CHAPTER
3
Invasion of the Body Snatchers:
The Diversity and Evolution
of Manipulative Strategies in
Host–Parasite Interactions
Thierry Lefèvre,* Shelley A. Adamo,†
David G. Biron,‡ Dorothée Missé,*
David Hughes,§,k,1 and Frédéric Thomas*,},1
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66
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Contents
3.1. Introduction
3.2. How Parasites Alter Host Behaviour
3.2.1. Parasitic effects on host neural function
3.2.2. Proteomics and proximate mechanisms
3.3. A Co-Evolutionary Perspective
3.3.1. Exploiting host-compensatory responses
3.2.2. Facultative virulence
3.4. The (River) Blind Watchmaker
3.5. Concluding Remarks
References
Abstract
Parasite-induced alteration of host behaviour is a widespread transmission strategy among pathogens. Understanding how it works is
an exciting challenge from both a mechanistic and an evolutionary
perspective. In this review, we use key examples to examine the
* Génétique et Evolution des Maladies Infectieuses, UMR CNRS/IRD 2724, Montpellier, France
{
{
§
}
k
1
Department of Psychology, Dalhousie University, Halifax, Canada
PIAF, UMR 547 INRA/Université Blaise-Pascal, Clermont-Ferrand, France
Department of Organismal Biology, University of Harvard, Cambridge, MA, USA
Institut de recherche en biologie végétale, Département de sciences biologiques Université de Montréal,
Montréal, Québec, Canada
School of Biosciences, University of Exeter, Exeter, UK
Both authors contributed equally
Advances in Parasitology, Volume 68
ISSN 0065-308X, DOI: 10.1016/S0065-308X(08)00603-9
2009 Elsevier Ltd.
All rights reserved.
#
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Thierry Lefèvre et al.
proximate mechanisms by which parasites are known to control the
behaviour of their hosts. Special attention is given to the recent
developments of post-genomic tools, such as proteomics, for
determining the genetic basis of parasitic manipulation. We then
discuss two novel perspectives on host manipulation (mafia-like
strategy and exploitation of host compensatory responses), arguing
that parasite-manipulated behaviours could be the result of compromises between host and parasite strategies. Such compromises
may occur when collaborating with the parasite is less costly for
the host in terms of fitness than is resisting parasite-induced
changes. Therefore, even when changes in host behaviour benefit
the parasite, the host may still play some role in the switch in host
behaviour. In other words, the host does not always become part
of the parasite’s extended phenotype. For example, parasites that
alter host behaviour appear to induce widely disseminated changes
in the hosts’ central nervous system, as opposed to targeted
attacks on specific neural circuits. In some host–parasite systems,
the change in host behaviour appears to require the active participation of the host (e.g., via host immune-neural connections).
Even when the change in host behaviour results in clear fitness
benefits for the parasite, these behavioural changes may sometimes
be produced by the host. Changes in host behaviour that
decrease the fitness costs of infection could be selected for,
even if these changes also benefit the parasite.
3.1. INTRODUCTION
Animal behaviour is complex. The dance of a honeybee, the dawn chorus
of birds, the group hunting of wolves or the cognitive behaviour of toolusing crows and chimps are examples that illustrate this point. Organisms
choose where to go, when and where to forage, how and with whom to
mate, and whether or not to invest in parental care of the resultant
offspring. The study of animal behaviour is a one of the oldest and most
established of the natural sciences and remains one of the more accessible
arenas of science for the general public through natural history programming. However, the behaviour of parasites is usually neglected. This is
not to say that parasites do not behave but only that their behaviour has
been considered simple and not particularly interesting. Most parasites
are phage or bacteria whose behaviour consists of habitat choice. For
multi-cellular parasites such as the liver fluke, Fasciola hepatica, a wider
range of behaviours exist such as choosing an optimal location, choosing
to mate or whether to self-fertilise, and when to reproduce. But it is hardly
behaviour on par with the courtship dance of a bower bird.
However, in some host–parasite systems parasites induce complex
behavioural changes in their host. For example, some parasitoid wasps
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
47
coerce spiders into spinning ‘sleeping bags’ suspended from branches,
thus providing a safe pupating site for the wasp (Eberhard, 2000). Crickets,
ants and other insects infected with hairworms (nematomorpha) or nematodes dive into water, allowing the aquatic parasite to exit their body and
mate (Maeyama et al., 1994; Thomas et al., 2002a). Rats infected with
Toxoplasma develop a fatal attraction for cats, increasing parasitic transmission to their next host (Berdoy et al., 2000). These are just some of the many
examples of the dramatic behavioural impact parasites can have on their
host. Parasites can also have less extreme changes on host behaviour such
as shifts in foraging, location or activity (reviewed in Moore, 2002). If the
change in host behaviour benefits the parasite (e.g., by increasing transmission to a new host) we suggest that the parasite has been selected to
produce this behavioural change in its host. In this case, the altered behaviour of the host is a phenotype of the parasite and is controlled by the
parasite’s genes. Therefore, it is part of the parasite’s extended phenotype.
This concept of the extended phenotype was first developed by
Richard Dawkins (1982). In his book, The Extended Phenotype, he argues
that a gene can produce a phenotype that extends beyond the body of a
single individual, if such a phenotype results in increased transmission of
the gene to the next generation. A phenotype is usually defined as a trait
of the individual organism such as eye or flower colour. The extended
phenotype perspective includes abiotic structures such as birds’ nests.
Birds’ nests increase the fitness of bird genes; therefore, a nest is an
example of an extended phenotype. Parasitic manipulation of host behaviour leading to increased transmission of the parasite’s genes is another
example of an extended phenotype (Dawkins, 1982, 1990, 2004).
The extended phenotype perspective is not a theory, but is merely a ‘way
of viewing the facts’. We know that the presence of parasites alters the
behaviour of their hosts in ways that range from simple to dramatic. Behaviour is a phenotype and has a genetic basis. In infected hosts either parasite
genes or host genes are responsible for its altered behaviour. The extended
phenotype perspective merely postulates that in some host–parasite interactions the parasite genes are responsible for the aberrant behaviour. This
parasite-centred view has been relatively ignored in evolutionary ecology
(Poulin, 2007), sometimes for good reason (Thomas et al., 2005, see Box 3.1).
In this review we will examine the mechanisms by which parasites are
known to control the behaviour of their hosts. Despite years of study, we
lack unequivocal evidence that parasite genes cause host behavioural
change. Thus we advocate that future studies should use a more sophisticated approach than has been previously adopted (e.g., the incorporation
of more molecular techniques for determining the genetic basis of manipulation). We review the advances that have been made in the field using
proteomic tools. We also explore the degree to which host behavioural
changes could be a compromise between host and parasite strategies.
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Thierry Lefèvre et al.
BOX 3.1 Brief history of parasitic manipulation
Cram (1931) and Van Dobben (1952) first suspected that parasites
might have the ability to modify the behaviour of their hosts in a way
that increases their transmission efficiency. The pioneering works of
Bethel and Holmes on acanthocephalan worms (1973, 1974, 1977) significantly advanced this hypothesis. However, it was only with the
publication of Richard Dawkins’ book entitled ‘The Extended Phenotype’
(1982, see main text for details) that the field of parasitic manipulation
acquired a conceptual framework. Henceforth, parasitologists considered that host alteration may be regarded as the expression of the genes
of the parasite in the host phenotype and that some of the parasite’s
genes are selected for their effect on host phenotype.
Dawkins’ way to view facts has led researchers to consider all
behavioural changes observed in an infected organism as beneficial
for the parasite. However, not all parasite-induced alterations of the
host phenotype necessarily enhance parasite transmission. Some
alterations can be adaptations of the hosts to defend themselves
against parasites (e.g., behavioural fever, Moore, 2002). Moreover,
changes might be pathological consequences of infection, adaptive to
neither host nor parasite. These are termed ‘boring by-products’ of
infection (Dawkins, 1990; Edelaar et al., 2003; Webster et al., 2000).
Robert Poulin (1995) wrote an important paper that helped
address the issue of adaptive versus non-adaptive host behavioural
changes by highlighting the need for a clear approach to interpreting
potential cases of parasitic manipulation (Poulin, 1995). Four criteria
were proposed in order to consider changes as adaptive for the parasite in the context of transmission: complexity, purposiveness of
design (i.e., conformity between a priori design and the host phenotypic alterations), convergence (similar changes in several independent lineages) and fitness consequences. Poulin’s (1995) paper marked
the start of a new period during which many studies taking into
account these recommendations appeared in the scientific literature.
It also marked a departure from purely adaptationist reasoning.
This paper has nonetheless left one point obscure: should we consider the changes that are pathological consequences of infection and
are coincidentally beneficial for the parasite as adaptations? In his
paper, Poulin (1995) distinguished between ‘true’ parasite manipulation and ‘by-products’ of infection (the latter being changes coincidentally beneficial that may be a fortuitous payoff of other adaptations).
This point faced criticism since it is almost impossible to distinguish
between the primary focus of historical selection and concomitant
effects on transmission (see Lefèvre and Thomas, 2008; Moore, 2002
and Thomas et al., 2005 for details).
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
49
Two scenarios of parasitic manipulation are presented (i.e., the exploitation of host compensatory responses and ‘mafia-like manipulation’)
in which the parasite-manipulated behaviours are not necessarily an
illustration of the extended phenotype and can benefit both partners.
As has been common in the field of parasitic manipulation of host
behaviour, our discussion will span multiple fields. For parasitologists we
aim to provide key information regarding parasite-mediated activities;
for behavioural ecologists, whose focus is behaviour, we want to highlight
the myriad forms of manipulation and how we are beginning to understand the proximate mechanisms underlying them; for evolutionary
biologists, who are interested in trait evolution and co-evolutionary processes, we want to review this exciting field for them; and for applied
scientists who either deal with human or veterinary diseases or use
parasites as biocontrol, we want to emphasise that behavioural studies
are highly relevant to applied fields.
3.2. HOW PARASITES ALTER HOST BEHAVIOUR
Most research on parasitic manipulation of behaviour has focused on the
effects of parasites on host neural function. This emphasis is reasonable
given that behaviour is controlled by the central nervous system (CNS).
Below we review two examples in which parasites are known to alter the
neural function of their host (for more examples see Adamo, 1997, 2002;
Klein, 2003; Moore, 2002; Thomas et al., 2005). These examples illustrate
that the mechanisms mediating host behavioural change are often complex. Parasites do not manipulate the brain of their hosts the way a
puppeteer controls a puppet, delicately tweaking only those neural
circuits responsible for specific behaviours. Instead parasites appear to
slug the host’s brain with a number of diffuse and widespread effects,
some of which induce changes in host behaviour. We continue by
showing how post-genomic era approaches can lead to great advances
in our understanding of the proximate mechanisms mediating host behavioural change. In particular we discuss the recent parasito-proteomics
studies of infected host brains. We end with a discussion of the importance
of this new technique, especially in light of the complex mechanisms that
are typically involved in host behavioural change.
3.2.1. Parasitic effects on host neural function
3.2.1.1. Rabies
Rabies is often cited as a classic example of parasitic manipulation of host
behaviour (Klein, 2005). As in other cases of parasitic manipulation, the
parasite is thought to commandeer the neural circuits that regulate
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Thierry Lefèvre et al.
specific host behaviours. Changing these specific host behaviours benefits
the parasite. Below we examine the evidence for this scenario.
Rabies is caused by RNA viruses of the genus Lyssavirus (Rupprecht
et al., 2002). Rabies virus infects the CNS of its host and induces profound
behavioural changes (Rupprecht et al., 2002). Some of these behavioural
changes (e.g., aggressiveness and hyper-salivation) increase viral transmission (Hemachudha et al., 2002). The rabies virus docks with specific
neural receptors suggesting specificity in its attack on the host’s CNS
(Hemachudha et al., 2002). Once inside a neuron, the rabies virus alters
ion homeostasis and synaptic physiology, both of which alter neural
transmission (Dhingra et al., 2007). This effect may explain why neural
transmission is abnormal in some brain regions in rabies (Fu and Jackson,
2005). Interestingly, changes also occur in neurons that do not appear to
be directly infected with the virus, suggesting that the virus can also
influence neural function indirectly (Fu and Jackson, 2007). Neuronal
damage is minimal during the period in which an infected animal is
transmitting the virus (i.e., prior to severe motor symptoms, Scott et al.,
2008). Therefore, the virus has the tools to selectively alter host behaviour
by manipulating specific target neurons without killing them.
Nevertheless, the rabies virus does not selectively alter either behaviour or neural function. For example, rabies virus induces more than just
aggression and hyper-salivation in its host. Infected hosts also suffer from
a lack of appetite and have reduced co-ordination (Ruppecht et al., 2002).
These behaviours are unlikely to enhance viral transmission and demonstrate that the effects of rabies are not entirely selective. Although nonspecific effects might be expected from any virus that infects the brain,
behaviours that are important for enhanced transmission (e.g., increased
aggression) would be expected to occur in all hosts of a manipulative
parasite. However, not all animals infected with rabies are aggressive
(Hemachudha et al., 2002). Most rabies victims can be divided into two
groups based on their behavioural symptoms: encephalitic (furious) and
paralytic (dumb) (Hemachudha et al., 2002). Aggressive behaviour is
observed only in encephalitic rabies. In paralytic rabies, the host gradually loses motor control and consciousness (Hemachuda et al., 2003).
Although these symptoms would increase the host’s contact with predators, this is unlikely to lead to increased viral transmission because the
rabies virus is fragile and non-bite transmission of rabies (e.g., via mucous
membranes) is rare (Rupprecht et al., 2002). In paralytic rabies, the lack of
aggression coupled with the animal’s decreased mobility and increased
lethargy probably results in reduced viral transmission. Nonetheless,
paralytic rabies is not a rare form and about 25% of infected humans
have paralytic rabies (Hemachudha et al., 2002). The paralytic form of
rabies is also common in dogs (Laothamatas et al., 2008), even though
dogs are the co-evolved host for the canine variant of the virus
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
51
(Hemachudha et al., 2003). Differences in the genetic code of the virus are
not responsible for the differences in the behaviour of infected hosts
(Hemachudha et al., 2003). For example, Hemachudha et al. (2002) report
a case in which the same rabid dog induced paralytic rabies in one victim
and encephalitic rabies in the other. Therefore, the rabies virus induces
aggression in only some of its hosts, despite the likely importance of this
behaviour for viral transmission. Moreover, the virus also induces other
behaviours in its host that probably impede viral transmission.
The rabies virus does not selectively target those brains areas responsible for regulating aggression (Laothamatas et al., 2008). For example, in
humans, the amygdala (a part of the limbic system) and the orbitofrontal
cortex regulate aggression (Coccaro et al., 2007). Although the virus reliably strikes the limbic system, the virus does not infect these structures
exclusively, or even preferentially (Laothamatas et al., 2003). During
rabies in humans, magnetic resonance imaging (MRI) shows changes in
brainstem, cerebellum, hippocampi (and other parts of the limbic system,
including the amygdala), hypothalamai, deep and sub-cortical white
matter, and deep and cortical gray matter (Laothamatas et al., 2003). The
amygdala is thought to be critical for the regulation of aggression in nonhuman mammals too (Kandal et al., 1991). Nevertheless, the rabies virus
does not target the amygdala in non-human hosts either. For example,
rabid dogs have high concentrations of rabies viral messenger RNA
(mRNA) in the basal ganglia, caudate nucleus, cerebellum, hippocampus
(and other parts of the limbic system), medulla, mid-brain, pons, thalamus and the frontal, parietal, occipital and temporal lobes of the cerebrum
(Laothamatas et al., 2008). Interestingly, the distribution of virus in the
brain is the same in both paralytic and encephalitic forms of rabies
(Laothamatas et al., 2003, 2008; Smart and Charlton, 1992). The limbic
system is attacked in both forms, but only results in increased aggression
in encephalitic rabies.
The evidence above demonstrates that the simplest postulated mechanism of manipulation—that is, that the rabies virus selectively infects and
manipulates those brain areas that regulate aggressive behaviour in mammals—is false. How then does rabies produce enhanced aggression in a
large portion of its hosts? Hemachudha et al. (2002) suggest that the
immunological reactions provoked by the virus (see Hooper, 2005) play
a role in changing host behaviour. For example, cytokines, released during the body’s response to the rabies virus, could alter limbic system
function (Hemachudha et al., 2002) and this may increase aggression.
Increases in some cytokines can increase aggressiveness (Kraus et al.,
2003), supporting this hypothesis. In fact, immune reactions alone can
produce aggressive behaviour. For example, during auto-immune disorders such as paraneoplastic limbic encephalitis, the immune system
damages the limbic system (Osborne, 1994) and this induces aggressive
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Thierry Lefèvre et al.
behaviour in some patients (Tardiff, 1998). Therefore, the effect of the
virus on host behaviour may depend on the host’s immune response
(Hemachudha et al., 2002), and this would explain why the effects of the
virus on host behaviour are variable. However, Charlton et al. (1984)
found no significant change in the aggressiveness of rabid skunks given
the immunosuppressant cyclophosphamide compared to controls
(Charlton et al., 1984). Rabies virus replication was increased by cyclophosphamide treatment (i.e., brains of treated animals had higher viral
titres), demonstrating that cyclophosphamide did suppress host immune
responses (Charlton et al., 1984). Recently, Laothamatas et al. (2008) found
that dogs with paralytic rabies had a more robust immune response to the
virus and showed greater cytokine release in all brain areas (including the
limbic system) than dogs with encephalitic rabies, the opposite to what
would be predicted if cytokines are driving the increase in aggression.
Moreover, MRI studies revealed greater brain abnormalities in the nonaggressive paralytic dogs than in encephalitic dogs, even though dogs
with paralytic rabies have less viral mRNA expressed in their brains
compared to dogs with encephalitic rabies (Laothamatas et al., 2008).
These results suggest that the robust immune response of some animals
may prevent the virus from altering host behaviour, leading to the paralytic form of rabies. Further studies are required to clarify the role of the
host’s immune system in the production of aggressive behaviour during
rabies.
The Borna disease virus (BDV) is another virus of the CNS that induces
aggressive behaviour in its host (Klein, 2003). However, similar to rabies,
not all infected animals show an increase in aggressive behaviour
(Carbone et al., 1987). As with rabies, BDV infects multiple brain areas,
including the limbic system (see Klein, 2003). In BDV infections, the virus
replicates first in the hippocampus (Carbone et al., 1987). However, by the
time behavioural symptoms such as aggressive behaviour occur, the virus
has widely disseminated throughout the brain (Carbone et al., 1987).
Moreover, the behavioural symptoms occur at the same time that the
host’s immune response produces widespread inflammation in the
brain (Carbone et al., 1987). Therefore, the immune system may play a
role in inducing host aggression in both rabies and BDV.
3.2.1.2. Gammarids, parasites and serotonin
Unravelling the connections between parasites, neural transmission and
altered host behaviour may be easier to discover when the host is an
invertebrate rather than a vertebrate host (Helluy and Holmes, 2005). In
this section we review the mechanisms used by different parasites to alter
the behaviour of small crustaceans known as gammarids. Gammarids are
attacked by parasites that often have complex life cycles in which the
parasite requires transmission to a vertebrate host to complete its
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
53
development (e.g., Kennedy, 2006). In some of these systems, once the
parasite reaches the infective stage, the parasitised host shows changes in
escape behaviour resulting in an increased likelihood that the infected
gammarid will be consumed by the parasite’s appropriate vertebrate host.
Some of these changes probably occur because of parasite-induced
changes in the host’s serotonergic neural signalling system (Table 3.1).
For example, when the acanthocephalan Polymorphus paradoxus
reaches the infective stage, its gammarid host, Gammarus lacustris,
changes its escape behaviour. The parasitised host swims towards
the light and clings to the nearest solid material when disturbed, instead
of swimming away from the light and burrowing into the mud as
non-parasitised controls do. Some of the same behaviours induced by
the presence of the parasites can be mimicked by injections of serotonin.
Injections of other biogenic amines, such as octopamine or dopamine, do
TABLE 3.1 Relationship between presence of the parasite, increased host phototaxis
and serotonin immunohistochemistry
Effect of
parasite on
phototaxis
Effect of
serotonin on
phototaxis
Gammarus
Microphallus
insensibilis
papillorobustus
(within CNS)
Increase
Increaseb
Decrease
TGN
smaller
Gammarus
lacustris
Increase
Increase
Increase in
varicosities
Increase
Increase
Increase
None
Increase
None
None
Increase
None
Gammarid
(Host)
Gammarus
pulex
Gammarus
roeseli
a
Effect of
parasite on
serotonin
staining of
the CNSa
Parasite
Polymorphus
paradoxus
(within
haemocoel)
Pomphorhynchus
laevis (within
haemocoel)
Polymorphus
minutus
(within
haemocoel)
Pomphorhynchus
laevis (within
haemocoel)
The study on G. lacustris examined only the ventral nerve cord. All other studies examined staining in the
cerebral ganglion
cited in Helluy and Thomas (2003); TGN, tritocerebral giant neuron.
Notes: See text for references.
b
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Thierry Lefèvre et al.
not induce these behaviours. Serotonin haemolymph concentrations need
to be raised by approximately three orders of magnitude above physiological levels to produce the effect. The need for such large concentrations
may suggest that serotonin is acting through the CNS and not via peripheral
receptors (Helluy and Holmes, 1990).
Immunohistochemical staining for serotonin reveals that infected animals have the same number of serotonergic cells as controls. However, the
fine structure of the neurons differs in infected animals. Infected individuals have an apparent increase in the serotonergic staining of structures
thought to be axon terminals (Maynard et al., 1996). This result could signal
a change in the amount of serotonin released into the synapse. For example,
reduced serotonin release would result in a build up of serotonin within the
axon terminal of the neuron, creating the increase in staining. Regardless of
whether serotonin release is increased or decreased, Maynard et al.’s (1996)
results suggest that the parasite has an impact on the host’s serotonergic
system. How the parasite exerts this effect is unknown.
A related gammarid, Gammarus pulex, is infected with the acanthocephalans Polymorphus minutus and Pomphorhynchus laevis. Hosts infected
with P. minutus show a reversed geotaxis compared to control animals
and swim towards the surface. This change in behaviour probably
increases the chance that the host comes in contact with its definitive
host, a bird. P. minutus does not induce phototaxis. P. laevis, however,
changes the photophobia of G. pulex into phototaxis, resulting in the host
swimming towards the light. This behaviour makes the host more vulnerable to fish predation, the definitive host for this species. Injections of
serotonin induce phototactic behaviour but do not change geotactic behaviour in G. pulex. As in G. lacustris, large doses of serotonin are needed to
induce the effect (Tain et al., 2006).
Immunohistochemical staining of the cerebral ganglion for serotonin
shows no gross differences between hosts infected with either parasite
and uninfected controls (e.g., in the number of serotonergic cells). Tain
et al. (2006) also found no difference in the gross anatomy of the giant
serotonergic neuron found in the brain (i.e., the tritocerebral giant neuron
(TGN)) in infected animals. However, hosts infected with P. laevis had
enhanced immunohistochemical staining for serotonin, but there was no
difference in the intensity of staining when they were infected with
P. minutus. Therefore, staining for serotonin only increased when host
phototactic behaviour increased (Tain et al., 2006).
A related gammarid (Gammarus roeseli) is also infected with the parasite
P. laevis. However, in this gammarid, P. laevis does not induce phototactic
behaviour, even though injections of serotonin can induce phototaxis
in G. roeseli. G. roeseli shows no change in serotonergic staining when
infected (Tain et al., 2007), supporting the hypothesis that altered serotonin
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
55
signalling is causally involved in the change in host phototactic behaviour
(Table 3.1).
The gammarid Gammarus insensibilis is parasitised by the trematode
Microphallus papillorobustus. In the previous examples, the parasites
remain outside of the CNS (Kennedy, 2006). In this system, however,
the trematode lodges within the host’s protocerebrum, a part of the
cerebral ganglion and CNS. The host is not debilitated, but instead
shows altered responses to specific sensory stimuli such as light. Once
the parasite reaches the infective stage, the host shows aberrant escape
behaviours making it more likely to be consumed by the parasite’s definitive host, a bird (Helluy and Thomas, 2003).
Immunohistochemical staining for serotonin reveals profound
changes between infected and control animals. For example, the TGN is
stunted in infected animals suggesting some degeneration of serotonergic
fibres. Such a change in neural architecture is very likely to produce
decreases in serotonergic signalling within the CNS because of likely
decreases in the synaptic field. However, some parts of the brain showed
no change in serotonergic staining, suggesting that the effect was specific
to certain neurons or brain areas. The parasite does not appear to influence the TGN by mechanically squeezing it; the giant neuron and the
parasite reside on opposite sides of the brain (Helluy and Thomas, 2003).
How the parasite alters the morphology, and presumably the function, of
this serotonergic neuron remains unknown. Unfortunately the role the
TGN plays in the host’s escape behaviour is also unknown.
Taken together, the results (Table 3.1) suggest that parasites can influence gammarid phototactic behaviour by altering some aspect of the
serotonergic system. However, the results are puzzling because it is
unclear whether an increase or decrease in serotonin release within the
CNS is responsible for altering phototactic behaviour. Immunohistochemical studies do not provide a reliable estimate of neural activity or
neurotransmitter release (see de Jong-Brink and Koene, 2005) especially
when looking across different physiological states (e.g., parasitised vs
non-parasitised, see Zitnan et al., 1995).
The observation that injections of serotonin into the haemocoel induce
increased phototaxis suggests that enhanced serotonergic release is
responsible for the increase in phototaxis. However, all the parasites
except M. papillorobustus remain outside the host’s CNS (Kennedy,
2006). It is unlikely that the parasites residing in the haemocoel can
produce enough serotonin to induce phototaxis (Holmes and Zohar,
1990; Tain et al., 2006; Thomas et al., 2005). Most likely the parasites induce
the host’s CNS to produce serotonin. Ponton et al. (2006a) found that one
of the enzymes important for serotonin production, aromatic amino acid
decarboxylase (Cooper et al., 2002), was not visible on two-dimensional
(2D) electrophoresis gels of the brains of G. pulex parasitised with
56
Thierry Lefèvre et al.
P. minutus, but was visible on gels of uninfected brains. Ponton et al.
(2006a) interpreted their results as indirect evidence of an increase in
aromatic acid decarboxylase activity. However, these data are equivocal,
and like immunohistochemical staining, can also support the hypothesis
that serotonin production has declined. Moreover, in vertebrates the decarboxylation step is not the rate-limiting step in the synthesis of serotonin; the
rate-limiting step is governed by tryptophan hydroxylase and the availability of tryptophan (Cooper et al., 2002). Given that the amount of L-tryptophan in the crayfish brain is typically more than five times greater than that
of 5-hydroxytryptophan (Rodriguez-Sosa et al., 1997) the situation is probably similar in crustaceans. Therefore if serotonin production is increased
in parasitised brains, there should be a concomitant increase in tryptophan
and tryptophan hydroxylase concentrations. More direct measurements
of serotonin synthesis in parasitised brain tissue are needed (e.g., using
high-performance liquid chromatography (HPLC)). Pharmacological
(e.g., Tierney et al., 2004) and electrophysiological studies would also be
helpful in determining how altered serotonergic activity is related to the
increase in phototaxis.
As with rabies, the mechanisms mediating behavioural manipulation
of infected gammarids are complex. For example, host immune responses
may also play a role in producing the change in host behaviour (Tain et al.,
2007). As in rabies, the manipulative parasites (e.g., P. laevis, Cézilly and
Perrot-Minnot, 2005) induce other behavioural changes in their host, in
addition to phototaxis. This effect may reflect the fact that serotonin
signalling is involved in many behaviours in crustaceans (e.g., see
Weigner, 1997). Most of the studies in Table 3.1 suggest widespread
alterations in the functioning of the serotonergic system, not a selective
strike on specific neural circuits.
3.2.2. Proteomics and proximate mechanisms
Post-genomic technology promises to revolutionise many fields in biology by providing enormous amounts of genetic data from non-model
organisms. Proteomics is a case in point and promises to bridge the gap
between our understanding of genome sequences and cellular behaviour;
it can be viewed as a biological assay or tool for determining gene
function (for explanations of genomic terms see Box 3.2). Parasito-proteomics is the study of the reaction of the host and parasite genomes through
the expression of the host and parasite proteomes (genome-operating
systems) during their complex biochemical cross-talk (Biron et al., 2005a,b).
Proteomics, with the ability to investigate the translation of genomic information, offers an approach to study the global changes in protein expression
of the host CNS caused by parasites. Fig. 3.1 outlines the essential steps to
any proteomics study of parasite manipulation of host behaviour.
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
57
BOX 3.2 Glossary for the ‘omics’ tools use in parasite-proteomics
Genome: The full complement of genes carried by a single (haploid)
set of chromosomes. The term may be applied to the genetic information carried by an individual or to the range of genes found in a given
species.
Genomics: It is the study of an organism’s genome and the use of
the genes. It deals with the systematic use of genome information,
associated with other data, to provide answers in biology, medicine
and industry.
Immunochemistry: A branch of chemistry that involves the study
of the reactions and components on the immune system. Various
methods in immunochemistry have been used in scientific study,
from virology to molecular evolution.
Interactome: The interactome is the whole set of molecular interactions in cells. It is usually displayed as a directed graph. When
spoken in terms of proteomics, it refers to protein–protein interaction
network (PPI) or protein network (PN).
Gene knock-out: This is a genetic technique in which an organism
is engineered to carry genes that have been made inoperative. Gene
knock-in is similar to knock out, but instead it replaces a gene with
another instead of deleting it.
Neuropeptidome: In recent years, the introduction of highly sensitive mass spectrometry paved the way for rapid screening of the
neuropeptide profile (neuropeptidome) even to the single cell level,
in species as small as insects.
Neuropeptides: Neuropeptides are the most structurally diverse
messenger molecules that influence a wide range of physiological
processes. They are present in all Metazoa that have developed a
nervous system.
Proteome: The term proteome was first used in 1995 and has been
applied to several different types of biological systems. A cellular
proteome is the collection of proteins found in a particular cell type
under a particular set of environmental conditions such as exposure to
hormone stimulation. It can also be useful to consider an organism’s
complete proteome. The complete proteome for an organism can be
conceptualised as the complete set of proteins from all of the various
cellular proteomes. This is very roughly the protein equivalent of the
genome. The term ‘proteome’ has also been used to refer to the collection of proteins in certain sub-cellular biological systems. For example,
all of the proteins in a virus can be called a viral proteome.
(continued )
58
Thierry Lefèvre et al.
BOX 3.2 (continued )
Proteomics: The large-scale study of proteins, particularly their
structures and functions. This term was used to make an analogy
with genomics, and is often viewed as the ‘next step’ but proteomics
is much more complicated than genomics.
RNAi: Small fragments of double-stranded RNA whose sequence
matches the transcribed sequence of a gene. This technique is used to
decrease the expression of a gene by disabling the transcribed mRNA.
Transcriptome: Is the whole set of mRNA species in one or a
population of cells.
Transcriptomics: Techniques to identify mRNA from actively
transcribed genes.
Biological treatments for a chosen host-parasite system
From laboratory strains and/or from field sampling collection, samples pooled from at least five host CNS
categories and three for the parasite. Each individual used for the experiment need to be the same biological age.
Parasite categories
Host CNS categories
(i) Non-parasitised host as control
(ii) Non-parasitised host exposed to a mechanical treatment
(i.e. category used to reveal the specific host proteome
response to manipulative process.
(iii) Non-manipulated host before manipulation
(iv) Manipulated host during manipulation
(v) Non-manipulated host after manipulation
(i) Non-manipulative parasite before manipulation
(ii) Manipulative parasite
(iii) Manipulative parasite post-manipulation
Choose one or more proteomic tools (2-DE, 2-DIGE, SELDI-TOF, etc.)
to reveal the differential expression of host and parasite proteomes.
Analysis of proteomics results with specialised software and
identification of candidate proteins by mass spectrometry.
Directly on
the host CNS
Categorisation of results according to the chart
Constitutive
Non-specific
Specific
Induced
Indirectly on
the host
CNS
FIGURE 3.1 Flowchart for the study of manipulative strategies with parasito-proteomics.
CNS, central nervous system; 2-DE, two-dimensional gel electrophoresis; 2D-DIGE,
two-dimensional-difference gel electrophoresis; SELDI-TOF, surface enhanced laser
desorption/ionization time-of-flight.
3.2.2.1. Pioneer parasito-proteomics studies on parasitic manipulation
Pioneer proteomics studies have been carried out on six arthropod
host–parasite systems: two orthoptera–hairworm systems, two insect
vector–pathogen systems and two gammarid–parasite systems. Table 3.2
summarises the proteomics tools used and the proteome responses for the
TABLE 3.2 Synopsis of ‘parasito-proteomics’ studies on parasitic manipulation
Host–parasite association
Proteomics tools
Host species
Parasite species
Separation
of proteins
IP scale;
Mw scale
Identification
of proteins
Nemobius
sylvestris (Bosc)
(Orthoptera,
Gryllidae)
Paragordius
triscupidatus
(Dufour)
(Nematomorpha,
Gordiidae)
Spinochordodes tellinii
(Nematomorpha,
Spinochordodidae)
2-DE
pH 5–8;
19–122 kDa
2-DE
Plasmodium berghei
(Haemosporida,
Plasmodiidae )
Trypanosoma brucei
brucei
(Kinetoplastida,
Trypanosomatidae)
Microphallus
papillorobustus
(Trematoda,
Microphallidae)
Polymorphus minutus
(Acanthocephala,
Polymorphidae)
Meconema
thalassinum
(De Geer)
(Orthoptera,
Tettigoniidae)
Anopheles gambiae
(Giles)
(Diptera,
Culicidae)
Glossina palpalis
gambiensis
(Diptera,
Glossinidae)
Gammarus
insensibilis
(Amphipoda,
Gammardiae)
Gammarus pulex
(Amphipoda,
Gammardiae)
Proteome response
In head host
In parasite
TNSA
PPSLMP
TNSA
PPSLMP
References
MS, MS/MS,
Sequencer
902
3.8
729
5.0
Biron et al.,
2006
pH 5–8;
19–122 kDa
MS
566
16.8
763
5.0
Biron et al.,
2005
DIGE
pH 3–10;
14–100 kDa
MS, MS/MS
1400
0.9
No data
No data
Lefèvre et al.,
2007a
2-DE
pH 3–10;
20–122 kDa
MS
816
2.9
No data
No data
Lefèvre et al.,
2007b
2-DE
pH 3–6;
20–122 kDa
MS
556
12.9
No data
No data
Ponton et al.,
2006a
2-DE
pH 3–6;
20–122 kDa
MS
838
8.1
No data
No data
Ponton et al.,
2006a
Notes: 2-DE, two-dimensional gel electrophoresis; DIGE, difference gel electrophoresis; IP, isoelectric point; Mw, molecular weight; TNSA, total number of proteins spots analysed; PPSLMP,
percentage of protein spots potentially linked to manipulative process; MS, mass spectrometry.
60
Thierry Lefèvre et al.
host CNS of each host–parasite association. In each study, multiple treatments were carried out to control for potential confounding effects and to
exclude the proteins that are non-specific to the manipulative
process making it easier to find the proteins potentially linked with host
behavioural changes.
Initially, proteomics was used to explore the mechanisms in host CNS
underlying the suicidal behaviour of crickets and grasshoppers when
manipulated by their hairworms (Biron et al., 2005c, 2006). Two
orthoptera-hairworm systems have been investigated: (i) the cricket,
Nemobius sylvestris, parasitised by the hairworm, Paragordius tricuspidatus;
(ii) the long-horned grasshopper, Meconema thalassinum, parasitised by
the hairworm, Spinochordodes tellinii (details on the background biology
can be found in Thomas et al., 2002a). Because hairworm parasites are
very big (i.e., worm length exceeds that of the host by 3–4 times) and
because they are located in the body cavity, it is very easy to separate the
host CNS and the parasite, thereby allowing the simultaneous study of
both proteomes without the risk of contamination.
Proteomics studies suggest that adult hairworms produce host
mimetic proteins and manipulate behaviour with them. These proteins
are from the Wnt family suggesting a direct action of the hairworms on
the host’s CNS that can lead directly to an alteration of the host behaviour
or indirectly via a host genome response. The analysis of the head proteomes revealed that the percentage of proteins potentially linked to the
hairworm manipulative process is higher for M. thalassinum compared to
N. sylvestris (see Table 3.2) (Biron et al., 2006). For the hairworms, some of
the proteins potentially linked to the manipulative process are the same
(see Table 3.2). The altered functions are similar for both orthopteran
species except for some families of proteins that are involved in geotactic
behaviour, in protein biosynthesis and in recovery following an infection
being only differentially expressed in M. thalassinum (Fig. 3.2). In the brain
of manipulated orthoptera, differential expression of proteins specifically
linked to neurogenesis, the visual process, the geotactic process, and
neurotransmitter activities have been observed (Fig. 3.2). The altered
physiological compartments are similar for both nematomorph species
except for some families of proteins implicated in endopeptidase inhibition, in protein folding and in transcriptional regulation that are only
expressed in S. tellinii (Fig. 3.3; Biron et al., 2006).
Insect vectors (e.g., mosquitoes carrying malaria) are often manipulated to increase encounter rates with vertebrate hosts in ways that
enhance the pathogen’s transmission (Hurd, 2003; Lefèvre and Thomas,
2008; Lefèvre et al., 2006; Moore, 1993; Rogers and Bates, 2007). Two
parasito-proteomics studies have been performed on such systems:
(i) Anopheles gambiae-Plasmodium berghei (Lefèvre et al., 2007a); (ii) Glossina
papalis gambiensis-Trypanosoma brucei brucei (Lefèvre et al., 2007b).
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
61
100
Percentage (%)
80
60
40
20
0
N. sylvestris
M. thalassinum An. Gambiae
Orthoptera
Synaptic transmission
Molecular chaperone
Cytoskeleton
Immunity defences
Apoptosis inhibitor activity
Protein biosynthesis
Cell proliferation
Miscellaneous
G. palpalis
gambiensis
Diptera
Neurotransmitter synthesis
Metabolism
Transcriptional regulation
Transposase activity
Proteolysis & peptidolysis
Geotactic behaviour
DNA binding
G. insensibilis
G. pulex
Amphipoda
Signalling
Glycolysis
Vision
Transferase activity
Cell adhesion
Recovery following an infection
Endopeptidase activity
FIGURE 3.2 Proportion of identified proteins linked to a biological process and
differentially expressed during the manipulative process in head proteomes of the
arthropod hosts for six host–parasite systems. (i) the cricket, Nemobius sylvestris,
parasitised by the hairworm, Paragordius tricuspidatus; (ii) the long-horned grasshopper,
Meconema thalassinum parasitised by the hairworm, Spinochordodes tellinii;
(iii) Anopheles gambiae-Plasmodium berghei; (iv) Glossina papalis gambiensisTrypanosoma brucei brucei; (v) Gammarus insensibilis parasitised by the trematode,
Microphallus papillorobustus; (vi) Gammarus pulex parasitised by the ancantocephalan,
Polymorphus minutes.
These studies provide evidence that the pathogens can alter the head
proteome of their insect vectors (see Table 3.2; Fig. 3.2). Some of the
altered protein families are similar between dipterans (i.e., sugar metabolism, signal transduction and heat shock response) (see Fig. 3.2). An
alteration in energy metabolism has been observed in the CNS of both
parasitised hosts (Lefèvre et al., 2007a,b). Finally, these parasitoproteomics studies suggest that P. berghei and T. b. brucei can alter host
apoptosis pathways and sugar metabolisms.
Several parasites such as trematodes, cestodes and acanthocephalans
alter the behaviour of their intermediate host to enhance trophic transmission (Moore, 2002; Thomas et al., 2005). To date we have proteomes of
two Amphipoda-parasite systems that were also discussed in Section
3.2.1.2: (i) Gammarus insensibilis parasitised by the trematode, Microphallus
62
Thierry Lefèvre et al.
100
Percentage (%)
80
60
40
20
0
S. tellinii
P. tricuspidatus
Nematomorpha
R and S of Neurotransmitters
Regulation of apoptosis
Signalling
Protein binding
Protein biosynthesis
Cytoskeleton
Transcriptional regulation
Nucleic acid binding
Endopeptidase inhibition
Metabolism
Protein folding
Miscellaneous
FIGURE 3.3 Proportion of identified proteins linked to a biological process and
differentially expressed during the manipulative process in proteomes of two nematomorph species for two orthoptera-hairworm systems. (i) the cricket, Nemobius sylvestris, parasitised by the hairworm, Paragordius tricuspidatus; (ii) the long-horned
grasshopper, Meconema thalassinum parasitised by the hairworm, Spinochordodes
tellinii.
papillorobustus; (ii) Gammarus pulex parasitised by the acanthocephalan,
Polymorphus minutes (Table 3.2). M. papillorobustus has a complex life
cycle, including snails as first intermediate hosts, gammarids as second
intermediate hosts and various sea- and shorebirds as definitive hosts. The
life cycle of P. minutus displays broad ecological similarities with
M. papillorobustus since it also involves a gammarid as intermediate host
and aquatic birds (mainly ducks) as definitive hosts. Metacercariae
of M. papillorobustus are always encysted in the brain of G. insensibilis,
while cystacanths of P. minutus are located in the body cavity of G. pulex.
Both parasites manipulate the behaviour of their gammarid intermediate
host, making them more likely to be eaten by predatory definitive hosts at
the water surface. M. papillorobustus induces a positive phototaxis and a
negative geotaxis to alter the behaviour of its intermediate hosts while
P. minutus induces only a negative geotaxis (Cézilly et al., 2000; Helluy, 1984).
For the two gammarid species, the proteome of G. insensibilis displayed
a slightly stronger response to the manipulative process caused by its
trematode compared to G. pulex manipulated by its acanthocephalan
(see Table 3.2, Fig. 3.2). The altered functions are similar for both gammarid
species except for some families of proteins only expressed in G. insensibilis:
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
63
those involved in visual process, DNA binding, cell proliferation and
metabolism. The proteomic results (Ponton et al., 2006a) obtained for
G. insensibilis–M. papillorobustus corroborated previous studies suggesting
a major role of serotonin in the expression of the aberrant evasive
behaviour (see Section 3.2.1.2).
It has been suggested that immune responses may secondarily affect
host nervous system functions and hence behaviour and it is increasingly
suggested that parasites could exploit host defence reactions in order to
manipulate host behaviour (see above; Adamo, 2002; Thomas et al., 2005).
The proteomics results have shown that arginine kinase is differentially
expressed in the brain of infected G. insensibilis and G. pulex compared to
uninfected individuals. This phosphotransferase is known to be one of the
regulating factors in nitric oxide (NO) synthesis (Mori and Gotoh, 2000).
NO is liberated during immunological reactions, but it also acts as
a neuromodulator. Thus, these proteomic results provide supportive
evidence for the hypothesis suggesting that parasites could exploit host
defence reactions in order to manipulate host behaviour.
3.2.2.2. Parasito-proteomics and parasite manipulation:
A bright future?
Parasito-proteomics studies have contributed to the discovery of candidate genes and new biochemical pathways potentially involved in parasitic manipulation. Future work should build upon this promising start.
We suggest some additional considerations to move this work forwards.
For instance, existing parasito-proteomics studies are missing: (i) the
insoluble proteome linked to the manipulative process; (ii) the neuropeptidome response; and (iii) the host proteome response in a molecular
weight (Mw) range of 20 kDa or less and a pH range 4 or less and 7 or
greater. In addition, functional analysis in association with behavioural
assays and interactome bioassays (see Box 3.2) will be necessary to confirm the involvement of the candidate proteins. Thus, a new integrative
approach is necessary to bridge the gaps in our knowledge of how
parasites manipulate their hosts (see Fig. 3.4).
Several new proteomics tools have been developed and can be used
in the understanding and the deciphering of the manipulative process.
For instance, SELDI-TOF can provide a complementary visualisation
technique to two-dimensional (2D) electrophoresis. SELDI-TOF is more
sensitive and requires smaller amounts of proteins than 2D electrophoresis (Bischoff and Luider, 2004; Issaq et al., 2002; Seibert et al., 2004). SELDITOF is most effective at profiling low Mw proteins (i.e., <20 kDa) and
permits a rapid comparison of the host CNS proteome for many treatments by taking into consideration many physiochemical characteristics
of proteins using SELDI protein chips with various chemical surfaces
(hydrophobic, cationic, anionic, hydrophilic and metal ion preventing)
64
Thierry Lefèvre et al.
Biological treatments for a host-parasite system
From laboratory strains and/or from field sampling collection, recuperation of at least four host
categories of individuals and three parasite categories obtained following behavioural assays.
Non-parasitized
hosts as control
Before manipulation
-Non-manipulated hosts
-Non-manipulative parasite
During manipulation
-Manipulated hosts
-Manipulative parasite
After manipulation
-Manipulated hosts
-Manipulative parasite
Proteomics tools used to reveal the differential expression
of host and parasite proteomes in one or more tissues.
Soluble and non-soluble proteins > 20 kDa
Soluble and non-soluble proteins ≤ 20 kDa
2D-DIGE and/or 2D-LC/MS
SELDI-TOF
Identification of candidate proteins with mass spectrometry tools (MS, MS/MS) and/or with a protein sequencer.
Functional analysis in synergy with behavioural assays to
determine the key role of the candidate proteins linked to the
manipulative process:
I. Microinjections
II. Immunochemistry
III. Suppression of the expression of the candidate proteins by
using the knock-out and/or the RNAi techniques.
Interactome bioassays:
I. Visualizing gene expression and protein
interactions with fluorescent proteins as GFPs
and new fluorescent protein variants.
II. By using bioinformatic tools, biochemical
classification of the protein-protein interactions
identified.
Some fundamental and applied perspectives
I. Measurement of the intensity of the host manipulation by a parasite within and between host populations.
II. Test the molecular convergence hypothesis for host-parasite systems showing similar host behavioural modifications.
II. Identification of biochemical signature linked to a particular habitat and/or environmental conditions.
IV. Test the hypothesis of local adaptations of the manipulative strategies.
FIGURE 3.4 New integrative approach to study the proximate mechanisms in any
host–parasite system. 2D-DIGE, two-dimensional-difference gel electrophoresis;
2D-LC/MS, 2 dimensional liquid chromatography/mass spectroscopy; GFP, Green
Fluorescent Protein; MS, mass spectroscopy; RNAi, small fragments of double-stranded
RNA; SELDI-TOF, surface enhanced laser desorption/ionization time-of-flight.
(Bischoff and Luider, 2004; Issaq et al., 2002; Sanchez et al., 2008; Seibert
et al., 2004). In the previous parasito-proteomics studies, no data were
obtained about these key molecules (i.e., peptides and neuropeptides)
influencing the physiological processes involved in the expression of
host behaviour. For the proteins with a Mw greater than 20 kDa, the
multi-dimensional liquid chromatography/mass spectrometry (LC/MS)
offers a promising alternative and complementary approach to 2D
electrophoresis for the analysis of complex protein mixtures. Multidimensional LC/MS has increased in popularity because this technique
is relatively straightforward, the available software is convenient to use
and once protein fractions are ‘spotted’ on matrix-assisted laser desorption/ionisation (MALDI) targets there are no time constraints on carrying
out further analysis for the protein identification (Brand et al., 2005;
Greibrokk et al., 2005). However, the 2D-difference gel electrophoresis
(2D-DIGE) remains a very efficient option for the analysis of the differential
expression of common proteins between different treatments.
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
65
3.2.2.3. Summary
The proximate mechanisms mediating changes in host behaviour are
complex. This complexity probably exists because these mechanisms
evolved from the mechanisms required for the survival of the parasite
within the host (see also Combes, 2005). Given the fortuitous nature of
evolution, it is not surprising that parasites influence host behaviour
using multiple methods (see Fujiyuki et al., 2005; Tomonaga, 2004). We
will need a greater understanding of parasito-proteomics, immune-neural
interactions (see Adamo, 2008; Dantzer et al., 2008) and a more neuroethological approach to understand how parasites manipulate their host’s
behaviour fully. This necessitates an increase in our own ‘crosstalk’ with
researchers investigating the proximate mechanisms of behaviour, such
as neuroimmunologists and neurobiologists.
BOX 3.3 The three main types of manipulation
A. Manipulation sensu stricto
Host behavioural alteration may be regarded as a compelling illustration of the extended phenotype (Dawkins, 1982), that is, the expression
of the parasite’s genes in the host phenotype. The extended phenotype
perspective thus postulates that in some host–parasite interactions the
parasite genes are responsible for the aberrant behaviour. In this view,
genes of the parasite are selected for their effect on host behaviour.
B. Exploitation of host compensatory responses
Host behavioural alteration may be regarded as a host response to
parasite-induced fitness costs. Parasites may affect fitness-related
traits in their hosts such as fecundity and survival in order to stimulate
host compensatory responses because these responses can increase
parasitic transmission. In this view, genes of the parasite are selected
for their pathological effects that induce a host compensatory
response. Since behavioural changes both mitigate the costs of infection for the host and meet the objectives of the parasite in terms of
transmission, natural selection is likely to favour all the genes involved
in this interaction.
C. Mafia like manipulation
Host behavioural alteration may be regarded as a forced collaboration. Parasites may select for collaborative behaviour in their hosts by
imposing extra fitness costs in the absence of compliance. The parasite
would be able to adopt a plastic strategy (i.e., facultative virulence)
depending on the level of collaboration displayed by the host. In this
view, genes of the parasite are selected for their ability to detect noncollaborative behaviours and their ability to produce retaliatory
behaviour.
66
Thierry Lefèvre et al.
3.3. A CO-EVOLUTIONARY PERSPECTIVE
Parasitic manipulation often dramatically reduces host fitness. For this
reason, the hypothesis of ‘manipulation sensu stricto’ is commonly seen as
a game with evident winners (i.e., parasites) and losers (hosts) (Wellnitz,
2005) (Box 3.3(A)). The ability of parasites to manipulate host behaviour
results from a long-term co-evolutionary interaction that probably leads
to the mechanisms being complex (Section 3.3). Co-evolutionary dynamics implies that the host behavioural changes should thus be considered as
an equilibrium state, a compromise resulting from an on-going arms race
rather than a total parasite takeover (Poulin et al., 1994; Wellnitz, 2005).
From an evolutionary point of view, these considerations are relevant as
they suggest that behavioural changes in infected hosts, even when they
result in clear fitness benefits for the parasite, are not necessarily pure
illustrations of the extended phenotype of the parasite. In a host–parasite
system, natural selection is acting on the host genome as well. At present,
very few studies on manipulative changes have explored the degree to
which parasite-manipulated behaviours could be a compromise between
the strategies of host and parasite. We present here two scenarios in which
parasitic ‘manipulation’ can enhance host fitness as well.
3.3.1. Exploiting host-compensatory responses
In this section, we propose that certain parasites could affect fitnessrelated traits in their hosts (e.g., fecundity, survival, growth, competitiveness, etc.) in order to stimulate host compensatory responses because
these host responses enhance parasitic transmission (Lefèvre et al., 2008)
(Box 3.3B).
3.3.1.1. Compensatory responses in the living world
The phenotype of an organism results from both its genotype and the
environment in which the genes are expressed. Phenotypic plasticity is
the capacity of a genotype to express different phenotypes under different
environmental conditions (Pigliucci and Preston, 2004). When faced with
adverse environmental conditions, many organisms are able to alter some
life history traits resulting in reduced fitness loss (Metcalfe and
Monaghan, 2001). For instance, when facing potential resource limitations, plants possess a remarkable degree of developmental plasticity
that enables them to balance their resource acquisition and maximise
their fitness (Wise and Abrahamson, 2005). Similarly, it can be adaptive
for parents in many animal species to avoid producing poor-quality
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
67
offspring when food is rare (e.g., by re-absorbing embryos or by reducing
the production of offspring of the more vulnerable sex, see Uller et al.,
2007). Animals can also respond to adverse environmental conditions
by using fecundity compensation (i.e., reproducing earlier in life and
producing more offspring). For instance, in the presence of predatory
fish, the cladoceran crustacean Daphnia galeata reproduce early and
produce larger clutches of smaller offspring (Sakwinska, 2002).
Parasites influence the optimal strategies of their free-living hosts. Like
other environmental factors, parasites have the potential to play an
important role in the evolution of plastic compensatory responses. Selection will favour hosts that will react to parasite-induced fitness cost by
adjusting their life history traits when they cannot resist infection by other
means (e.g., immunity). Several theoretical and empirical studies back up
this assumption by showing that infected hosts can adjust their reproductive effort or growth in such a way as to increase their fitness. For
example, parasitised hosts react to a fitness loss due to infection via
mechanisms such as an increased rate of egg laying (Adamo, 1999;
Minchella and Loverde, 1981), enhanced courtship behaviour (McCurdy
et al., 2000; Polak and Starmer, 1998), higher offspring number and/or size
(e.g., Kristan, 2004; Sorci and Clobert, 1995) and/or stronger parental
effort (Christe et al., 1996, Hurthrez-Boussès et al., 1998; Tripet and
Richner, 1997). High risk of infection can also select for early-onset sexual
maturity in the entire population (Agnew et al., 1999; Fredensborg and
Poulin, 2006; Lafferty, 1993). In other cases, hosts compensate by diminishing their reproductive effort, presumably to enhance survival, which
could in return increase the probability of outliving or sequestering
the parasite (Forbes, 1993; Hurd, 2001; Sorensen and Minchella, 2001).
Therefore, compensatory changes in behaviour may be a widespread
strategy among organisms facing adverse conditions such as parasitism.
In some cases, parasites can exploit host compensatory responses that
have been selected in other ecological contexts by mimicking the causes that
induce them. In other cases, parasites themselves can be the triggers of the
compensatory response because of their significant effects on host fitness.
3.3.1.2. Empirical support
To our knowledge, theoretical and/or experimental studies specifically
designed to test this scenario have never been carried out. However, in
the literature there are several examples of parasite-induced phenotypic
changes that have been interpreted either as cases of adaptive host
responses or manipulation sensu stricto but these same cases could, in
fact, illustrate the exploitation of host compensatory responses. Below, we
present some of these examples.
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Thierry Lefèvre et al.
3.3.1.2.1. Foraging activity
(a) Predation risk. An increased predation risk is a change that can potentially be of interest for trophically transmitted parasites since, by
definition, this type of parasite requires a predation event to complete
its life cycle. Parasitised hosts often have increased energy requirements and forage more to compensate for the negative effect of
infection. However, until now the subsequent increased predation
risk has been traditionally viewed as a by-product of the infection
that is coincidentally beneficial for the parasite (but see Thomas et al.,
2005). Parasites live at the expense of their hosts, and consequently
there are many reasons, other than transmission, for parasites to
divert energy away from the host (growth, maturation of gonads).
We agree with this parsimonious way of thinking (Box 3.1) but we feel
that in the present evolutionary context, parsimony can be viewed
differently. Host exploitation by parasites can potentially affect a
broad range of fitness-related traits in hosts such as survival, fecundity or sexual attractiveness. These phenomena are expected to favour
the evolution of compensatory responses in the host, such as an
increased foraging or reproductive activity. For instance, three-spined
sticklebacks (Gasterosteus aculeatus) infected by the cestode Schistocephalus solidus exhibit marked differences in their anti-predator, foraging and shoaling behaviour compared with uninfected conspecifics
(Barber and Huntingford, 1995; Godin and Sproul, 1988; Ness and
Foster, 1999). The increased nutritional demand of parasitised fish
(Pascoe and Mattey, 1977) may stimulate foraging behaviour that
exposes them to greater predation risk than uninfected counterparts
(Godin and Sproul, 1988; Milinski, 1985). This example has been
interpreted as an illustration of the ‘side-effect’ hypothesis according
to which these changes result from pathological effects of infection
that are coincidentally beneficial for the parasite (Box 3.1; Poulin,
1995). However, the behavioural changes observed in sticklebacks
infected by S. solidus are consistent with the view that the fish benefits
by obtaining more food to compensate for the resources taken by the
cestodes. Thus the host will gain, at least until predated, and by that
time it could have reproduced. The parasite clearly gains by making
the host more vulnerable to predation. However, one cannot exclude
active manipulation sensu stricto of host neuroendocrine systems by
the parasite, for instance by the release of a neuroactive substance
(Overli et al., 2001). What we wish to emphasise here is that competing
ideas need consideration when searching for proximate mechanisms
of manipulation.
(b) Qualitative change. It has been frequently reported that parasitised
organisms change their foraging behaviour (Moore, 2002). If foraging
leads to increased uptake of resources that can help fight the infection
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
69
it is often seen as a case of self-medication (Hart, 1994). When infected
with the tachinid parasitoid Thelaira americana, the caterpillar host
Platyprepia virginalis, changes its feeding preference from lupine to
hemlock (Karban and English-Loeb, 1997). This change apparently
reduces the costs of the infection for the host because infected caterpillars feeding on hemlock survived the emergence of the parasite
and even metamorphosed into sexually mature adults without losing
fecundity (English-Loeb et al., 1990, 1993). This response also seems to
be beneficial to the parasite. The pupal mass of flies (a good correlate
of fecundity) emerging from caterpillars reared on hemlock was
indeed greater than that emerging from lupine-fed caterpillars
(Karban and English-Loeb, 1997). In this example both host and
parasite interests are aligned (Dawkins, 1990).
(c) Biting behaviour in haematophagous insects. When haematophageous
insects feed on their hosts, they are liable to transmit many pathogens.
Vector-borne parasites manipulate several phenotypic traits of their
vertebrate hosts and vectors in ways that favour parasite transmission
(Hurd, 2003; Lefèvre and Thomas, 2008; Molyneux and Jefferies, 1986;
Moore, 2002; Section 3.3). For instance, infected-insect vectors seem to
develop an increased probing and feeding rate (e.g., tsetse flies infected
with African trypanosomes, Jenni et al., 1980; Roberts, 1981; bugs
infected with Trypanosoma spp., Anez and East, 1984; Botto-Mahan
et al., 2006; Garcia et al., 1994; sandflies infected with Leishmania spp.,
Beach et al., 1985; Killick-Kendrick et al., 1977; Rogers and Bates, 2007;
fleas infected with plague bacterium, Bacot and Martin, 1914; Gage and
Kosoy, 2005; mosquitoes infected with Plasmodium spp., Koella et al.,
1998, 2002; Rossignol et al., 1986; Wekesa et al., 1992; and viruses,
Grimstad et al., 1980; Platt et al., 1997). Increased biting is usually
associated with mechanical interference, that is, the vector’s ability to
engorge fully is impaired and therefore this induces them to bite
vertebrate hosts several times (Hinnebusch et al., 1998; Molyneux and
Jenni, 1981; Rogers and Bates, 2007). This would appear to be manipulation sensu stricto. However, Rossignol et al. (1986) demonstrated
reduced fertility in Aedes aegypti parasitised with Plasmodium gallinaceum. When infected mosquitoes were free to bite more, they recovered
a normal level of fecundity (i.e., equal to uninfected conspecifics).
In this view, the increased biting rate of A. aegypti may represent a
host compensatory response to parasite-induced fecundity reduction.
3.3.1.2.2. Sexual behaviour Longevity and reproduction are crucial
fitness determinants of most organisms (Clutton-Brock, 1988). A tradeoff between these two key life-history traits is expected so that reductions
in longevity leads to increased reproductive effort (Polak and
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Thierry Lefèvre et al.
Starmer, 1998). Parasites often reduce the survival of their host, and
infected hosts are expected to respond by increasing their reproductive
effort. Parasites with direct transmission could benefit from decreasing
the reproductive output of their host. Decreased offspring production
should promote a compensatory increase in sexual behaviour, and
hence parasite transmission. The sexually transmitted ectoparasite, Chrysomelobia labidomera, reduces the survival of its leaf beetle host (Labidomera
clivicollis). In response, infected males exhibit increased sexual behaviour
before dying (Abbot and Dill, 2001). The host compensation hypothesis
predicts a positive relationship between parasite load and reproductive
effort (Forbes, 1993; Polak and Starmer, 1998). As expected, the study by
Abbot and Dill (2001) showed a positive relationship between male parasite load, the frequency of sexual contact and duration of copulation. This
behavioural modification clearly benefits the sexually transmitted parasite
since enhanced inter- and intra-sexual contact (i.e., copulation and competition) provide more opportunities for transmission (Abott and Dill, 2001;
Drummand et al., 1989).
In the same vein, it has been reported that females of the amphipod
Corophium volutator compensate for the negative effect of the trophically
transmitted trematode Gynaecotyla adunca on survival by increasing their
reproductive activity (McCurdy et al., 2000, 2001). Males appeared to
compensate for parasitism by being more likely to mate, and perhaps by
increasing ejaculate size. In amphipods mating occurs only during a
narrow part of the female’s moult cycle. Since moulting is asynchronous,
the operational sex ratio is strongly male biased, and males compete for
access to larger, more fecund females. In response, pre-copulatory mate
guarding has evolved in amphipods. Interestingly, such behaviour is
known to increase the predation risk because pairs are more conspicuous,
less manoeuvrable and more profitable as prey than single individuals
(Cothran, 2004; Ward, 1986). Thus one can hypothesise that parasites
trigger host fecundity compensation because host mating increases the
chance of being preyed upon by the definitive hosts. This example,
however, must be considered carefully because the increased sexual
activity of parasitised gammarids may occur before the trematode is
infective to vertebrate predators.
3.3.1.2.3. Inclusive fitness In the Hawaiian Islands, corals from the genus
Porites are susceptible to infection by the digenetic trematode Podocotyloides stenometra (Aeby, 1991, 1992). This parasite has a complex life cycle
involving a molluscan as first intermediate host, Porites as the second
intermediate host, and coral-feeding fish as the final host. Porites infected
with this trematode display pink swollen nodules. Given that these parasitised polyps represent a burden for the coral (reduced growth), the coral
would benefit from eliminating and replacing them, for example, by
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
71
offering them to predators. As a matter of fact, the Butterfly fish (definitive host) do prefer the parasitised polyps and hence contribute to the
regeneration of a healthy polyp (Aeby, 1992). Whereas the higher susceptibility to fish of infected polyps seems to be a case of host manipulation
sensu stricto by a parasite, it also agrees with the idea that the parasite
relies on host compensatory responses for its transmission.
3.3.1.2.4. Gigantism Many parasite species can reduce host fecundity,
either partially or via full castration, by channelling energy away from
host reproduction toward their own growth (Poulin, 2007). This fecundity
reduction often results in host gigantism, especially in molluscs serving as
first intermediate hosts of larval trematodes (Minchella, 1985). This phenomenon is consistent with the idea that phenotypic changes following
infection can be considered as co-evolved traits. As size and fecundity are
positively correlated in snails, the parasitised hosts can benefit from
investing energy in growth, with fecundity compensation occurring
later, after the death of the parasite. However, the parasite remains the
first beneficiary of such a compensatory strategy since the larger size of
the host allows the parasite to increase the biomass of the sporocyst and
thus produce thousands of infective larvae.
3.3.1.3. Future directions
Most studies on parasitic manipulation assume that host phenotypic
changes that benefit the parasites are compelling illustrations of the
extended phenotype (sensu Dawkins, 1982; but see Ponton et al., 2006b),
that is, the expression of the parasite’s genes in the host phenotype.
The perspective presented above attempts to balance this view. We suggest that changes in host behaviour, even those that benefit the parasite,
can be due to compromises between host and parasite strategies (i.e., a
shared phenotype).
To our knowledge, it is novel to consider that parasites could achieve
transmission by triggering host compensatory responses, when the latter
fit (totally or in part) with the transmission route. Is this strategy common? Further studies are clearly needed at the moment to answer this
question, but it may be a widespread strategy. This type of host manipulation seems parsimonious for several reasons when compared with the
hypothesis of manipulation sensu stricto, in which the parasite must
maintain a certain degree of manipulative effort with putative fitness
costs. Indeed, if among the arsenal of compensatory responses displayed
by the host, some are beneficial for transmission, selection is likely to
favour parasites that exploit these responses, not only because this meets
their objectives, but also because this requires no manipulative effort: the
host is doing the job. Another good reason to believe that exploiting host
compensatory responses is a likely scenario from an evolutionary
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Thierry Lefèvre et al.
perspective comes from the fact that it is also advantageous for the host:
once infected, it is better for the host to behave in a way that alleviates the
costs of infection, even when this also ultimately benefits the parasite
(aligned desiderata, Dawkins, 1990). Under these conditions, resistance is
less likely to evolve than when there is no compensation for the host.
Based on these considerations, we could predict that manipulation
sensu stricto will exist most often in systems in which there are no host
compensatory mechanisms that would result in increased parasite transmission. As a possible example of such a situation, we suggest the case of
the well-known example involving the small liver fluke (Dicrocoelium
dendriticum). It is indeed difficult to imagine what kind of compensatory
responses could make the ant climb to the tip of a grass blade.
Besides the relevance of considering host compensatory responses in
the context of transmission strategies, we believe that it could also be a
promising approach for the study of many other aspects of host–parasite
relationships.
Natural selection should favour parasites that impose specific costs on
their host (with a precise schedule adjusted by selection) each time there is
a host compensatory response that is beneficial for them. In our opinion,
these ideas are very promising for the understanding of the ultimate basis
of parasite pathogenicity and virulence (Lefèvre et al., 2008).
3.2.2. Facultative virulence
The mafia-like strategy of manipulation is probably the most extreme
scenario demonstrating the interactive nature of the relationship between
parasites and hosts (Zahavi, 1979). This strategy suggests that parasites
may select for collaborative behaviour in their hosts by imposing extra
fitness costs in the absence of compliance. In this scenario the parasite
would be also able to adopt a plastic strategy (i.e., facultative virulence)
commensurate to the rate of collaboration displayed by the host.
In response to a host’s opposition to manipulation, a parasite could
increase virulence because the host does not behave as expected. Therefore, non-collaborative behaviours are a more expensive option for the
host than collaborative ones. This ‘mafia-like strategy’ can, in theory, force
the host to accept behaving in ways that benefit the parasite (Box 3.3(C)).
Here, we discuss and review possible evidence around this idea.
3.2.2.1. Host–parasite interactions and state-dependent models
Both the host and the parasite must be able to adjust their life history
decisions in a state-dependent manner for the mafia strategy of manipulation to evolve. Numerous lines of evidence suggest that free-living
organisms are able to recognise environmental cues, including parasitic
infection, and to adjust their life history traits accordingly (Section 3.3.1.1).
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
73
There are recent suggestions that parasites are also able to perceive a
large set of environmental variables and respond to these in a statedependent manner (thereby maximising their lifetime reproductive success) (Lewis et al., 2002; Thomas et al., 2002b). Parasites are, for instance,
expected to recognise many physiological and biochemical conditions of
their internal host environments that are of selective importance (age and
sex of the host, presence/absence of other parasites). There are also good
reasons to believe that parasites are able to perceive cues concerning the
external environment of their hosts. For example, parasites can respond to
host population density, the presence of predators, or the presence of
sexual partners or competitors (see Thomas et al., 2002b). Poulin (2003)
provided empirical evidence that the environmental perception of parasites can be much more sophisticated than traditionally thought. The
trematode Coitocaecum parvum from New Zealand is able to accelerate its
development and reach precocious maturity in its crustacean intermediate
host in the absence of chemical cues emanating from its fish definitive host.
Juvenile trematodes can also mature precociously when the mortality rate
of their intermediate hosts is increased (Poulin, 2003). These results show
that growth decisions and developmental strategies in this parasite are
plastic, and conditional upon the opportunities for transmission. More
generally, these results suggest that parasites can exploit several sources
of information both internal and external to the host.
3.3.2.2. Mafia strategy of manipulation
By imposing extra fitness costs in absence of compliance, parasites have
the potential to select for collaborative behaviour in their hosts. Of course,
these collaborative behaviours do not result from conscious choices. Over
time, selection is expected to produce shifts in the behaviour of infected
individuals if such a shift increases their chance of survival and reproduction. In some systems, hosts that alter their behaviour in such a way
that benefits the parasite may have better survival and more offspring
than infected hosts that do not.
3.3.2.3. Empirical support
The cuckoo is the best exemplar of the mafia hypothesis. Zahavi (1979)
hypothesised that cuckoos force their hosts to tolerate non-self eggs by
making the consequences of rejection more damaging than acceptance.
Soler et al. (1995) studied the relationship between the great spotted
cuckoo (Clamator glandarius) and its magpie host (Pica pica). In this host–
parasite system, the host can raise at least part of its own young along
with those of the cuckoo. Soler et al. (1995) showed that ejector magpies
suffered from considerably higher nest predation levels by cuckoos than
did accepters. The interpretation being that the cuckoo retaliates and
punishes non-compliant hosts. As a result, the frequency of ‘accepting
74
Thierry Lefèvre et al.
genes’ is more likely to increase in the host population than ‘rejecting
genes’ (Soler et al., 1999). In an area with a high density of cuckoos, Soler
et al. (1998) showed that magpies that rejected cuckoo eggs from their first
clutch were more likely to be parasitised by cuckoos during their second
clutch than magpies that accepted the cuckoo eggs during the first clutch.
Pagel et al. (1998) modelled the evolution of retaliation by brood
parasites. Retaliation evolves even when hosts rear only the parasite’s
young (its own offspring having been ejected by the parasite, which is the
case when nests are parasitised by Cuculus canorus). This is possible if,
during the breeding season, non-ejectors enjoy lower rates of parasitism
in later clutches compared to ejectors, making non-ejectors able to rear a
clutch of their own following the rearing of a cuckoo nestling, while
ejectors are likely to be re-parasitised. Pagel et al. (1998) stressed that, for
this scenario to function, it implies that brood parasites have a good
memory for the location and status of nests in their territory.
Recently, Hoover and Robinson (2007) provided experimental
evidence for the mafia strategy in the brood parasite, the brown-headed
cowbird (Molothrus ater). In manipulating ejection of cowbird eggs and
cowbird access to nests of their warbler host, they showed that 56 % of
ejector-nests compared with only 6% of accepter-nests were destroyed by
cowbirds (Hoover and Robinson, 2007). This mafia behaviour selects
for collaborative hosts not only in evolutionary time by decreasing the
proportion of hosts that bear rejector genes, but also within the lifetime of
an individual host through a learning process. Learning probably occurs
in parasitic systems in which individual host females are likely to be
parasitised repeatedly within or across breeding seasons. In addition, the
authors also showed that collaborative behaviours benefit the hosts as well,
since warblers produced significantly more offspring by complying with
the parasite.
3.3.2.4. Future directions
Examples of mafia strategy of manipulation remain scarce at the moment,
but this is likely to reflect a lack of appropriate studies. We encourage
researchers to imagine experiments that place infected hosts in a situation
of ‘disobedience’ as regard to what they should do to benefit the parasite,
and to study the fitness consequences of such non-compliance. It would
also be necessary to determine whether pre-adaptations (physical location
of the parasite with respect to the host, number and kind of hosts involved
in the life cycle and phylogenetic constraints) exist for behavioural
changes. In addition, do these factors matter more in cases of manipulation sensu stricto, than in one of the ‘interactive’ strategies presented
above? Knowing that manipulative costs should, in theory, be lower for
parasites when the host has some fitness compensation in performing the
altered behaviour, we might even expect that the transition from ‘pure’
Diversity and Evolution of Manipulative Strategies in Host–Parasite Interactions
75
manipulation to ‘interactive’ strategies of manipulation is likely to be a
scenario favoured by selection. Finally, this co-evolutionary perspective
suggests that host behavioural changes can benefit the host even if they
also benefit the parasite.
3.4. THE (RIVER) BLIND WATCHMAKER
In what is the most well-known argument from design, the Reverend
William Paley (1802) said that just as we conclude that a watch we find
lying on the ground must have had a creator, then so too must other
complex things such as animals have had a creator. In Paley’s case, the
creator was divine but since the publication on the Origin of Species
(Darwin, 1859), we now accept the theory of natural selection as a more
satisfying explanation. In defending Darwin’s theory Richard Dawkins
(1986) said of natural selection that ‘‘It has no mind and no mind’s eye. It does
not plan for the future. It has no vision, no foresight, no sight at all. If it can be
said to play the role of watchmaker in nature, it is the blind watchmaker’’.
How well do we understand the interactions between parasites and
their hosts? In many cases we have an enviable level of understanding of
these interactions (e.g., our understanding of the antigenic variation of the
protein coat of malaria, Schmid-Hempel, 2008). However our understanding is far from complete, even though parasites have the reputation of
being simple organisms. (Admittedly it is non-parasitologists putting
forwards this view.) Parasites are generally reduced in morphology.
Also, their genomes are often reduced compared to free-living relatives
(Keeling and Slamovits, 2005). The effects that parasites have on their host
are likewise viewed as crude. River blindness, caused by the nematode,
Onchocerca volvulus, is a case in point. Adult worms produce thousands of
microfilaria each day and these cause a range of symptoms that often
occur after these immature stages die in the human host without ever
being transferred to the fly vector. The most infamous effect of these
larvae is the scarring of the eye leading to blindness. River blindness
causes great morbidity and mortality in hosts and reinforces the view
that parasites appear to take a sledgehammer approach to the host
(Section 3.3.1).
By contrast the specific changes in host behaviour that are observed in
some systems can be viewed as the parasite extending its phenotype and
taking control of the actions of the host. In our review we have sought to
temper that view by saying that in many cases parasites appear to induce
multiple and widely disseminated changes in their hosts’ CNS as
opposed to targeted attacks on specific neural circuits. Moreover, the
behavioural change is not always the sole property of the parasite: the
reaction of the host may also be important.
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Thierry Lefèvre et al.
3.5. CONCLUDING REMARKS
When presented with a parasite causing an elaborate and often times
bizarre behavioural change in its host, an obvious question that arises is
how? Yet, by any admission, the field has been overly focused on why
(i.e., explaining the behaviour in an adaptationist framework where the
fitness benefit is ascribed to the parasite, host or neither (Box 3.1)). In this
review we considered the evidence of how parasites induce changes.
Overall, the evidence is slight and even the best-studied examples require
further data before behavioural changes can be considered parasite
manipulation in its most strict sense. Recognising this short fall we
have further tempered the manipulation sensu stricto view by pointing
to other factors such as host immune responses, compensatory responses
and facultative virulence. Our goal has been to present the current evidence for parasitic manipulation of host behaviour. To move forwards we
require less debate and more evidence. How might this be achieved?
Researchers interested in behavioural manipulation need a fuller discourse with colleagues who understand how physiology, neuroanatomy
and omics contribute to behavioural trait expression. This is requisite to
avoid situations where the evidence of some aberration (e.g., hormone
titres, smaller brain regions or distinctive proteomes) is taken as evidence
of adaptive manipulation. It is possible and probable that other scenarios
in uninfected hosts (e.g., stress, senescence) lead to similar signatures. In
addition to greater collaboration, the field might benefit from focusing on
some systems that could be developed into models of host–parasite
manipulation events. Clearly, some of those reviewed above would be
good contenders. In a related vein, genomic approaches will herald a new
era in understanding how parasites control behaviour. A goal of the field
should be a full understanding of the proximate mechanisms of how a
parasite affects host behaviour. It is our hope that one day a collaborative
and multi-disciplinary research approach will be able to peel back a
particularly compelling example of an extended phenotype to shows its
physiological, neurological and ultimately its genetic basis. Then we will
know how parasites manipulate a host.
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