HOW PERNICIOUS PARASITES TURN VICTIMS INTO ZOMBIESALTERATION OF HOST BEHAVIOR
Parasites come in all shapes and forms. From skinny tapeworms that infest intestines to the microscopic infectious agent of malaria (Plasmodium), parasites are usually inconvenient and sometimes lethal. But there is one group of parasites that is particularly pernicious – they are the parasites that hijack their host’s nervous system, turning their victims into zombies. ‘The fact that parasites can so efficiently alter host behaviour is fascinating’, says JEB Editor Michael Dickinson, from the University of Washington, USA, adding, ‘There is something horrifying and wondrous about a tiny “implant” being able to control such a large animal machine’. What is more, it appears that these minute manipulators can have a significant, and often under-appreciated, impact on ecology, physiology and evolution, orchestrating the behaviour of vertebrates and invertebrates alike. ‘Neuroparasitology is a science where science meets science fiction’, Dickinson observes. However, the community tackling the thorny question of how parasites take possession of their hosts by manipulating their nervous systems, and the large-scale implications of these behavioural changes, is tiny. Shelley Adamo – an insect behavioural physiologist from Dalhousie University, Canada – adds that working with parasitic systems is particularly challenging because of the necessity of raising two different organisms in the lab. ...
Parasites: evolution’s neurobiologistsNEUROIMMUNOLOGY
For millions of years, parasites have altered the behaviour of their hosts. Parasites can affect host behaviour by: (1) interfering with the host’s normal immune–neural communication, (2) secreting substances that directly alter neuronal activity via non-genomic mechanisms and (3) inducing genomic- and/or proteomic-based changes in the brain of the host. Changes in host behaviour are often restricted to particular behaviours, with many other behaviours remaining unaffected. Neuroscientists can produce this degree of selectivity by targeting specific brain areas. Parasites, however, do not selectively attack discrete brain areas. Parasites typically induce a variety of effects in several parts of the brain. Parasitic manipulation of host behaviour evolved within the context of the manipulation of other host physiological systems (especially the immune system) that was required for a parasite’s survival. This starting point, coupled with the fortuitous nature of evolutionary innovation and evolutionary pressures to minimize the costs of parasitic manipulation, likely contributed to the complex and indirect nature of the mechanisms involved in host behavioural control. Because parasites and neuroscientists use different tactics to control behaviour, studying the methods used by parasites can provide novel insights into how nervous systems generate and regulate behaviour. Studying how parasites influence host behaviour will also help us integrate genomic, proteomic and neurophysiological perspectives on behaviour.
An overview of parasite-induced behavioral alterations – and some lessons from bats
An animal with a parasite is not likely to behave like a similar animal without that parasite. This is a simple enough concept, one that is now widely recognized as true, but if we move beyond that statement, the light that it casts on behavior fades quickly: the world of parasites, hosts and behavior is shadowy, and boundaries are ill-defined. For instance, at first glance, the growing list of altered behaviors tells us very little about how those alterations happen, much less how they evolved. Some cases of parasite-induced behavioral change are truly manipulative, with the parasite standing to benefit from the changed behavior. In other cases, the altered behavior has an almost curative, if not prophylactic, effect; in those cases, the host benefits. This paper will provide an overview of the conflicting (and coinciding) demands on parasite and host, using examples from a wide range of taxa and posing questions for the future. In particular, what does the larger world of animal behavior tell us about how to go about seeking insights – or at least, what not to do? By asking questions about the sensory–perceptual world of hosts, we can identify those associations that hold the greatest promise for neuroethological studies of parasite-induced behavioral alterations, and those studies can, in turn, help guide our understanding of how parasite-induced alterations evolved, and how they are maintained.
Parasite manipulation of host personality and behavioural syndromes
The past decades have seen mounting evidence that parasites alter their host’s behaviour in ways that benefit transmission, based on differences in the expression of behavioural traits between infected and control individuals, or on significant correlations between trait expression and infection levels. The multidimensional nature of host manipulation has only recently been recognised: parasites do not target single host traits, but instead suites of interrelated traits. Here, I use recent research on animal personality (behavioural differences among individuals consistent across time and situations) and behavioural syndromes (correlations at the population level among distinct behavioural traits, or between the same trait expressed in different contexts) to provide a framework from which simple testable patterns of host behavioural changes can be predicted. Following infection, a manipulative parasite could (i) change the temporal consistency of its host’s behavioural responses, (ii) change the slope of a host reaction norm, i.e. the way host behavioural traits are expressed as a function of an environmental gradient, or (iii) decouple two or more host behavioural traits and/or change the way in which they correlate with each other. Two case studies involving trematode parasites and their freshwater hosts are used to provide empirical illustrations of the above scenarios. These clearly illustrate the full richness of behavioural alterations induced by parasites, and how these effects would go unnoticed using the classical trait-by-trait comparisons of mean values between parasitised and non-parasitised individuals. However, the power of animal personality and behavioural syndromes to inform research on host manipulation by parasites will only be fully realised when underlying mechanisms are elucidated and linked to their phenotypic impacts.
Multidimensionality in parasite-induced phenotypic alterations: ultimate versus proximate aspects
In most cases, parasites alter more than one dimension in their host phenotype. Although multidimensionality in parasite-induced phenotypic alterations (PIPAs) [FULL TEXT] seems to be the rule, it has started to be addressed only recently. Here, we critically review some of the problems associated with the definition, quantification and interpretation of multidimensionality in PIPAs. In particular, we confront ultimate and proximate accounts, and evaluate their own limitations. We end up by introducing several suggestions for the development of future research, including some practical guidelines for the quantitative analysis of multidimensionality in PIPAs.
Diversity and evolution of bodyguard manipulation
Among the different strategies used by parasites to usurp the behaviour of their host, one of the most fascinating is bodyguard manipulation. While all classic examples of bodyguard manipulation involve insect parasitoids, induced protective behaviours have also evolved in other parasite–host systems, typically as specific dimensions of the total manipulation. For instance, parasites may manipulate the host to reduce host mortality during their development or to avoid predation by non-host predators. This type of host manipulation behaviour is rarely described, probably due to the fact that studies have mainly focused on predation enhancement rather than studying all the dimensions of the manipulation. Here, in addition to the classic cases of bodyguard manipulation, we also review these ‘bodyguard dimensions’ and propose extending the current definition of bodyguard manipulation to include the latter. We also discuss different evolutionary scenarios under which such manipulations could have evolved.
How much energy should manipulative parasites leave to their hosts to ensure altered behaviours?
Although host manipulation is likely to be costly for parasites, we still have a poor understanding of the energetic aspects underlying this strategy. It is traditionally assumed that physiological costs are inevitably associated with mechanisms evolved by parasites to induce the required changes in host behaviours. While most energetic expenditures of parasites relate primarily to bringing about the altered behaviours, manipulative parasites also have to consider the condition of their host during the manipulation. Here, we suggest that because of this trade-off, the energy required to accomplish parasite-induced behaviours may represent a key energetic constraint for parasites. Depending on the energetic expenditures specific to each type of manipulation, parasites should undergo selection to secure resources for their host to allow them to perform manipulated behaviours.
What can parasitoid wasps teach us about decision-making in insects?
Millions of years of co-evolution have driven parasites to display very complex and exquisite strategies to manipulate the behaviour of their hosts. However, although parasite-induced behavioural manipulation is a widespread phenomenon, the underlying neuronal mechanisms are only now beginning to be deciphered. Here, we review recent advancements in the study of the mechanisms by which parasitoid wasps use chemical warfare to manipulate the behaviour of their insect hosts. We focus on a particular case study in which a parasitoid wasp (the jewel wasp Ampulex compressa) performs a delicate brain surgery on its prey (the American cockroach Periplaneta americana) to take away its motivation to initiate locomotion. Following a brief background account of parasitoid wasps that manipulate host behaviour, we survey specific aspects of the unique effects of the A. compressa venom on the regulation of spontaneous and evoked behaviour in the cockroach host.(Big awesome post about parasitoid wasps previously: The players in a mutualistic symbiosis: insects, bacteria, viruses, and virulence genes.)Comparing mechanisms of host manipulation across host and parasite taxa
Parasites affect host behavior in several ways. They can alter activity, microhabitats or both. For trophically transmitted parasites (the focus of our study), decreased activity might impair the ability of hosts to respond to final-host predators, and increased activity and altered microhabitat choice might increase contact rates between hosts and final-host predators. In an analysis of trophically transmitted parasites, more parasite groups altered activity than altered microhabitat choice. Parasites that infected vertebrates were more likely to impair the host’s reaction to predators, whereas parasites that infected invertebrates were more likely to increase the host’s contact with predators. The site of infection might affect how parasites manipulate their hosts. For instance, parasites in the central nervous system seem particularly suited to manipulating host behavior. Manipulative parasites commonly occupy the body cavity, muscles and central nervous systems of their hosts. Acanthocephalans in the data set differed from other taxa in that they occurred exclusively in the body cavity of invertebrates. In addition, they were more likely to alter microhabitat choice than activity. Parasites in the body cavity (across parasite types) were more likely to be associated with increased host contact with predators. Parasites can manipulate the host through energetic drain, but most parasites use more sophisticated means. For instance, parasites target four physiological systems that shape behavior in both invertebrates and vertebrates: neural, endocrine, neuromodulatory and immunomodulatory. The interconnections between these systems make it difficult to isolate specific mechanisms of host behavioral manipulation.
Parasite-induced alterations of sensorimotor pathways in gammarids: collateral damage of neuroinflammation?TOXOPLASMOSIS
Some larval helminths alter the behavior of their intermediate hosts in ways that favor the predation of infected hosts, thus enhancing trophic transmission. Gammarids (Crustacea: Amphipoda) offer unique advantages for the study of the proximate factors mediating parasite-induced behavioral changes. Indeed, amphipods infected by distantly related worms (acanthocephalans, cestodes and trematodes) encysted in different microhabitats within their hosts (hemocoel, brain) present comparable, chronic, behavioral pathologies. In order to evaluate the potential connection between behavioral disturbances and immune responses in parasitized gammarids, this Review surveys the literature bearing on sensorimotor pathway dysfunctions in infected hosts, on the involvement of the neuromodulator serotonin in altered responses to environmental stimuli, and on systemic and neural innate immunity in arthropods. Hemocyte concentration and phenoloxidase activity associated with melanotic encapsulation are depressed in acanthocephalan-manipulated gammarids. However, other components of the arsenal deployed by crustaceans against pathogens have not yet been investigated in helminth-infected gammarids. Members of the Toll family of receptors, cytokines such as tumor necrosis factors (TNFs), and the free radical nitric oxide are all implicated in neuroimmune responses in crustaceans. Across animal phyla, these molecules and their neuroinflammatory signaling pathways are touted for their dual beneficial and deleterious properties. Thus, it is argued that neuroinflammation might mediate the biochemical events upstream of the serotonergic dysfunction observed in manipulated gammarids – a parsimonious hypothesis that could explain the common behavioral pathology induced by distantly related parasites, both hemocoelian and cerebral.
The significance of cerebral toxocariasis: a model system for exploring the link between brain involvement, behaviour and the immune response
Toxocara canis is a parasitic nematode that infects canines worldwide, and as a consequence of the widespread environmental dissemination of its ova in host faeces, other abnormal hosts including mice and humans are exposed to infection. In such abnormal or paratenic hosts, the immature third-stage larvae undergo a somatic migration through the organs of the body but fail to reach maturity as adult worms in the intestine. The presence of the migrating larvae contributes to pathology that is dependent upon the intensity of infection and the location of the larvae. A phenomenon of potential public health significance in humans and of ecological significance in mice is that T. canis larvae exhibit neurotrophic behaviour, which results in a greater concentration of parasites in the brain, as infection progresses. Toxocara larval burdens vary between individual outbred mice receiving the same inocula, suggesting a role for immunity in the establishment of cerebral infection. Although the systemic immune response to T. canis has been widely reported, the immune response in the brain has received little attention. Differential cytokine expression and other brain injury-associated biomarkers have been observed in infected versus uninfected outbred and inbred mice. Preliminary data have also suggested a possible link between significant memory impairment and cytokine production associated with T. canis infection. Mice provide a useful, replicable animal model with significant applicability and ease of manipulation. Understanding the cerebral host–parasite relationship may shed some light on the cryptic symptoms of human infection where patients often present with other CNS disorders such as epilepsy and mental retardation.
Immune–neural connections: how the immune system’s response to infectious agents influences behavior
Humans and animals use the classical five senses of sight, sound, touch, smell and taste to monitor their environment. The very survival of feral animals depends on these sensory perception systems, which is a central theme in scholarly research on comparative aspects of anatomy and physiology. But how do all of us sense and respond to an infection? We cannot see, hear, feel, smell or taste bacterial and viral pathogens, but humans and animals alike are fully aware of symptoms of sickness that are caused by these microbes. Pain, fatigue, altered sleep pattern, anorexia and fever are common symptoms in both sick animals and humans. Many of these physiological changes represent adaptive responses that are considered to promote animal survival, and this constellation of events results in sickness behavior. Infectious agents display a variety of pathogen-associated molecular patterns (PAMPs) that are recognized by pattern recognition receptors (PRRs). These PRR are expressed on both the surface [e.g. Toll-like receptor (TLR)-4] and in the cytoplasm [e.g. nucleotide-binding oligomerization domain (Nod)-like receptors] of cells of the innate immune system, primarily macrophages and dendritic cells. These cells initiate and propagate an inflammatory response by stimulating the synthesis and release of a variety of cytokines. Once an infection has occurred in the periphery, both cytokines and bacterial toxins deliver this information to the brain using both humoral and neuronal routes of communication. For example, binding of PRR can lead to activation of the afferent vagus nerve, which communicates neuronal signals via the lower brain stem (nucleus tractus solitarius) to higher brain centers such as the hypothalamus and amygdala. Blood-borne cytokines initiate a cytokine response from vascular endothelial cells that form the blood–brain barrier (BBB). Cytokines can also reach the brain directly by leakage through the BBB via circumventricular organs or by being synthesized within the brain, thus forming a mirror image of the cytokine milieu in the periphery. Although all cells within the brain are capable of initiating cytokine secretion, microglia have an early response to incoming neuronal and humoral stimuli. Inhibition of proinflammatory cytokines that are induced following bacterial infection blocks the appearance of sickness behaviors. Collectively, these data are consistent with the notion that the immune system communicates with the brain to regulate behavior in a way that is consistent with animal survival.
Toxoplasma gondii infection, from predation to schizophrenia: can animal behaviour help us understand human behaviour?NEW APPROACHES
We examine the role of the protozoan Toxoplasma gondii as a manipulatory parasite and question what role study of infections in its natural intermediate rodent hosts and other secondary hosts, including humans, may elucidate in terms of the epidemiology, evolution and clinical applications of infection. In particular, we focus on the potential association between T. gondii and schizophrenia. We introduce the novel term ‘T. gondii–rat manipulation–schizophrenia model’ and propose how future behavioural research on this model should be performed from a biological, clinical and ethically appropriate perspective.
Toxoplasma gondii infection and behaviour – location, location, location?
Parasite location has been proposed as an important factor in the behavioural changes observed in rodents infected with the protozoan Toxoplasma gondii. During the chronic stages of infection, encysted parasites are found in the brain but it remains unclear whether the parasite has tropism for specific brain regions. Parasite tissue cysts are found in all brain areas with some, but not all, prior studies reporting higher numbers located in the amygdala and frontal cortex. A stochastic process of parasite location does not, however, seem to explain the distinct and often subtle changes observed in rodent behaviour. One factor that could contribute to the specific changes is increased dopamine production by T. gondii. Recently, it was found that cells encysted with parasites in the brains of experimentally infected rodents have high levels of dopamine and that the parasite encodes a tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of this neurotransmitter. A mechanism is proposed that could explain the behaviour changes due to parasite regulation of dopamine. This could have important implications for T. gondii infections in humans.
Parasite-augmented mate choice and reduction in innate fear in rats infected by Toxoplasma gondii
Typically, female rats demonstrate clear mate choice. Mate preference is driven by the evolutionary need to choose males with heritable parasite resistance and to prevent the transmission of contagious diseases during mating. Thus, females detect and avoid parasitized males. Over evolutionary time scales, parasite-free males plausibly evolve to advertise their status. This arrangement between males and females is obviously detrimental to parasites, especially for sexually transmitted parasites. Yet Toxoplasma gondii, a sexually transmitted parasite, gets around this obstacle by manipulating mate choice of uninfected females. Males infected with this parasite become more attractive to uninfected females. The ability of T. gondii to not only advantageously alter the behavior and physiology of its host but also secondarily alter the behavior of uninfected females presents a striking example of the ‘extended phenotype’ of parasites. Toxoplasma gondii also abolishes the innate fear response of rats to cat odor; this likely increases parasite transmission through the trophic route. It is plausible that these two manipulations are not two distinct phenotypes, but are rather part of a single pattern built around testosterone-mediated interplay between mate choice, parasitism and predation.
Influence of latent Toxoplasma infection on human personality, physiology and morphology: pros and cons of the Toxoplasma–human model in studying the manipulation hypothesis
The parasitic protozoan Toxoplasma gondii infects about one-third of the population of developed countries. The life-long presence of dormant stages of this parasite in the brain and muscular tissues of infected humans is usually considered asymptomatic from the clinical point of view. In the past 20 years, research performed mostly on military personnel, university students, pregnant women and blood donors has shown that this ‘asymptomatic’ disease has a large influence on various aspects of human life. Toxoplasma-infected subjects differ from uninfected controls in the personality profile estimated with two versions of Cattell’s 16PF, Cloninger’s TCI and Big Five questionnaires. Most of these differences increase with the length of time since the onset of infection, suggesting that Toxoplasma influences human personality rather than human personality influencing the probability of infection. Toxoplasmosis increases the reaction time of infected subjects, which can explain the increased probability of traffic accidents in infected subjects reported in three retrospective and one very large prospective case-control study. Latent toxoplasmosis is associated with immunosuppression, which might explain the increased probability of giving birth to a boy in Toxoplasma-infected women and also the extremely high prevalence of toxoplasmosis in mothers of children with Down syndrome. Toxoplasma-infected male students are about 3 cm taller than Toxoplasma-free subjects and their faces are rated by women as more masculine and dominant. These differences may be caused by an increased concentration of testosterone. Toxoplasma also appears to be involved in the initiation of more severe forms of schizophrenia. At least 40 studies confirmed an increased prevalence of toxoplasmosis among schizophrenic patients. Toxoplasma-infected schizophrenic patients differ from Toxoplasma-free schizophrenic patients by brain anatomy and by a higher intensity of the positive symptoms of the disease. Finally, five independent studies performed in blood donors, pregnant women and military personnel showed that RhD blood group positivity, especially in RhD heterozygotes, protects infected subjects against various effects of latent toxoplasmosis, such as the prolongation of reaction times, an increased risk of traffic accidents and excessive pregnancy weight gain. The modern human is not a natural host of Toxoplasma. Therefore, it can only be speculated which of the observed effects of latent toxoplasmosis are the result of the manipulation activity of the Toxoplasma aimed to increase the probability of its transmission from a natural intermediate to the definitive host by predation, and which are just side effects of chronic infection.
Investigating candidate neuromodulatory systems underlying parasitic manipulation: concepts, limitations and prospects
Studies addressing the functional basis of parasitic manipulation suggest that alteration of the neuromodulatory system is a common feature of manipulated hosts. Screening of the neuromodulatory system has so far been carried out by performing ethopharmacological analysis, biochemical quantification of neurotransmitters and neuromodulators, and/or immunocytochemistry. Here, we review the advantages and limitations of such approaches through the analysis of case studies. We further address whether the analysis of candidate neuromodulatory systems fits the current view of manipulation as being multidimensional. The benefits in combining ethopharmacology with more recent molecular tools to investigate candidate neuromodulatory pathways is also emphasized. We conclude by discussing the value of a multidisciplinary study of parasitic manipulation, combining evolutionary (parasite transmission), behavioural (syndrome of manipulation) and neuroimmunological approaches.
Pathways to understanding the extended phenotype of parasites in their hosts
The study of the adaptive manipulation of animal behavior by parasites is entering very exciting times. Collectively the field has moved from its important and instructional natural history phase into proximate-level studies aiming to elucidate the mechanisms by which one organism controls another. Because many cases studies involve cross-kingdom control of behaviour, the findings are sure to be exciting. In this review I examine what possible pathways we can take to understanding the controlling behavior of parasites and how host behavior has become an extended phenotype of the parasites that is often hidden from view.
Host–parasite molecular cross-talk during the manipulative process of a host by its parasite
Many parasite taxa are able to alter a wide range of phenotypic traits of their hosts in ways that seem to improve the parasite’s chance of completing its life cycle. Host behavioural alterations are classically seen as compelling illustrations of the ‘extended phenotype’ concept, which suggests that parasite genes have phenotype effects on the host. The molecular mechanisms and the host–parasite cross-talk involved during the manipulative process of a host by its parasite are still poorly understood. In this Review, the current knowledge on proximate mechanisms related to the ‘parasite manipulation hypothesis’ is presented. Parasite genome sequences do not themselves provide a full explanation of parasite biology nor of the molecular cross-talk involved in host–parasite associations. Recently, first-generation proteomics tools have been employed to unravel some aspects of the parasite manipulation process (i.e. proximate mechanisms and evolutionary convergence) using certain model arthropod-host–parasite associations. The pioneer proteomics results obtained on the manipulative process are here highlighted, along with the many gaps in our knowledge. Candidate genes and biochemical pathways potentially involved in the parasite manipulation are presented. Finally, taking into account the environmental factors, we suggest new avenues and approaches to further explore and understand the proximate mechanisms used by parasite species to alter phenotypic traits of their hosts.
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