Time to start taking time seriously: circadian rhythms in infection and immunity

25 - 26 September 2023 09:00 - 17:00 INNSiDE Newcastle
Night and day

Theo Murphy meeting organised by Professor Sarah Reece, Dr Rachel Edgar and Professor Annie Curtis.

The time of day when infection occurs can dictate live-or-die outcomes for hosts, but how timing impacts host-pathogen interactions remains largely unknown. Leaders in the fields of circadian biology, immunology, microbiology, parasitology, virology and evolutionary ecology explored how and why rhythms in pathogen activities and host immune responses drive disease processes, ultimately determining the severity and transmission of infections.

The schedule of talks and speaker biographies is available below. Speaker abstracts are also available below. 

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Organisers

  • Sarah Reece

    Professor Sarah Reece, University of Edinburgh, UK

    Sarah works at the interface of infectious disease and evolutionary ecology. Sarah completed her PhD in 2003 having researched the reproductive strategies of sea turtles, parasitoid wasps, and malaria parasites. After a short-term lecturing position, Sarah won a fellowship from the Natural Environment Research Council UK to set up her lab at the University of Edinburgh. Next, Sarah secured a Wellcome Trust Career Development fellowship, followed by a Royal Society University Research Fellowship. Sarah is also a Wellcome Trust Investigator and became Chair of Evolutionary Parasitology in 2014, and is co-director of the Women in Malaria, Scottish Parasitology Partnership in Research, Innovation, and Training, and Edinburgh Infectious Diseases networks. She has authored over 100 papers and been awarded several prizes including a L'Oréal-UNESCO fellowship for women in science, the Zoological Society London Scientific Medal, fellowship of the Royal Society of Edinburgh, and the British Society for Parasitology’s Wright Medal. Sarah has two children and works part time. 

    Research in the Reece lab takes a highly interdisciplinary approach to investigating what makes a successful parasite, and the evolutionary limits on their success. These strategies underpin the severity of infections and the transmission of disease and are best understood through the lenses of parasitology, chronobiology, and evolutionary ecology with occasional dabbling in biophysics, population genetics, and theoretical models. The Reece lab is also committed to public engagement and have developed a diverse program of activities for primary school children.

  • Rachel Edgar

    Dr Rachel Edgar, Imperial College London, UK

    Dr Rachel Edgar completed their PhD in 2012 at the University of Cambridge, investigating the kinetics of viral transmission between cells, then pursued their interest in circadian biology as a post-doctoral researcher at the University of Cambridge Institute of Metabolic Science and the MRC Laboratory of Molecular Biology. In 2018, Dr Edgar was awarded a Royal Society-Wellcome Trust Sir Henry Dale Fellowship and established a research group at Imperial College London. Their research focuses on the intersection of biological timing, cellular homeostasis and infectious disease, investigating how changes in baseline cell-intrinsic immunity, proteostasis, osmotic and metabolic state influence virus replication and the establishment of infection. They also develop translational applications of this research to combat viral infections and prevent transmission.

  • blank avatar

    Professor Annie Curtis, Royal College of Surgeons in Ireland, Ireland

    Biography not available

Schedule

Chair

Tyler Stevenson

Dr Tyler Stevenson, University of Glasgow, UK

09:00-09:15 Welcome
Professor Sarah Reece, University of Edinburgh, UK

Professor Sarah Reece, University of Edinburgh, UK

Dr Rachel Edgar, Imperial College London, UK

Dr Rachel Edgar, Imperial College London, UK

09:15-09:45 Introduction to session 1 and session 2
Dr Rachel Edgar, Imperial College London, UK

Dr Rachel Edgar, Imperial College London, UK

09:45-10:15 Fundamentals: language of oscillators

Drawing on diverse examples, this talk will cover core concepts of biological rhythms and their measurement. The evidence supporting various models for circadian rhythm generation will be presented.

Dr John O'Neill, MRC Laboratory of Molecular Biology, UK

Dr John O'Neill, MRC Laboratory of Molecular Biology, UK

10:15-10:45 Fundamentals: ecology of oscillators

In this presentation Professor Hut will address the functional ecology of oscillators: how do rhythms help organisms to increase fitness. He will discuss natural circadian entrainment, but also highlight the importance of flexibility in the expression of circadian rhythms (circadian vs ultradian) and the impact of flexible phase angle of entrainment on energetics at the organismal level. Such adequate acute stress responses are essential for survival under natural conditions. However chronic stress conditions may lead to mal-adaptive responses and circadian mis-alignment of internal rhythms in organs and tissues, which may lead to health problems.

Professor Roelof Hut, University of Groningen, The Netherlands

Professor Roelof Hut, University of Groningen, The Netherlands

10:45-11:15 Break
11:15-11:45 Fundamentals: molecular operation of oscillators

Circadian rhythms persist across kingdoms and all levels of biological scale. At their most fundamental level, however, circadian rhythms occur at the level of the single cell and are driven by sub-cellular molecular processes, most particularly the circadian Transcriptional-Translational Feedback Loop (TTFL). Dr Crosby will introduce the primary features of this core timekeeping circuit, with particular emphasis on how this system manifests in mammals. Additionally, she will present some of the major tools used to study molecular circadian rhythms in cells and how we can use these to understand both how cellular rhythms are maintained and how cellular rhythms are influenced by specific extracellular events. Finally, she will use examples from recent work looking at the core mammalian circadian transcriptional activator, CLOCK:BMAL1, to highlight the substantial insights that can be obtained by combining cell biology techniques with molecular biophysics and structural biology. By developing a deeper mechanistic understanding of how cellular 'clocks' function at the molecular level, the group hopes to capitalise on the temporal regulation of physiology to develop new and innovative strategies to treat the broad spectrum of diseases that are associated with disruption of these fundamental cellular timekeeping systems.

Dr Priya Crosby, University of California Santa Cruz, USA

Dr Priya Crosby, University of California Santa Cruz, USA

11:45-12:15 Intersection of clocks, behaviours and physiological rhythms

The mammalian circadian timing system evolved to drive circadian rhythm in behaviour and physiology that anticipate regular, recurring events in the environment. A hypothalamic clock is synchronised to the external light-dark cycle and drives timing of behaviours such as the sleep-wake cycle and feeding timing. Alongside this, clocks in almost every nucleated cell of the body are synchronised to non-photic timing signals and drive tissue-specific rhythms in physiology through (post)transcriptional regulation. In turn, these behaviours and physiological rhythms themselves also act as non-photic synchronisers and as such feedback to circadian clocks, resulting in a reverberating landscape of rhythms that align dependant biological processes in time, or segregate incompatible processes.

When behaviours such as sleeping and eating are mistimed, this invokes desynchrony in this reverberating landscape, which is associated with downstream health issues including metabolic disorders, cancers and disturbed immune function which bring major social, economic and personal costs. Of interest here is how the immune system sits within the circadian landscape, and particularly what timing information infecting agents may present to the host circadian timing system. Recent mouse studies show that when the donor of malaria parasites is on a different time zone than the host, this affects parasite replication and host circadian rhythms. This suggests that the parasite conveys a timing signal that disrupts the host timing system, and Dr van der Veen will present new data showing that infection with mismatched parasites leads to circadian desynchrony in the host transcriptome which is reminiscent of desynchrony caused by mistimed sleeping or eating.

Dr Daan R van der Veen, University of Surrey, UK

Dr Daan R van der Veen, University of Surrey, UK

12:15-13:00 Discussion: integration across scales of biological organisation
Dr Tyler Stevenson, University of Glasgow, UK

Dr Tyler Stevenson, University of Glasgow, UK

Chair

Laura Roden

Dr Laura Roden, Coventry University, UK

14:00-14:30 Circadian anti-tumour immune responses

The immune system acts in a circadian manner. In this talk, Professor Scheiermann will focus on the anti-tumour immune response and discuss how these underlying oscillations can be targeted by chrono-immunotherapy.

Professor Christoph Scheiermann, University of Geneva, Switzerland

Professor Christoph Scheiermann, University of Geneva, Switzerland

14:30-15:00 Sleep and immunity

The circadian system and sleep are closely intertwined. However, when investigating 24-hour rhythms in the immune system, the role of sleep is often neglected. In this talk, Professor Besedovsky will provide a general introduction to the interactions between sleep and the immune system, with a specific focus on the effects of sleep on peripheral immune functions in humans. Sleep has potent effects on adaptive immune responses and inflammatory homeostasis. The underlying mechanisms as well as potential consequences of the effects of sleep on the immune system for a variety of diseases, including neurodegenerative, metabolic, and cardiovascular diseases, will be outlined. They will also give examples of 24-hour immune rhythms that are largely independent of sleep as well as of such that are predominantly driven by the sleep-wake cycle and are, thus, not truly circadian (ie not directly driven by the circadian clock). With this talk, Professor Besedovsky hopes to provide a bridge between circadian clock and sleep research in the context of immunity and to make a case for the importance of considering effects of both the circadian system as well as of sleep when investigating 24-hour rhythms in the immune system.

Professor Luciana Besedovsky, Ludwig-Maximilians-Universität München, Germany

Professor Luciana Besedovsky, Ludwig-Maximilians-Universität München, Germany

15:00-15:30 Break
15:30-16:00 Beyond immune cell clocks – the influence of extrinsic signals on rhythmic inflammatory responses

Research over the last two decades has well-defined the presence of cell intrinsic timers within almost every cellular component of the innate and adaptive immune system. Numerous studies have used genetic disruption of these molecular clocks to demonstrate the importance of cellular timers for driving rhythmicity, both in terms of maintaining immune homeostasis and in responses to acute or chronic challenge. However, many of these rhythmic outputs of the immune system can be additionally manipulated through modification of cell extrinsic rhythmic signals including: outputs from the adrenergic nervous system, hormones and feeding-derived cues. 

Here Professor Gibbs presents the group's recent studies addressing the impact of rhythmic extrinsic signals, including glucocorticoids and microbiota derived metabolites, on the function of the adaptive immune system. The gut microbiome is a critical source of immune modulatory signals which influence the development, maturation and function of the immune system. The group has explored how the composition and metabolic outputs of the gut microbiome are regulated by the circadian clock, and what happens to this rhythmicity in the setting of chronic disease. Using reverse feeding and an arrhythmic feeding paradigm, they are addressing consequences of disrupted feeding-fasting signals on both the microbiome and rhythmic immunity.

This work highlights the importance of looking beyond cellular timers to cell extrinsic signals (in which rhythmicity is highly sensitive to lifestyle factors) when considering circadian regulation of immunity. 

Professor Julie Gibbs, University of Manchester, UK

Professor Julie Gibbs, University of Manchester, UK

16:00-16:30 Circadian control of innate immunity, mechanisms and consequences

Inflammation is essential for survival, and is responsible for organising the defence against infections, and recovery from injuries. A major cell type responsible for driving inflammation, and the recovery from injury is the macrophage. Inflammation, and the macrophages, are strongly regulated by the circadian clock. This is a conserved mechanism which allows anticipation of changes in the environment, eg from light to dark. The circadian clock, or body clock, is able to respond to changes in the environment eg light, and feeding time, and alters how cells, tissues, and whole animals respond to infection, or injury.  

There remains a massive burden of chronic inflammatory disease, with associated metabolic co-morbidity. For example, rheumatoid arthritis (RA) is prevalent, and even with effective treatment is associated with accelerated cardiovascular disease. The group has discovered that the circadian organisation of energy balance is disturbed by inflammation. 

The circadian clock also plays a very important role in energy metabolism. The clock affects appetite, and feeding behaviour, as well as regulating how energy is stored in the body, how fat is stored during the day, and released for use as fuel overnight when fasting. Energy metabolism is also regulated by inflammation. The critical role for the circadian clock in both inflammation and energy metabolism, and the abnormal energy metabolism seen in chronic inflammation led us to test if the circadian organisation of energy metabolism was disrupted by inflammation. 

The group made several surprising findings. They found that the macrophages, essential for inflammation, and tissue repair, lost their circadian clock in inflamed joints. They have identified two major macrophage phenotypes affected by the core circadian machinery. In one BMAL1 action affects inflammatory cytokine response, in a REVERBa dependent manner. In the second the macrophage cytoskeleton, migratory, and phagocytic activity is high inhibited by BMAL1, in this case in a REVERBa independent and RhoA dependent manner. The group has been investigating the BMAL1 mechanism of action, using primary macrophages harvested from animal at distinct circadian phases, with and without BMAL1. These studies have identified a network of genes that are circadian phase, and BMAL1 dependent.  

The group discovered that the circuits in the liver responsible for storing, or using fat, and other essential nutrients showed a change in circadian organisation. They discovered that fatty acids were being driven to form ceramides. These molecules were accumulating in liver, and muscle. Experimental manipulation of ceramides impacted the circadian amplitude in isolated liver cells.

In summary, the circadian machinery is responsible for regulating diverse elements of the inflammatory response. There are clear and direct actions through BMAL1 in the effector macrophages, and also we see actions on the systemic regulation of energy metabolism. Here, Professor Ray proposes that an adaptive response to acute inflammation becomes maladaptive, and may contribute to delayed resolution of inflammation, through the propagation of bioactive lipid species of the ceramide class.

Professor David Ray, University of Oxford, UK

Professor David Ray, University of Oxford, UK

16:30-17:15 Discussion: key questions and how to tackle them
Dr Laura Roden, Coventry University, UK

Dr Laura Roden, Coventry University, UK

Chair

Megan Greischar

Dr Megan Greischar, Cornell University, USA

09:00-09:30 Introduction to session 3 and session 4
Professor Sarah Reece, University of Edinburgh, UK

Professor Sarah Reece, University of Edinburgh, UK

09:30-10:00 Circadian and extra-circadian roles of clock components: lessons from pathogenic and mycoparasitic fungi

Circadian clocks are essential for individuals' fitness, and recent studies underline their role in the outcome of biological interactions. Thus, for example, the authors provided for the first-time evidence of the importance of clock regulation in the interaction between a phytopathogenic fungus and a plant host. However, the relevance of circadian clocks in fungal-fungal interactions remains largely unexplored. They have now characterised a functional clock in the biocontrol agent Trichoderma atroviride to assess its importance its mycoparasitic action against the phytopathogen Botrytis cinerea. By utilising luciferase reporters to monitor the T. atroviride core-clock, they confirmed the existence of circadian oscillations that are temperature compensated and can be modulated by environmental cues such as light and temperature. Notably, the presence of such rhythms appears to be highly dependent on the nutritional composition of the media, which suggest a conditional gating of clock mechanisms. The free running period of Trichoderma is ~26 h, which can be recapitulated by expressing Trichoderma’s frq in the model circadian fungus Neurospora crassa. Confrontation assays between T. atroviride and B. cinerea under light/dark cycles, reveal that Trichoderma’s biocontrol capacity is enhanced when inoculations occur at dawn compared to dusk, albeit that phenotype is mainly regulated by the clock in B. cinerea and not in T. atroviride.

Additionally, the authors observed that T. atroviride clock components largely modulate development and secondary metabolism in this fungus, affecting the production of a large set of metabolites. Importantly, they detected the rhythmic production of distinct T. atroviride volatile organic compounds (VOCs), which are under circadian control. 

Notably, both in B. cinerea and T. atroviride the authors have evidence indicating that the clock negative element FRQ exhibits extra-circadian roles, particularly in the cross-roads of development, metabolism and signalling pathways impinging Nitrogen assimilation and impacting secondary metabolite- and ROS- production, raising interesting questions about the origin and evolution of clock components in fungi.

Professor Luis Larrondo, iBio, Pontificia Universidad Catolica de Chile, Chile

Professor Luis Larrondo, iBio, Pontificia Universidad Catolica de Chile, Chile

10:00-10:30 Cyanophage infection rhythms: infection time affects viral fitness

Diurnal rhythms are ubiquitous in living organisms as basic adaptations to the daily light–dark cycles and are thought to be exploited as defensive mechanisms in host-parasite interactions. However, it still remains unclear whether viral infection disrupts the host’s diurnal rhythm and whether the infection time affects the fitness of viruses under light-dark cycles. The marine cyanobacterium Prochlorococcus is the smallest but the most abundant phototroph on Earth. Previously, the group reported on cyanophages that infect Prochlorococcus as the first viral model that exhibits a diurnal rhythm and identified their distinct diel-dependent life history traits. The cyanomyovirus P-SSM2 can adsorb to the host cell in the dark but cannot replicate without light. Under light-dark cycles, most P-SSM2 viruses infect their host cells at night, forming synchronised infections. Although P-SSM2 does not replicate, transcribe, or interfere with the host’s fundamental physiology at night, they found that phage transcription and replication are enhanced in the following day. Their RNA-seq experiments revealed that night infection of P-SSM2 does not disrupt the host transcriptional rhythm, while day infection represses the transcriptional activity of the host circadian clock and metabolic pathways. Their results suggest that maintenance of the host transcriptional rhythm during night infection underpins the competitiveness and fitness of P-SSM2 under light-dark cycles. 

Associate Professor Qinglu Zeng, Hong Kong University of Science and Technology, Hong Kong, China

Associate Professor Qinglu Zeng, Hong Kong University of Science and Technology, Hong Kong, China

10:30-11:00 Break
11:00-11:30 Circadian rhythms in hosts, malaria parasites and their vectors

Earth rotation shaped the biology of many organisms. Animals, plants and microbes evolved circadian rhythms to anticipate the predictive daily rhythms of their environment. Multiple parasitic diseases show daily rhythms, a contribution of both hosts and parasite biology. Malaria, a disease that kills over half a million people each year is one of such infections, in which infected individuals experience periodic fevers. Dr Rijo-Ferreira's group recently showed that the parasite biology is intrinsically rhythmic, with rhythms persisting in the absence of host rhythmic cues. Remarkably, rhythms in malaria parasite biology exist beyond their presence in the mammalian host, to when they infect their mosquito vector. For malaria transmission, sporozoite parasites need to be leave the salivary glands of the mosquito and be deposited in the skin of the mammalian host, upon the mosquito blood meal. Here Dr Rijo-Ferreira uncovers the rhythmic biology of both the salivary gland of mosquitos and the parasites within them. These findings provide insight into the co-evolution of the clocks of hosts, malaria parasites and their vectors with potential impact to the transmission of this disease. 

Dr Filipa Rijo-Ferreira, University of California Berkeley, USA

Dr Filipa Rijo-Ferreira, University of California Berkeley, USA

11:30-12:00 The pathogenesis of Chlamydia is dependent on the time of infection

Chlamydia is the most common bacterial sexually transmitted infection in the world. Complications from Chlamydia pathogenesis results in several outcomes including tubal factor infertility. The molecular mechanisms underpinning the processes leading to this pathologic outcome of Chlamydia pathogenesis is not fully understood. Dr Omosun's group has reported that several factors including time of day of infection and the disruption of the circadian clock are associated with the different outcomes in chlamydial infectivity and pathogenesis. Their results showed that mice infected in the early active period had fewer pathological changes in the upper genital tract compared to mice infected in the early rest period. The group reported that mice with their circadian clock disrupted were more susceptible to upper genital tract complications arising from Chlamydia infection. In addition time of day of infection also determined the phylum of bacteria that were found in the genital tract. Their study gives them a basis to predict the level of severity of pathogenesis after Chlamydia infection and identify new underlying mechanisms involved in Chlamydia pathogenesis. They predict that the results garnered from our studies will positively impact women's reproductive health. This talk will present results from these studies and what the future holds in their work.

Dr Yusuf Omosun, Morehouse School of Medicine, USA

Dr Yusuf Omosun, Morehouse School of Medicine, USA

12:00-12:45 Discussion: key questions and how to tackle them
Dr Megan Greischar, Cornell University, USA

Dr Megan Greischar, Cornell University, USA

Chair

David Wilcockson

Dr David Wilcockson, Aberystwyth University, UK

13:45-14:15 Rhythmic host-microbe interactions

The cross-talk between mammalian hosts and pathogens is characterised by the balance between resistance and tolerance mechanisms, the first aimed at limiting colonisation and promoting the clearance, the second at reducing tissue damage induced by both the pathogen and the host itself. Such interaction is associated with energy costs that come from shared nutrient requirements between the host, the pathogens and commensal micro-organisms. The circadian regulation of the availability of nutrients is therefore a fundamental aspect that may influence the outcome of the infection. Among nutrients, the essential aromatic amino acid tryptophan and its downstream metabolites are crucial regulators of both immunity and the circadian clock. Tryptophan is metabolised by both host and microbial enzymes through three different pathways: the host kynurenine and serotonin pathway and the microbial indole pathway. Dr Bellet will present her recent studies demonstrating that a circadian regulation of the three arms of tryptophan catabolic pathway plays an important role in the modulation of the host response to opportunistic fungal infections in both the lung and the gut. It will be discussed the potential contribution that a yet unrecognised endogenous clock in fungal species important for human health might have in defining their virulence in human hosts. Finally, it will be described the possibility that the switch between pathogenicity and commensalism might be influenced by variation, as well as malfunctions, of the clock system in the immunocompromised host. 

Dr Marina M Bellet, University of Perugia, Italy

Dr Marina M Bellet, University of Perugia, Italy

14:15-14:45 Immune regulation of host energy metabolism and periodicity of malaria parasites

The mechanism wherein millions of Plasmodium parasites differentiate and proliferate in synchrony with the vertebrate host’s circadian cycle is mostly unknown. The authors' results indicate that the underlying mechanism involves cyclic production of TNF and changes on host energy metabolism. Professor Gazzinelli will address the importance of highly glycolytic monocytes and host energy metabolism in control of parasitemia and pathogenesis of P. chabaudii infection in mice.

Professor Ricardo Gazzinelli, University of Massachussetts Medical School, USA

Professor Ricardo Gazzinelli, University of Massachussetts Medical School, USA

14:45-15:15 Break
15:15-15:45 Harnessing circadian rhythms for a healthier planet

A safe, nutritious, and sustainable supply of food is critical for human health. All of our food ultimately derives from the products of photosynthesis in plants. In plants, the circadian clock is a crucial determinant of performance and nutritional composition. For example, the circadian clock controls the rate of photosynthesis, the accumulation of starch, the amount of water transpired from the leaves, the season of flowering, and interactions between plants and pathogenic or beneficial microorganisms. The latter is especially intriguing, given the emerging evidence from our collaborative work identifying circadian programs in non-photosynthetic bacteria, including bacteria that colonise plant surfaces. Circadian regulation can also impact food production in unexpected ways. For example, the group found that the clock can produce 24 hour fluctuations in the responses of plants to agrochemicals, which is reminiscent of the circadian fluctuations in the effectiveness of some drugs. In this talk Professor Dodd will explore some of these processes, with a focus on insights from model systems that can have relevance across the field of chronobiology.

Professor Antony Dodd, John Innes Centre, UK

Professor Antony Dodd, John Innes Centre, UK

15:45-16:30 Discussion: key questions and how to tackle them
Professor Sarah Reece, University of Edinburgh, UK

Professor Sarah Reece, University of Edinburgh, UK

16:30-17:00 Synthesis: integrating concepts, approaches and terminology across disciplines
Professor Sarah Reece, University of Edinburgh, UK

Professor Sarah Reece, University of Edinburgh, UK

Dr Rachel Edgar, Imperial College London, UK

Dr Rachel Edgar, Imperial College London, UK