; Sabbatani et al., 2010). Wild habituated AGA communities
are ideal targets to pursue investigations on illness related to malaria
infection. In a more indirect way, studying the AGA malaria parasites'
genes, which might play a role in pathogenesis, can also provide valuable
information. For example, the very diverse var genes, found only in
Laverania parasites, are unique to P. falciparum in humans
and play an important role in its pathogenesis by coding for proteins which
mediate the cytoadherence of infected erythrocytes (Smith et al., 2013). Analysis of var
and var-like gene sequences from human and ape Laverania
species showed that many characteristics of these genes are conserved across
the different Laverania species and that these evolved well before
the emergence of all the Laverania species
(Larremore et al., 2015). In addition, the
var2csa genes, known to be associated with the adherence of
P. falciparum-infected erythrocytes to the placenta and placental
malaria in humans, have also been identified in P. reichenowi and
P. gaboni (Pacheco
et al., 2013; Trimnell et al., 2006). However, the question of whether the
expression of var genes is also associated with pathogenicity
in AGAs remains open. Some significant differences have also
been found between var genes from P. gaboni and var genes from
P. falciparum and P. reichenowi, suggesting potential
disparities in their biology.
Conclusions and perspectives
It is apparent that, to date, most of the knowledge on wild AGA malaria is
concentrated around parasite diversity, distribution and phylogenetic
relationships with malaria parasites infecting other species, humans in
particular. Indeed, the majority of research studies ultimately aim at
identifying potential animal reservoirs with ongoing zoonotic transmission
as well as assessing the risk of emergence of new malaria strains in human
populations (by, inter alia, exploring the origins of the current human malaria
parasites). Many gaps, however, still need to be filled in order to achieve
these objectives – e.g. further exploration of vectors, of phylogenetic
relationships of ape-derived P. malariae and P. ovale
strains with human strains, and of zoonotic infections in humans living close
to AGA communities.
The epidemiological determinants and the effects of malaria infection in
wild AGAs have been left largely unexplored. This also leaves many questions
that need to be addressed in order to further understand the basic epidemiology and biology
of malaria parasites in AGAs. What are the influences of other known
intrinsic and extrinsic factors affecting human malaria on infection,
parasite density or, perhaps, disease in AGAs? Are there visible patterns of
infection in specific populations? How frequently and for how long are
individuals infected? What are the pathological consequences of malaria
infection? Does infection have a significant impact on great ape health?
Could the impact of malaria be sufficiently subtle to be misleading? Is this just
like SIV (simian immunodeficiency virus)
infection in chimpanzees, which was believed for many years to be
rather trivial for their health (non-pathogenic), but whose actual
deleterious impact on their health only became apparent recently when examined at
the level of an entire community (Keele et
al., 2009; Rudicell et al., 2010)? Does malaria play a role in sociality,
demographics, population dynamics and general fitness? Are there any
indications of selective pressures exerted by malaria on AGA evolution or
development of resistance? These are just a fraction of the multiple
questions that still need to be addressed. Using faecal samples has proven
suitable and efficient, not only to address broad-scale questions such as
those on the geographic distribution and genetic diversity of great ape
malaria parasites, but also to address small-scale epidemiological questions
which might, in comparison, require a higher (finer-scale) resolution and
thus more sensitive screening (De Nys et al., 2013, 2014). As non-invasive
methods to study pathogen infections and monitor health parameters
(e.g. body temperature, inflammation markers and hormone levels) are now
available, attempts to answer some of these questions are actually
conceivable. In the meantime, further exploration, improvement and testing
of non-invasive methods need to be pursued in order to enhance sensitivity,
facilitate the interpretation of results and broaden research possibilities.
This is a review article; therefore, no data were
obtained.
The authors declare that they have no conflict of
interest.
Acknowledgements
This research was funded by the Deutsche Forschungsgemeinschaft (LE 1813/10-1) and has profited from numerous discussions in the Sociality and Health in Primates (FOR2136) research group.
Edited by: K. Mätz-Rensing
Reviewed by: L. Duval and one anonymous referee
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