The missing link in parasite manipulation of host behaviour
© The Author(s). 2018
Received: 18 January 2018
Accepted: 19 March 2018
Published: 3 April 2018
The observation that certain species of parasite may adaptively manipulate its host behaviour is a fascinating phenomenon. As a result, the recently established field of ‘host manipulation’ has seen rapid expansion over the past few decades with public and scientific interest steadily increasing. However, progress appears to falter when researchers ask how parasites manipulate behaviour, rather than why. A vast majority of the published literature investigating the mechanistic basis underlying behavioural manipulation fails to connect the establishment of the parasite with the reported physiological changes in its host. This has left researchers unable to empirically distinguish/identify adaptive physiological changes enforced by the parasites from pathological side effects of infection, resulting in scientists relying on narratives to explain results, rather than empirical evidence. By contrasting correlative mechanistic evidence for host manipulation against rare cases of causative evidence and drawing from the advanced understanding of physiological systems from other disciplines it is clear we are often skipping over a crucial step in host-manipulation: the production, potential storage, and release of molecules (manipulation factors) that must create the observed physiological changes in hosts if they are adaptive. Identifying these manipulation factors, via associating gene expression shifts in the parasite with behavioural changes in the host and following their effects will provide researchers with a bottom-up approach to unraveling the mechanisms of behavioural manipulation and by extension behaviour itself.
Letter to the Editor
Case 1: A rat contracts Toxoplasma gondii via contact with cat faeces (Event A). Following this, testicular testosterone production increases in the rat leading to hypomethylation of the amygdala (Event B). This is suggested to cause the loss of aversion to cat urine in the infected rats [8, 9].
Case 2: A mouse contracts Leishmania amazonensis via a sand fly bite (Event A). Two to four months post-establishment, several key cytokines levels are altered in the mouse’s pre-frontal cortex (Event B), potentially resulting in a set of observed anxiety behaviours in infected mice .
Case 3: The parasitoid wasp Cotesia congregata injects an egg into the caterpillar Manduca sexta (Event A). During egression of the larvae from the caterpillar, removal of octopamine from the hemolymph of the caterpillar is significantly reduced (Event B). This is thought to suppress the caterpillar’s feeding, thus enabling the larvae to egress unimpeded .
In what follows, we attempt to further clarify the thought process needed to generate definitive evidence for adaptive behavioural manipulation. By using an analogy from a different discipline and the jewel wasp-cockroach host-parasitoid system, and comparing them to the cases described above, we hope to clearly point out the gaps in our present knowledge. Furthermore, we suggest a step-by-step process that parasites should logically follow to adaptively manipulate behaviour and propose a potential avenue for researchers to begin generating evidence for the currently overlooked steps. Note that we are in no way dismissing earlier empirical studies or undermining their importance. Indeed, correlative evidence is a crucial stepping-stone toward uncovering the underlying causal mechanisms, and earlier results may point towards the true mechanisms of host manipulation. However, there is a dire need to push the field of host manipulation study to the next step and the search for the actual causative mechanisms.
Tobacco and Jewel wasps
In order to demonstrate the correlative nature of many earlier host manipulation studies, allow for an analogy: consider the addiction induced by smoking tobacco as a form of behavioural manipulation, and compare this against the cases presented above. Smoking tobacco (Event A) causes the nicotine stored in the plant leaves to be released and inhaled into the lungs where it rapidly travels to the brain. Once there, it saturates receptors normally reserved for binding acetylcholine, culminating in the excessive release of dopamine in the brain (Event B). Dopamine signals pleasure and is crucial in reinforcing behaviours. Constant, large releases of this neurochemical quickly result in addiction to nicotine and thus smoking . Albeit simplified, this system of behavioural modification has clear causative evidence, specifically the release of nicotine, connecting Event A and B. Consider a correlative explanation for tobacco addiction, similar to the three host manipulation cases presented above, in which we would only know that smoking tobacco results in higher dopamine levels in the brain, but have no idea of nicotine’s existence. Nicotine is the causative factor (i.e. the substance released by smoking tobacco) directly triggering the cascade of processes leading to addiction. Identification of nicotine and its role marked the transition from correlation to causation in research on tobacco addiction.
Although equating the mechanisms of tobacco addiction and those of host manipulation may appear obtuse, it is a clear way to demonstrate the gaps in the host manipulation research. Research on tobacco addiction may serve as a benchmark for the rigour needed in the search of mechanisms behind behavioural manipulation. Indeed, what is the causative factor that enables parasites to manipulate behaviour?
The jewel wasp-cockroach parasitoid-host system is one of the best understood examples of host behavioural manipulation. The wasp injects its venom directly into the cockroach’s brain (Event A). A component of the venom interferes with octopaminergic neurons (Event B), resulting in the loss of self-directed locomotion in the cockroach. This allows the wasp to lead the cockroach to its burrow [3, 13]. In both tobacco addiction and jewel wasp-cockroach system, nicotine and venom, respectively, unarguably connects Event A and B. Identification of the specific factors (nicotine and wasp’s venom) allows us to reliably conclude that the molecular changes observed in the smoker/host are a direct result of the cigarette/parasitoid and not just some other coincidental side effect of smoking/infection.
Connecting parasite establishment and molecular changes
Steps toward adaptive host manipulation compared against the known steps in Toxoplasma-rat, Leishmania-mouse, wasp-caterpillar and wasp-cockroach parasite-host systems. Additionally, tobacco addiction pathway included for comparison
Steps to adaptive host manipulation
Jewel-wasp and cockroach
Step 1/Event A: Parasite/tobacco establishment
Toxoplasma gondii infects a rat (Rattus norvegicus)
Leishmania amazonensis infects a mouse
Wasp Cotesia congregata injects its larvae into the catepilliar Manduca sexta
Wasp Ampulex compressa stings cockroach Periplaneta americana
Inhalation of tobacco smoke
Step 2: Manipulation factors released from source
Venom stored in the glands released into CNS
Nicotine released into lungs/brain from tobacco root
Step 3: Manipulation factors impacts physiological functioning
Neurotoxin in venom impacts octopaminergic neurons
Nicotine saturates acetylcholine receptors
Step 4/Event B: Molecular change in host
Testosterone release causes hypomethylation of the medial amygdala
Cytokine levels altered in pre-frontal cortex
Octopamine removal from hemolymph severely reduced
Sharp decrease in firing rate of affected neurons
Large dopamine release in the brain
Step 5: Behavioural change
Loss of innate aversion to cat odor
Set of anxiety behaviours
Suppression of feeding
Loss of self-directed movement
Addiction to tobacco
Finding manipulation factors and their source
In order to validate this thought process, we need to have avenues, other than observation, for identifying the potential existence of manipulative factors and their source. Recently it was found in a stickleback-cestode host-parasite system that major changes in parasite gene expression occurred during the transition from the cestode’s intermediate host to its definitive host . The transition from intermediate to definitive host is aided by loss of anti-predator behaviour in the intermediate host. Following the products of genes specifically switched on during transitional/manipulative phases in the parasite’s life-cycle could be an excellent place to start looking for manipulative factors. However, this may be an over-simplification. In this approach, we assume that the manipulative process in the parasite is a defined event initiated at a specific time, whereas achieving behavioural manipulation could instead result from a gradual process that starts early in the parasite’s life-cycle. Considering behavioural manipulation can range from a subtle change in pre-existing traits to the creation of entirely new behaviours, both punctual and gradual manipulation are distinct possibilities. Essentially, the aim here should be to pair gene expression changes in the parasite with behavioural changes in the host, and investigate these relationships for potential manipulative factors.
Finding the potential source of manipulation factors is equally important. Genomic analysis may allow researchers to identify simple manipulation factor sources such as enzymes. However, if the source is a complex structure (i.e. tissue, membrane, organelle) the number of genes involved in its development may make it difficult to identify it from genomic analysis alone, especially if that development is drawn out over the parasite’s life-cycle. Detailed histological analysis (or in-situ hybridization) of manipulative parasites, coinciding with adaptive behavioural changes in their host could serve to localise complex sources. The internal anatomy of parasites changes as they progress through their life-cycle (e.g. [15–18]). Therefore, it is not unlikely that a manipulation factor source may be absent early in a parasite’s life but present later on when manipulation occurs.
Host-parasite size disparity may also give insight into when the source becomes active. If host-parasite size disparity is great, we may expect a source that the parasite can store, as higher amounts of manipulation factor may be needed to impact host physiology. Alternatively, in host-parasite systems with little size disparity, such as hairworm-insect systems where the parasite induces its terrestrial host to seek and jump in water, the rate of production of manipulative factors may be high enough not to require storage. However, regardless of size disparity, sudden or rapid behavioural changes in the host may necessitate storage of manipulation factors by the parasite, whereas gradual behavioural changes in hosts may only require sustained production. Determining the probability that a parasite’s source of manipulation factor requires storage is important for two reasons: it informs histological searches for the source, and suggests when in the parasite’s life-cycle the source might appear.
Finally, it is also important to consider that parasites may repurpose or expand functionality of existing organelles/tissue for generating and secreting manipulation factors. Therefore, histological analysis should focus on existing structures/organelles as well as identification of new structures. Particular interest should be paid to existing organelles already capable of storage in high-disparity, rapid behavioural change host-parasite systems.
Earlier studies often use the term ‘proximate mechanism’ when reporting physiological changes in infected hosts. Proximate is an incorrect epithet for these mechanisms. If adaptive behavioural manipulation is occurring in these cases, the physiological changes in the host are actually several steps downstream from the true cause; the manipulation factors themselves and their source are thus likely the true proximate mechanisms. Adopting this alternative perspective provides a bottom-up approach that has the potential to empirically differentiate an adaptive physiological manipulation from other possible consequences of infection. When implemented, this approach will likely accelerate progress in the field of behavioural manipulation.
Availability of data and materials
RH: Initial conceptualization of articles premise, wrote manuscript. CL: Discussion of article premise and revision of manuscript. RB: Discussion of article premise and revision of manuscript. All authors read and approved the final version of the manuscript.
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