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EECG Epilogue: Schistocephalus solidus as a puppet master – Can this parasite manipulate the behavior of its threespine stickleback host?

About the Blog Author: Chloé Berger is a Postdoctoral researcher at the Institute of integrative and systems biology at Laval University, Québec Canada. She is interested in the molecular mechanisms underlying biodiversity and adaptations of organisms in their environments. During her PhD with Nadia Aubin-Horth, she worked on host behavior manipulation and used molecular/functional approaches to better understand how a cestode worm can disrupt the adaptive behavior of its threespine stickleback host. Her current work with Louis Bernatchez aims at experimentally studying the ecology of environmental DNA (eDNA) in aquatic environments. Follow Chloé on Twitter @chloe_berger05.

 

I was honored to be awarded an AGA EECG award in 2019 during the last year of my PhD thesis in Nadia Aubin-Horth’s research group. The aim of this award was to help me obtain new insights into the molecular cross-talk between a phenotype-altering cestode and its fish host, the threespine stickleback, using high throughput genomics and proteomics.

For years, behavioral manipulation has been a fascinating topic.  In 1947, in his classic novel The Plage, the French author Albert Camus described how rats infected by the disease would emerge from the sewers to die in the streets, ultimately infecting humans. Classic movies also loved to report the stories of silly scientists that become infected by some unknown parasites from outerspace, so that these scientists lose their mind and infect all their colleagues (see Chris Carter’s X-Files series from the 90s). Nowadays, a classical example of behavioral manipulation is found in Toxoplasmosis – a serious disease for pregnant women – as it can vertically be transmitted to the fetus. Rats infected by Toxoplasma become attracted to the smell of cat urine, which is the final host in which the parasite reproduces (Ajai et al 2007). Even in the context of the global pandemic, it has been suggested that behavioral manipulation could be the key to the successful global spread of COVID-19, as cases of infected persons ignoring self-confinement orders, intentionally disregarding physical distancing, and multiplying social interactions were reported (Bouayed and Bohn 2021). In all these cases, we talk about parasitic “manipulation”. It implies that the parasite would be able to “manipulate” the behavior of its host, to increase its transmission rate and fitness. However, this term is often mistakenly used as a synonym for all the behavioral changes induced by a parasite in its host. Instead, a more parsimonious explanation would be that these behavioral changes in the infected host are simply a pathological side-effect of infection (Grecias et al 2018; Herbison et al 2018), in the same way we modify our behavior when we are sick. This was the problem I addressed during my PhD thesis, using the threespine stickleback-Schistocephalus solidus system.

Figure1: Threespine stickleback infected by Schistocephalus solidus (picture by Chloé Berger)

The threespine stickleback-Schistocephalus solidus system is ideal to study the interaction between a vertebrate host and a parasite that is located outside the brain of its host. In this case, it’s inside the abdominal cavity. Threespine sticklebacks that are infected by the cestode Schistocephalus solidus show dramatic changes in behaviour. For instance, sticklebacks usually perform vertical migration in the water column, only swimming at the surface at night, potentially making them less visible to visual avian predators. When a fish is caught at the surface during the day, it has a higher probability of being infected by S. solidus (Quinn et al 2012). This parasite has a complex life cycle with three hosts: a crustacean, the threespine stickleback (obligatory intermediate host), and a fish-eating bird – where it reproduces. Previous studies suggested that these behavioral changes in the fish host could be the result of a direct manipulation by the parasite in order to increase its transmission probability to its final bird host (Barber and Scharsack 2010). However, because most of these studies failed to link the establishment of the parasite in its host with the behavioral changes observed in the host, it is difficult to determine if the behavioral changes are the result of a direct manipulation by the parasite or if these behavioral perturbations are a pathological side-effect of infection as discussed earlier. Furthermore, before my PhD, we didn’t have any information about the molecular mechanisms that could be used by the worm to interact with its host.

Figure2: Life cycle of Schistocephalus solidus (designed by Chloé Berger)

We, therefore, decided to focus on the secretome of S. solidus. The secretome is a substance secreted by parasites that can include lipids, nucleic acids, and proteins. This secreted substance is often considered as a key element for the interaction of a parasite with its host (Biron and Loxdale 2013). Using high throughput proteomics (LC-MS/MS), we described the proteome (i.e., all the proteins expressed in the worm tissues) and the proteomic fraction of the secretome of S. solidus. We found that the secretome included proteins not detected in the proteome (at least at our level of detection) and that were involved in cell-cell signaling, neural and immune functions, thus representing good candidates to explain the behavioral changes of infected sticklebacks (Berger et al 2021). Moreover, one important part of my PhD work was to functionally test the role of the secretome of S. solidus in the behavioral changes of the stickleback. To do so, we injected the secretome in the abdominal cavity of sticklebacks coming from two different populations (one that evolved with the worm, another one that was naturally not in contact with the parasite), and we measured their behavior before and after injection. We found that the secretome could alter the host’s behavior, but not in the way we expected, as it was not recapitulating the behavioral response to infection (Berger and Aubin-Horth 2020).  When we designed the experiment, we had no idea that the fact of using two distinct populations could give us access to such exciting discoveries, as it suggests local adaptation between host–parasite pairs that may extend to the response to the parasite’s secretome content.

Figure3: Setting to perform behavioural tests with threespine sticklebacks (pictures by Chloé Berger)

At the time I applied for the EECG award, we wanted to pursue the functional analyses of the proteins previously detected by LC-MS/MS in the secretome by injecting them (alone or in combination) into non-infected fish to try to reproduce the behavior of infected fish. These sticklebacks were planned to be caught in the wild. Working with wild animals is, in my point of view, a strength of my work as I don’t think that we can properly study behaviors described in the wild with fish that would only be raised in the lab. However, this strength also appears to be a weakness of my PhD research, as it is difficult, for various technical reasons, to catch fish in nature and maintain them in the lab. During the last year of my PhD, I therefore did not have access to wild fish to perform such injections, and the COVID-19 worsened the situation by preventing us to perform any field experiments these past two years. As I have now completed my PhD and embarked on new projects, I hope that I will be able to collaborate in the future with some enthusiastic graduate students that will be as thrilled as I was during my PhD to work on such an exciting system.

Another objective we have is to obtain a description of the genome of Schistocephalus pungitii. S. pungitii, which is phylogenetically close to S. solidus, is of particular interest as it has the ability to infect the ninespine stickleback, but it does not induce behavioral changes in the fish host following infection. We now benefit from a novel genome sequence and assembly of S. solidus. Comparing the genomes of S. solidus and of S. pungitii will especially provide new insights on the genes that are specific to S. solidus, and that could be thereby involved in parasitic manipulation.

All in all, our findings suggest that the secretome of S. solidus may be an important molecular messenger that could act on the host brain and physiological systems to impair adaptive behavior. As we continue to move on this project, it becomes clearer that host altered behaviors that we call “behavioral manipulation” are more probably of multifactorial nature. Schistocephalus solidus does not pull all the strings.

 

References:

Ajai V, Seon-Kyeong  K, Nicholas G, John B, Robert MS (2007). Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proceedings of the National Academy of Sciences. 104: 6442-6447.

Barber I,  Scharsack JP (2010) The three-spined stickleback – Schistocephalus solidus system: an experimental model for investigating host-parasite interactions in fish. Parasitology. 137:411-424.

Berger CS, Aubin-Horth N (2020).The secretome of a parasite alters its host’s behaviour but does not recapitulate the behavioural response to infection. Proceedings of the Royal Society B. 287: 20200412

Berger CS, Laroche J, Maaroufi H, Martin H, Moon KM, Landry CR, Foster LJ, Aubin-Horth N (2021).The parasite Schistocephalus solidus secretes proteins with putative host manipulation functions. Parasites&Vectors. 14: 436-456.

Biron DG, Loxdale HD (2013). Host-parasite molecular cross-talk during the manipulative process of a host by its parasite. Journal of Experimental Biology. 216:148-160.

Bouayed J, Bohn T (2021). Behavioral manipulation-key to the successful global spread of the new coronavirus SARS-CoV-2?. Journal of Medical Virology. 93: 1748–1751.

Grécias L, Valentin J, Aubin-Horth N (2018). Testing the parasite mass burden effect on alteration of host behaviour in the Schistocephalus–stickleback system. Journal of Experimental Biology. 221: jeb174748.

Herbison R, Lagrue C, Poulin R (2018). The missing link in parasite manipulation of host behaviour. Parasites&Vectors. 11: 222.

Quinn T, Kendall N, Rich H, Chasco B (2012). Diel vertical movements, and effects of infection by the cestode Schistocephalus solidus on daytime proximity of three-spined sticklebacks Gasterosteus aculeatus to the surface of a large Alaskan lake. Oecologia. 168: 43-51.


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