A growing number of studies demonstrate, or suggest, that vector-borne parasites manipulate
phenotypic traits of their vectors and hosts in ways that increase contacts between
them, and hence favour the parasites' transmission [1,2]. Understanding these processes
is not only exciting for purely scientific reasons but also important because of their
role in applied parasitology, such as epidemiology and medicine. The most frequently
reported changes induced by vector-borne parasites are alterations of biting rates
in vectors or of attractiveness in vertebrate hosts [3,4]. Our aim here is to elaborate
further on some potentially interesting and important avenues for future research
in this area. We begin this paper with a brief overview of the main mechanisms used
by vectors to locate their vertebrate host, as it helps to grasp the fundamentals
of the research on manipulation in vectors, as well as its current challenges.
Bloodsucking insects have well-developed sensorial machinery to locate and choose
their host [5]. Host location behaviour is usually organized into three areas which
show considerable variation among vector species: (i) the appetitive search, (ii)
the activation and orientation, and (iii) the attraction. The two last steps involve
insect responses to external stimuli, mainly visual and odour cues, but also heat
and to a lesser extent, water vapour and sound [5]. Vision is most widely used by
diurnal insect vectors (e.g., blackflies, tsetse flies, several mosquitoes). The detection
depends mainly on differences in colour contrast and intensity contrast; generally,
flies are attracted to blue/black objects while they are repelled by yellow ones.
Odour-mediated host-seeking has been more thoroughly studied and seems to be utilized
by virtually all bloodsucking insects. The olfactory stimuli used by the insects are
various, ranging from carbon dioxide to lactic acid, ammonia, acetone, octenol, phenolic
components of urine, and sweat. Bloodsucking insects can be also very sensitive to
heat [5]. Although some of these components (vision, olfaction, hearing) could be
theoretically altered by parasites in ways that may be predicted to enhance parasite
transmission, only a few have been considered.
Bite more or bite better?
Qualitative manipulation, according to which generalist bloodfeeding insects, once
infected, would develop a feeding preference for hosts targeted by the parasite, is
an underexplored scenario. Maximising transmission towards a suitable host could be
achieved by parasites by inducing in the vector a sensory bias for host traits that
are correlated with optimal suitability for the parasite. Qualitative manipulation
could theoretically occur at two levels: (i) at the interspecific level, with infected
vectors biting more than expected on suitable host species for the parasite and (ii)
at the intraspecific level, when infected vectors prefer feeding on less-immune hosts
or on individuals that are uninfected (and thus do not yet harbour potential competitors).
In particular cases, however (e.g., Plasmodium), the reverse tendency might be expected
in order to find a sexual partner of a different strain. To test for the qualitative
manipulation hypothesis, a dual-port olfactometer could be used to quantify the behavioural
responses of infected and uninfected insect vectors to volatiles emitted by different
host species. For instance, Glossina palpalis gambiensis has a broad range of hosts
in central Africa (humans, reptiles, bushbuck, and ox) and is the main vector of Trypanosoma
brucei gambiense responsible for the medically important Human African trypanosomiasis.
We would predict that once infected, flies are more attracted by human cues than by
those of other vertebrates.
Betrayed by smell.
All kinds of diseases are associated with changes in the infected individual's odour
profile [6–9]. These changes have generally been considered as nonspecific symptoms
of infection with no adaptive value. However, since the publication of several recent
studies [10–13], and especially Lacroix et al. [2] who showed that people infected
with transmissible stages of malaria produced something attractive to mosquitoes,
it seems clear that more research should be performed to explore the hypothesis that
alterations in odour profiles could be adaptive manipulative changes exerted by vector-borne
parasites to increase their transmission. Along the same idea, the hypothesis according
to which parasites inhibit some of the processes through which certain hosts are less
detected/chosen than others [14] deserves consideration. Experimental tests of these
hypotheses could be based on the same device as before (i.e., a dual-port olfactometer)
combined with a gas chromatography–electroantennograph approach to detect and identify
allomone/kairomone eventually emitted by infected and uninfected vertebrates.
Going beyond behaviour.
In addition to greater consideration of the proximate mechanisms mediating parasite-induced
changes in feeding behaviour, further research might benefit from also considering
traits other than behavioural ones. Reduction of fecundity has been reported frequently
in Plasmodium-infected mosquitoes [1]. Altering vector resource management may increase
available nutrient reserves or avoid the cost of laying eggs, which in turn could
enhance the vector's longevity and hence the parasite's overall transmission. Further
experiments are clearly needed to confirm this interesting hypothesis [1]. Protozoan
pathogens such as Plasmodium, Leishmania, and Trypanosoma also are able to evade the
immune system of their vertebrate hosts by, for example, penetrating and multiplying
within cells, varying their surface antigens, eliminating their protein coat, and
modulating the host immune response, e.g., the maturation of the dendritic cells [15,16].
Malaria also manipulates the immune system of its mosquito hosts in two ways [17].
First, in the early stages of infection, it actively suppresses the encapsulation
immune response within the mosquitoes. In addition, an indirect suppression occurs
when mosquitoes (already infected or not) are fed with plasma of infected hosts. The
underlying mechanisms are still unknown but there is a suggestion that this indirect
suppression results from complex interactions between the vertebrate and the mosquito
immune responses. The manipulation of the immune response is certainly an important
way for the parasite to ensure its transmission.
From phenotype to molecular mechanisms.
More generally, studying the molecular cross talks (e.g., with proteomics tools, see
for instance [18]) between parasites and vectors at several stages of their interaction
should not only permit us to understand the proximate mechanisms causing alterations
in feeding behaviour, but also to potentially discover new ways in which parasites
increase their transmission. Such an approach would appear promising to understand
who is actually running the show: the parasite, the host, both, or neither. Similarly,
this approach could bring relevant information when applied to interactions among
pathogens and their vertebrate hosts [19]. To go further in this direction, an important
hurdle that would also need to be overcome is the development of a population biology
view, assessing the populational polymorphism in these processes. This implies an
automation of molecular techniques in order to provide high throughput datasets.
Conflict of interest.
Conflicts of interest in behavioural patterns naturally underlie any kind of manipulation.
Mosquitoes, for example, would prefer to bite their hosts less frequently than what
is optimal for transmission stages of the parasites [20]. Such conflicts can become
quite complex if the parasite can manipulate several traits in its different hosts
and change the manipulation according to its stage of development [21]. Conflicts
between parasites are also expected when hosts harbour simultaneously transmissible
and nontransmissible stages (both at the intraspecific and interspecific level). However,
and unfortunately, very few studies consider these conflicts explicitly. How strong
is the selection to manipulate the hosts? How strong is the selection to resist being
manipulated? In addition to empirical approaches based on experimental infections,
the understanding of these complex interspecific and intraspecific interactions would
benefit from being explored from a theoretical point of view. Answers to such questions
could bring studies of behavioural manipulation from interesting observations to predictive
evolutionary biology.
Research on vector–pathogen interactions has unfortunately a bright future given the
increasing preoccupations caused by the emergence and the reemergence of numerous
infectious diseases. Because traditional medical approaches do not always provide
suitable solutions (e.g., too expensive for the countries concerned), fundamental
investigations of the ecology and the evolution of vector and pathogen interactions
remain a key aspect of the research in human and veterinary health. Additionally,
attention should be directed towards investigations in a field setting, as behaviour
in the laboratory may not reflect precisely that which occurs naturally. Behavioural
manipulations of vectors are phenomena so complex that one single method cannot totally
describe or understand them. For this reason, future research should benefit from
the expertise of different disciplines. Responses to the questions asked will indeed
need the integration of the concepts and techniques from epidemiology, behavioural
and evolutionary ecology, medicine, neurobiology, physiology, and molecular biology.
Despite the difficulty of performing such pluridisciplinary approaches, these efforts
will undoubtedly provide a much better basis for understanding the evolution of parasitic
manipulation in vectors. Although speculative in appearance, each of the scenarios
mentioned above is legitimate from ecological and evolutionary points of view. At
least because of this, and also because the above hypotheses would considerably change
the way we control and model the transmission of the most harmful pathogens affecting
humans, they should be verified.