Clockwork intruders: Do parasites manipulate their hostsʼ circadian rhythms?

Abstract

Most organisms have developed circadian clocks to adapt to 24-hour cycles in the environment. These clocks have become crucial for modulating and synchronizing complex behavioral and biological processes. A number of parasites seem to have evolved to take advantage of their hosts’ circadian rhythms to favor their own infection and survival. Some species, such as Microphallus sp. and Trypanosoma cruzi, can alter the patterns of locomotor behavior of infected intermediate hosts, which can promote transmission to a subsequent primary host. Some fungi of the genera Ophiocordyceps and Entomophthora, as well as hairworms (Nematomorpha), elicit complex behaviors that promote their host’s death at a time and place that optimizes continuation of the parasite’s life-cycle. At least in some cases, a proposed mechanism might involve a change in the expression of clock-controlled genes. Lastly, some disease-causing protozoan parasites of the genera Trypanosoma, Plasmodium, and Leishmania induce changes in the circadian rhythms of their primary hosts upon infection. Some of these changes may be attributed to circadian alterations resulting from the host’s inflammatory response to the infection or other unexplored responses or adaptations to the illness. Thus, a distinction must be made between manipulation of the parasite and response of the host when studying these alterations in the future. Parasitic manipulation of circadian rhythms, which vastly modulates behavior and physiology, is an essential issue that has been relatively understudied. A deeper understanding of this phenomenon could lead to the development of novel therapeutic approaches for the diseases that these parasites convey.

Graphical abstract

Highlights

• •Many parasites alter the circadian clock of their hosts upon infection.
• •Some parasites can change hosts' behavior at specific times to promote transmission.
• •Circadian manipulations may be present in some infections that cause human diseases.
• •The effect of inflammation on rhythms must be accounted for in infection studies.

1. Circadian rhythms

All organisms on Earth have evolved in environments with 24-hour rhythmic cycles, including the day-night cycles. Accordingly, they have implemented internal timing mechanisms that coordinate physiology and behavior with cyclic variations in the environment (Hut and Beersma, 2011). These mechanisms, called circadian clocks, help schedule biological functions with respect to the environment, and coordinate internal processes, including regulation of metabolism, temperature control, and hormones (Cox and Takahashi, 2019).

Although the circadian clocks can function endogenously, without input from the environment, organisms need external time cues to synchronize their clocks with the environmental cycles. In mammals, the primary environmental time cue is light, which can reset a central circadian clock located in the suprachiasmatic nucleus (SCN) in the brain. The SCN clock sends signals to synchronize peripheral clocks throughout the body (Fig. 1A) (Maywood, 2020).

Fig. 1.

The mammalian circadian system. A Light acts as an environmental time cue for the central circadian clock, the suprachiasmatic nucleus (SCN), which in turn sends signals to peripheral clocks all throughout the body to synchronize them. The circadian regulation from the SCN and the peripheral clocks give rise to physiological and behavioral rhythms. B The basic molecular clock functions as a transcription-translation feedback loop, in which transcriptional activators BMAL1 and CLOCK heterodimerize and bind to E-boxes. This promotes the expression of Per and Cry genes, as well as many clock-controlled genes (CCGs), serving to modulate various biological processes. PER and CRY proteins then repress the activity of CLOCK/BMAL1, and thus, their own transcription. The clock mechanism is much more complex, as additional feedback loops add to the core loop depicted here, as well as many post-transcriptional layers of regulation. CCGs can also be regulated by other rhythmic transcription factors besides CLOCK/BMAL1. C Changes in the characteristics of physiological and behavioral rhythms, like their period, amplitude and phase, are commonly evaluated to study alterations in the clock. Created with BioRender.com.

At the molecular level, the clock is made up of various genes and proteins that together form transcription-translation autoregulatory feedback loops (TTFLs). Although this principle is maintained across life forms, the specific clock genes underlying the mechanism can vary (Cox and Takahashi, 2019). The mammalian molecular clock is well known (Fig. 1B), with, at its core, the transcription factors CLOCK and BMAL1 activating the expression of Period and Cryptochrome genes, whose protein products feedback negatively on their own expression (Cox and Takahashi, 2019). The molecular clock also regulates the transcription of hundreds to thousands of clock-controlled genes (CCGs), a way by which the clock controls various cellular processes (Bozek et al., 2009; Zhang et al., 2014).

A recent body of literature has shown extensive circadian regulation of all aspects of the immune system. All immune cell types express clock genes, and their functions are regulated according to the time of the day (Labrecque and Cermakian, 2015). This includes the immune response to infections by bacteria, viruses, and parasites. Upon infection, these pathogens will encounter other types of rhythms in their host, such as rhythms of metabolites and hormones, which will represent important elements of the pathogens’ new environment (Westwood et al., 2019). Indeed, in parasitic infections, circadian rhythms play an important role in the probability, course, and outcome of the disease. This involves rhythms of the host, pathogen, vector and environment (Carvalho Cabral et al., 2022).

There are several cases of circadian regulation of parasitic infections by host clocks. For example, the severity of Leishmania infection and the host’s inflammatory response are modulated by the clocks of the immune cells (Kiessling et al., 2017); the timing and efficiency of worm expulsion after infection by Trichuris muris is altered by the dendritic cell clock (Hopwood et al., 2018); and Plasmodium’s developmental cycles inside red blood cells (RBCs) are regulated by the host’s immune and metabolic circadian rhythms (Hirako et al., 2018; Prior et al., 2018).

Not only can host rhythms regulate parasites, but there are also many examples of parasites altering the rhythms of the host upon infection. These alterations may be the result of sickness responses of the host or constitute a manipulation of the host by the parasite. The “manipulation hypothesis” is the proposal that some parasites have evolved to modify certain aspects of their host’s behavior in a way that favors their own survival and probability of transmission (Thomas et al., 2005). Since organisms rely heavily on rhythmic physiology, the clock can be a good target for manipulation by parasites that tend to take advantage of hosts to favor their propagation and survival (Rankawat et al., 2023). In this review, we aim to provide an overview of the effects of parasitic infections on the hostsʼ circadian rhythms.

2. Alteration of rhythms and transmission to the primary host

One aspect of such effects is the alteration of rhythms in the behavior of intermediate hosts upon infection by parasites (Fig. 2A; Table 1). These alterations could enhance parasite transmission through trophic or vector-borne infection of a primary host, as has been observed with comparable non-circadian cases of parasitic manipulation (Cézilly et al., 2010).

Fig. 2.

Patterns of circadian manipulation by parasites. A Some parasitic infections alter patterns of locomotor activity of intermediate hosts, which may favor interaction with primary hosts. B Some others evoke complex behaviors that kill their host at a time and place that could optimize continuation of the parasite’s life-cycle. C Some parasites produce alterations in the circadian system of the primary host, either as a direct consequence of the infection or due to the inflammatory response of the host. Created with BioRender.com.

Table 1.

Hypotheses and alternative explanations for altered host rhythms.

	Parasite	Altered host rhythm	Hypothetical benefit to parasite (and likelihood*)	Alternative explanation (and likelihood*)	How to differentiate
Intermediate hosts	Microphallus sp.	Rhythm of activity and foraging behavior.	Increased exposure to primary host. (Likely)	Change of activity to increase foraging or energy conservation to fight the infection. (Unlikely)	Measure feeding behavior and transmission in ecologically relevant environments.
	Trypanosoma cruzi	Rhythm of locomotor activity.	Increased exposure to primary host. (Likely)	Change of activity to increase foraging or energy conservation to fight the infection. (Unlikely)	Measure feeding behavior and transmission in ecologically relevant environments.
Timely death	Ophiocordyceps spp.	Induction of stereotyped behaviors resulting in death, at specific times of the day.	Ideal conditions for increased spore proliferation and transmission. (Very likely)	Leaving the community to avoid further infection. Climbing and biting, not obvious. (Unlikely)	Study of mechanism and tangible effect in transmission.
	Entomophthora muscae	Induction of stereotyped behaviors resulting in death, at specific times of the day.	Ideal conditions for increased spore proliferation and transmission. (Very likely)	Leaving the community to avoid further infection. Summiting and spreading wings, not obvious. (Unlikely)	Study of mechanism and tangible effect in transmission.
	Nematomorphs	Induction of stereotyped behaviors resulting in death, at specific times of the day.	Continuation of life-cycle in new environment. (Very likely)	Result of change in light perception as a result of sickness, preventing arthropods from avoiding bodies of water. (Unlikely)	Control for light perception and see if it causes behavior. See if the effect on light perception is specific to the parasite.
Primary hosts	Trypanosoma brucei	Dysregulation of sleep, amplitude of circadian activity and temperature, period of activity, and period of clock gene expression.	Not obvious. (Unknown)	Not obvious for the shortening of the period. (Unlikely)
	Trypanosoma cruzi	Amplitude of circadian activity, re-entrainment after phase shift.	Not obvious. (Unlikely)	-Effect of inflammation on amplitude (Likely). -Altered detection of light due to sickness. (Unknown)	Compare against effects of proinflammatory agents. See if the effect on light detection is specific to the parasite.
	Plasmodium chabaudi	Amplitude of circadian activity, temperature, and clock gene expression, and electrophysiological rhythms in RBCs.	Dictate electrophysiological rhythms to alter morphology of RBCs to adjust to the developmental cycle of the parasite. (Unknown)	-Effect of inflammation on amplitude. (Likely). -Electrophysiological rhythms may be a result of RBC changes due to developmental cycle of the parasite. (Unknown)	Compare against effects of proinflammatory agents. Further study the relationship between parasite development cycles and electrophysiological rhythms.
	Leishmania major	Rhythm of macrophage receptor expression.	Improvement of the attachment of parasites to macrophages. (Unknown)	Not obvious. (Unknown)
	Trichuris muris	Amplitude of circadian activity and temperature.	Not obvious. (Unlikely)	Effect of inflammation. (Very likely)	Compare against effects of proinflammatory agents.

Note: *The “likelihood” of the explanation is our assessment based on the strength of the arguments and the current evidence for them.

This type of alteration has been observed for the trematode Microphallus sp., which changes the pattern of behavior of infected snails (intermediate hosts of the parasite), increasing the chances that they get eaten by waterfowl (primary hosts of the parasite) instead of other predators such as fish (Levri et al., 2007). Infected snails will move to safe locations at the time of the day in which fish predation is more likely, but will inhibit this behavior at the time in which waterfowl are more active, leaving them more vulnerable to being eaten by this parasite’s primary host. This manipulative mechanism might function as a change in the response to the direction of light at different times, or of their clock-controlled locomotor rhythms.

A similar phenomenon takes place for the protozoan parasite Trypanosoma cruzi, which is transmitted through the bite or feces of triatomine bugs, and causes Chagas disease in humans. This parasite alters the circadian locomotor activity pattern of its vectors, in a species-dependent manner. The triatomine Mepraia spinolai, a diurnal species, shifts its daily pattern of movement towards the night when infected by Trypanosoma cruzi (Pérez et al., 2021). Meanwhile, Triatoma infestans, a nocturnal species, moves more often and longer distances during the daytime after infection, and this increase in activity is correlated with the number of parasites in its system (Chacón et al., 2022). This shift in activity rhythms could potentially favor the infectivity of the vector to the primary host of the parasite, by increasing the opportunities of biting or defecating on a potential host. Triatoma infestans is a domestic species that feeds mainly on humans, who are diurnal, while M. spinolai tends to live in the wild and has a wider range of mammalian hosts, some of which are nocturnal (Canals et al., 2001). This could explain the opposite results in terms of the time of the day in which the activity increases, as the parasite may benefit from the vector being active at the same time as the primary hosts.

Although it is likely that these are cases of parasitic manipulation, this is yet to be formally demonstrated. Alternative explanations for the circadian alterations should therefore be considered. For example, hosts fighting an infection may have higher energetic needs, and could require changing their behavioral patterns in order to either forage more or conserve more energy, resulting in altered rhythms of activity.

3. Modification of rhythms and timely death

In the examples described above, it is clear that parasites can benefit from altering the behavioral circadian rhythms of the intermediate hosts, whether for trophic or vector-borne transmission. In other cases, the potential fitness does not come only from the circadian activity itself, but from the use of circadian clocks to take control over other broad mechanisms. In that sense, some parasites introduce in their hosts behaviors they would normally not present. This often includes relocation to the optimal place and time to die for the parasite to continue its life-cycle and promote its transmission (Fig. 2B; Table 1).

The fungus Ophiocordyceps spp., has this effect on carpenter ants upon infection. Infected “zombie ants” will stop their regular activities in order to climb to high vegetation (summiting), bite leaves, and die, leaving the infected cadaver in a high place, which would increase the area of spore proliferation. This manipulation happens at a specific time of the night. Release of the spores at this time provides ideal conditions of temperature, humidity, and lack of UV rays to protect the spores. It is also the same time that carpenter ants usually forage, further promoting infection (Andersen et al., 2009; de Bekker and Das, 2022). This deadly manipulation elicited by the fungus involves the downregulation of the ants’ circadian clock genes (de Bekker et al., 2015). A recent transcriptomic meta-analysis showed that the genes of carpenter ants that are differentially expressed upon parasitic manipulation are the same as those involved in the behavioral plasticity required for quick changes in division of labor that characterize these species (de Bekker and Das, 2022). Furthermore, the representation of these genes in infected ants is correlated to that of clock-controlled genes that follow 24-hour rhythms (de Bekker and Das, 2022).

Similarly, Entomophthora muscae, another fungal parasite, can infect fruit flies Drosophila melanogaster and compel them to suddenly stop flying and to summit, fix in place and spread their wings before dying, leaving the body in a position that is thought to be optimal for the dispersion of fungal spores (Elya et al., 2018). The flies’ pre-death process happens at specific times of the day, even in constant darkness, which suggests endogenous circadian control. Furthermore, it involves disruption of clock neurons (group 1 posterior dorsal neurons; DN1ps), and it is significantly decreased in clock gene knock-out flies, indicating that the fungus’ manipulation of the circadian system is key for the development of this behavior (Elya et al., 2023).

A comparable manipulation occurs in non-fungal parasites: species of Nematomorpha, or hairworms, are known to alter the behavior of infected arthropods (crickets, mantids) to look for a body of water and jump into it, dying inside. This behavior only occurs in the early night, which allows the hairworms to emerge from the host’s body and continue their natural life-cycle in the water (Thomas et al., 2002). The manipulation is accompanied by an alteration of the insects’ light perception, which they usually depend on to avoid bodies of water (Obayashi et al., 2021). This could potentially explain the diurnal variation in the behavior of these infected hosts.

These parasitic infections that result in completely novel behaviors in infected subjects could represent cases of parasitic manipulation, as they have a clear benefit to the parasite to the detriment of the host. However, studies testing the hypothesis that this alteration effectively results in increased parasite transmission are still missing in most cases.

The mechanisms behind these complex alterations must also be studied further. Although little is known about these mechanisms, it seems that in some cases, a key part of the process is the control over the circadian clock, in order to elicit the behavior in a timely manner to potentially optimize transmission.

4. Alteration of rhythms of primary hosts

The most studied type of circadian alteration after parasitic infection is that of protozoan parasites that affect the rhythms of their primary hosts (Fig. 2C; Table 1). These are generally parasites that cause diseases in their hosts, including humans, and can result in disruption or modification of their circadian rhythms.

The clearest example of this category is Trypanosoma brucei, which causes human African trypanosomiasis (more commonly known as sleeping sickness). Patients show a dysregulation of sleep-wake cycles, as well as of other biological rhythms such as temperature and endocrine rhythms (Buguet et al., 2001), suggesting that the infection has an effect on their circadian clocks. A recent study found that infection in mice results in decreased locomotor activity, increased percentage of activity during the daytime, and a shortening of the circadian period of activity (Fig. 1C) (Rijo-Ferreira et al., 2018). Furthermore, infected adipose tissue and SCN also reduced their period of clock gene expression, proving that this parasitic infection alters the expression of the molecular clock, resulting in circadian disruption (Rijo-Ferreira et al., 2018). Infected mice also have altered homeostatic sleep responses to sleep deprivation, suggesting that part of the symptoms in the disease can also be attributed to disruptions in the homeostatic system that balances sleep and arousal, caused by the infection (Rijo-Ferreira et al., 2020).

Some of these alterations are also observed in another parasite of the same genus, Trypanosoma cruzi, responsible for the development of Chagas disease. Infection by this parasite also causes circadian alterations, such as a decrease in the amplitude of circadian activity rhythms (Fig. 1C), a decreased response to light, and a slower re-entrainment after a phase shift (Fernández Alfonso et al., 2003). Unlike with Trypanosoma brucei though, a change in period was not observed.

A different case is that of malaria, a highly prevalent infectious disease caused by the parasite Plasmodium spp. The parasite is transmitted to primary hosts by the bite of mosquito Anopheles. Following transmission, parasites first replicate in the liver, then go into the circulation and invade RBCs, where they follow daily cycles of replication called the intraerythrocytic development cycle (IDC) (Prior et al., 2020). These cycles are coordinated with the host’s circadian rhythms reciprocally. In infected mice, immune rhythms of cytokine production follow the IDC, but do not directly entrain it (Prior et al., 2018). Then, blood glucose levels respond to the rhythmic differences in energetic demands of the immune response, causing rhythmic hypoglycemia during the host’s rest phase (Hirako et al., 2018). Finally, the IDC adapts and entrains to the resulting metabolic rhythms of the host (Hirako et al., 2018; Prior et al., 2018). Furthermore, a recent study has found that non-molecular rhythms in RBCs might be affected by these development cycles. Upon infection, the electrophysiological properties of infected RBCs change. Namely, the electrical capacitance of the membrane gains a rhythm, and rhythms of electrical conductivity of the cytoplasm are phase-shifted (Fig. 1C), aligning to the rhythms of parasitemia caused by the IDC (Labeed et al., 2022).

Additionally, infection by Plasmodium chabaudi was found to decrease the amplitude of circadian rhythms of activity, body temperature and clock gene expression in some organs, but with no change in period (Rijo-Ferreira et al., 2018; Prior et al., 2019). The severity and pattern of the behavioral changes on host rhythms can vary, and some of these variations can be attributed to genetic variation amongst the parasites. However, they always include lower amplitude of activity and temperature rhythms throughout the disease (Prior et al., 2019). As discussed below, these changes in rhythms upon Plasmodium infection might be mediated by inflammation.

Lastly, the Leishmania spp. parasites, responsible for the disease leishmaniasis, have also been studied for their relationship with their hostsʼ circadian rhythms. Leishmania spp. are transmitted through the bite of a sand fly, and are quickly taken up by innate immune cells, where they are able to survive and replicate. These parasites are well known to alter host functions to their advantage, including intracellular signalling (Atayde et al., 2016), and would benefit from modulating the clock to alter other mechanisms. Recent research has shown that the host circadian clocks regulate infection by Leishmania major. This interaction may go both ways, as the rhythmicity of macrophage receptors (CD206 and CD11b) was found to shift upon infection of the cells in vitro (Kiessling et al., 2017). Whether parasite manipulation or host’s response, this may play a part in the regulation of infection, as it could affect the attachment of the parasites to host’s macrophages.

There is much scarcer information on multicellular parasites altering primary hosts’ rhythms. However, infection by the gut helminth Trichuris muris modifies rhythmic behavior of murine hosts, which present a decrease of amplitude of both circadian activity and temperature (Hopwood et al., 2018).

It is important to point out that, in most of these cases, it is not obvious how these parasites may benefit from disrupting their hosts’ rhythms in order to prolong their survival or increase their infectivity. The possibility that these changes are not a direct effect of the parasite, but a consequence of the host’s response to the infection, must therefore be strongly considered.

5. Effects of inflammation on circadian rhythms

One important aspect that could explain some of these circadian alterations is the organism’s immune response to the infection. Inflammation is well known to result in a decreased amplitude of both behavioral and molecular circadian rhythmicity (Cermakian et al., 2014; Xu et al., 2021) including in the context of viral or bacterial infection (Rijo-Ferreira and Takahashi, 2022).

Many studies have used inflammation-inducing agents, such as lipopolysaccharide (LPS) or turpentine oil in rodents, and have found a dampening of clock gene expression in the SCN and peripheral organs (Okada et al., 2008; Westfall et al., 2013; Xiong et al., 2019). LPS injection also causes hypothermia (Mul Fedele et al., 2020) and “sickness behavior” that includes reduced locomotor activity (Santana-Coelho et al., 2023). In vitro experiments with cell lines have found a similar reduction of clock gene expression upon LPS treatment (Liu et al., 2017; Lin et al., 2023). Furthermore, a decrease in the amplitude of molecular and behavioral rhythms can be achieved by a direct introduction of the proinflammatory cytokine TNFα, but not IL-6 (Cavadini et al., 2007; Westfall et al., 2013), and LPS-induced hypothermia is partly mediated by TNFα (Mul Fedele et al., 2020). Also, LPS-induced TNFα can shift the phase of activity rhythms, in a manner similar to light, suggesting that it interacts with the clock as a modulator of clock-controlled variables (Leone et al., 2012; Paladino et al., 2014).

One proposed mechanism for the effect of inflammation on the clock is that TNFα downregulates circadian transcription through its downstream transcription factor NFκB. A recent study showed that the NFκB subunit RelA interacts with BMAL1 to repress its transcriptional activity (Shen et al., 2021). TNFα also inhibits the expression of CIRBP, a protein usually required for high-amplitude expression of circadian rhythms, through the other subunit of NFκB, RelB (Lopez et al., 2016). Additionally, the proinflammatory cytokine IFNγ could be involved in clock dampening as well, although not through its known canonical pathways (Chen et al., 2020).

In light of this, some cases of host circadian rhythm modification in response to parasitic infection may be explained as a response to inflammation. Trichuris muris (Hopwood et al., 2018) is a good example of this, as its main circadian consequence upon infection is a decrease in amplitude, also observed in response to proinflammatory cytokines. Trypanosoma cruzi infection may also fit into this category (Fernández Alfonso et al., 2003). However, alterations in response to light, and re-entrainment after a phase shift could also be explained by an altered detection of photic stimuli caused by the parasite.

The effects of Plasmodium on the clock may be two-fold. On one hand, decreased clock gene transcription levels and running wheel behavior (Rijo-Ferreira et al., 2018) could easily be attributed to the inflammatory response. On the other hand, recent findings on the alteration of electrophysiological rhythms of RBCs (Labeed et al., 2022) could point to a more specific and direct effect of the parasite. More studies are still required to determine whether this is a manipulation by the parasite, or an adapted response from the host to the parasite’s rhythmic replication cycles.

In contrast, the circadian effects of Trypanosoma brucei infection seem to be independent of the host’s immune response, as the clock alterations were also seen in isolated cells and organs cultured with the parasite, and in vivo they persisted at a time in the course of the infection when there is likely no significant inflammation (Rijo-Ferreira et al., 2018). Also, rhythm changes were characterized by a shortening of the circadian period of both activity and clock gene expression, which is unique to this infection, and not a likely consequence of inflammation (Rijo-Ferreira et al., 2018). Similarly, the effect of Leishmania on macrophage receptor expression rhythms also occurs in vitro, suggesting that it is not an effect of inflammation (Kiessling et al., 2017). More studies are needed to see if the parasite alters other aspects of host’s circadian clock rhythms, or if this is an isolated response to a parasite known for altering macrophage processes (Atayde et al., 2016).

6. Parasitic manipulation vs host response

The possibility that the response of the host, rather than the parasite itself, is responsible for these changes goes beyond inflammation, as other categories of direct behavioral and physiological responses to sickness could equally cause changes in the rhythms of the organism. Additionally, some of the circadian alterations could be adaptations of the host to respond to the infection. For example, organisms could try to leave their community in response to a fungal parasite infection as a means to prevent further infection of their colonies. In this example, however, the possibility of parasitic manipulation also affecting the climbing and biting behavior of the hosts could not be discarded. The prospect of both parasite and host responses contributing to the altered behavior further complicates the process of proving either.

In order to distinguish between a parasitic manipulation and the result of host responses, future studies should: (i) explore the molecular mechanisms behind the alterations to better understand how they work; (ii) properly quantify the effect of the alteration on the fitness of both the parasite and the host, testing the hypothesis that they are adaptations that increase survival and/or transmission; and (iii) test alternative explanations to the alterations (Heil, 2016). Some examples of alternative explanations for the cases discussed in this review can be found in Table 1.

An example of the relevance of these research strategies is that of Plasmodium spp., which can cause infected mosquitoes to increase their biting behavior in late-stage infections (Cator et al., 2013). This was assumed to be a parasitic manipulation; however, it was later proven that similar changes occur when mosquitoes were infected with killed E. coli instead, and that the alteration was associated with changes in the insulin signaling of the host, making the behavioral alteration more likely to be the result of a metabolic response of the host to an infection, rather than a specific manipulation of the parasite (Cator et al., 2013, 2015).

Combining the techniques harnessed by the fields of chronobiology and ecology to analyse these aspects of the alterations will be key to further our understanding of potential parasitic manipulations of circadian rhythms.

7. Final remarks

Parasites tend to take advantage of host’s malleable traits, and alter them to improve their own transmission and survival. Since rhythms form an essential part of most organisms’ behavioral patterns, and clocks profoundly control their physiology, many parasites seem to have evolved to take advantage of them. Therefore, chronobiology must be integrated into the study of parasitic infections, as understanding parasite action could help develop strategies to improve treatment and prevention of the diseases they carry.

As discussed, some of the effects observed on the rhythmicity of primary hosts may be the consequence of inflammation. In order to advance the study of these phenomena, host inflammatory responses to infection must be accounted for when studying the effect of parasites in rhythmicity in the future.

Lastly, even when the alteration of the clock is not the direct effect of inflammation, it is still difficult to differentiate between what constitutes manipulation of the clock by the parasite in contrast to a response of the host to the infection. Studying the mechanisms behind these alterations, and testing the fitness benefit they may represent for the parasites, will help making this important distinction, as well as elucidating how exactly circadian clocks may be used to control certain behaviors.

Funding

This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) (PJT-168847, to NC and MO). SBW was supported by a fellowship from Mexico’s National Council of Humanities, Science and Technology (CONAHCYT) and the Mexican Foundation for Education, Science and Technology (FUNED).

Data availability

The data supporting the conclusions of this article are included within the article.

CRediT authorship contribution statement

Sebastián Boy-Waxman: Writing – original draft, Writing – review & editing, Visualization. Martin Olivier: Writing – review & editing, Funding acquisition. Nicolas Cermakian: Supervision, Writing – review & editing, Funding acquisition.

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.