Human parasite’s daily rhythms could be targeted for better treatments

The parasitic worm that causes the neglected tropical disease, schistosomiasis, has daily rhythms in gene expression, including genes that could be targeted in drug development.

For the first time, the worm that causes schistosomiasis has been shown to have a daily rhythm that impacts which genes are switched on at different times.

The new research, from the Wellcome Sanger Institute and collaborators, identified certain genes that are switched on in the parasite to align with the mouse host’s daily rhythms. This gives novel insights into how these centimetre long worms can survive the 24-hour cycles of the immune and blood-clotting systems in the human blood vessels for over 30 years¹.

The study, published today (2 December 2021) in BMC Biology, highlights that many genes that could be targeted in the development of treatments and vaccines for schistosomiasis have 24-hour patterns of expression. It suggests that there are certain times of the 24 hour period where these treatments could be more effective, when aligned with peak gene activity in the worm.

Schistosomiasis is a neglected tropical disease caused by the eggs of the female parasitic worm, Schistosoma mansoni. This disease has a vast human impact, causing an estimated 140,000 cases and 11,500 deaths in 2019 alone². It is prevalent across sub-Saharan Africa, certain South American countries and the Caribbean, with some reports in the Arabian Peninsula³. Despite the profound global impact of schistosomiasis, there is complete reliance on a single drug for treatment, and new evidence suggests that there is growing drug resistance in some worm populations^4,5. Therefore, there is a need to develop a new generation of therapeutics.

The cycle of day and night, imposed by the Earth turning on its axis, is one of the most striking features of the world in which we live. To align with this, many species exhibit daily changes in their behaviour and/or physiology. The synchrony of an organism with the environment is critical to its survival, and a mismatch in this can lead to the organism being unable to survive.

Disease-causing single celled parasites, such as Plasmodium parasites that live in mosquitoes and humans and cause malaria, have been proven to have daily rhythms in gene expression and these have been shown to impact drug sensitivity^6-8. However, it has never been studied in a multi-celled parasite like Schistosoma mansoni before.

In this new study, researchers collected worm samples from three infected mice every four hours over a 44 to 48 hour period. The gene expression of the worms was analysed over the time course and 209 genes were revealed to have 24-hour patterns of abundance. The function of these genes suggest that when the host is active the parasite is stressed, switching on genes that help protect the parasite from the rise of the host’s body temperature. Comparatively, during the host’s resting phase the parasite interacts with the host’s immune and blood coagulating systems and experiences a rush in activity of genes involved in changing food into energy.

This study also found that many genes expressed in the female reproductive system and involved in egg laying have daily rhythms of expression, and these translated to daily patterns of egg laying. Some of these genes could be targeted to provide new therapies to help treat schistosomiasis.

Tracking when these genes are switched on, and the mechanisms behind this, could be utilised to ensure that the treatments or vaccines are given when the gene is most active to ensure optimum effectiveness of treatments.

“Our study is the first window into the time-of-day biology of the Schistosoma mansoni parasite within its mammalian host. The genes oscillating in a 24-hour pattern give us ideas about the molecular toolkit used by the worm to ensure long-term survival within the host and transmission between hosts. These genes may also synchronise the worms’ rhythms to our own rhythms.”

Dr Kate Rawlinson, first author and Janet Thornton Postdoctoral Fellow at the Wellcome Sanger Institute

“Our research is the first to uncover the daily dynamics of a parasitic animal’s genome. A strength of our study methodology is that we used an initial filtering step to give the most accurate picture possible, by excluding genes without clear differences in activity over time. This enabled us to focus on the genes with robust signatures of cyclical activity. Our data were therefore streamlined as much as possible at the start, and we hope this method will be a useful blueprint for other research in this field.”

Dr Adam Reid, an author and previously Senior Staff Scientist at the Wellcome Sanger Institute, now based at the Wellcome/Cancer Research UK Gurdon Institute

Further research is necessary to understand if these daily rhythms in the parasite are simply responding to the host’s daily rhythms or whether they are driven by a circadian clock in the worm. A circadian clock allows the organism to anticipate and prepare for the 24-hour changes in the internal and external environment. This ensures that the organism will do certain bodily functions at the right time of the day and that any internal changes required take place in coordination with one another.

Surprisingly, the worm genome lacks the core circadian clock genes that are found in most other animals suggesting it might have either lost its clock or that it uses a unique set of genes to drive an internal rhythm.

“Schistosoma mansoni manages to live in the human body, in the blood vessels, for years releasing eggs capable of causing serious human harm. Despite this, we know little about the mechanisms that it uses to adapt to changes within its host. By studying the cycling changes in activity of parasite genes, we are discovering parasite processes that could be targeted by new treatments, to help those who are living in affected areas.”

Dr Matt Berriman, senior author and Senior Group Leader at the Wellcome Sanger Institute

More information

1. Harris AR, Russell RJ, Charters AD. (1984) A review of schistosomiasis in immigrants in Western Australia, demonstrating the unusual longevity of Schistosoma mansoni. Trans R Soc Trop Med Hyg. 78(3):385-8.
2. Global Burden of Disease Study 2019 (GBD 2019). Results [Global Burden of Disease Collaborative Network] Institute for Health Metrics and Evaluation (IHME).
3. Schistosomiasis. DPDx – Laboratory Identification of Parasites of Public Health Concern. Centre for Disease Control and Prevention (CDC). Available https://www.cdc.gov/dpdx/schistosomiasis/index.html [Accessed November 2021]
4. Ismail M, Metwally A, Farghaly A, Bruce J, Tao LF, Bennett JL. (1996) Characterization of isolates of Schistosoma mansoni from Egyptian villagers that tolerate high doses of praziquantel. American Journal of Tropical Medicine and Hygiene.;55:214–218.
5. Crellen T, Walker M, Lamberton PH, Kabatereine NB, Tukahebwa EM, Cotton JA, Webster JP. (2016) Reduced efficacy of praziquantel against Schistosoma mansoni is associated with multiple rounds of mass drug administration. Clin Infect Dis. 63(9):1151-1159.
6. Rijo-Ferreira F, Pinto-Neves D, Barbosa-Morais NL, Takahashi JS, Figueiredo LM. (2017) Trypanosoma brucei metabolism is under circadian control. Nat. Microbiol. 2,17032.
7. Rijo-Ferreira F, Acosta-Rodriguez VA, Abel JH, Kornblum I, Bento I, Kilaru G, Klerman EB, Mota MM, Takahashi JS. (2020) The malaria parasite has an intrinsic clock. Science.368,746-753.
8. Smith LM, Motta FC, Chopra G, Moch JK, Nerem RR, Cummins B, Roche KE, Kelliher CM, Leman AR, Harer J, Gedeon T, Waters NC, Haase SB.(2020) An intrinsic oscillator drives the blood stage cycle of the malaria parasite Plasmodium falciparum. Science. 754-759.

Publication:

K.Rawlinson, A. Reid, Z. Lu, et al. (2021) Daily rhythms in gene expression of the human parasite Schistosoma mansoni. BMC Biology. DOI: 10.1186/s12915-021-01189-9

Funding:

This research was funded by Wellcome and a Sanger Institute Janet Thornton Fellowship.