The ecology and evolution of microbial immune systems

30 Sep - 01 Oct 2024 09:00 - 17:00 The Royal Society Free Watch online
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Image credit: Dr Anna Olina

Discussion meeting organised by Professor Edze Westra, Professor Stineke van Houte, Professor Uri Gophna and Professor Rotem Sorek.

Microbial immune systems are the centre of an exploding new field in microbiology. These systems are the origin of human immune functions and fascinating models for the evolution of complexity. This meeting will focus on the evolutionary aspects of these systems and their surprising ecological roles. The meeting will bring together scientists from diverse disciplines and stimulate fresh discussions.

Poster session

There will be a poster session on Monday 30 September. If you would like to present a poster, please submit your proposed title, abstract (up to 200 words), author list, and the name of the proposed presenter and institution to the Scientific Programmes team no later than 30 August 2024. Please include the text 'Poster submission - Microbial immune systems’ in the email subject line. 

Attending this event

  • This event is intended for researchers in relevant fields
  • Free to attend
  • Both in-person and online attendance available. Advance registration is essential. Please follow the link to register
  • Lunch is available on both days of the meeting for an optional £25 per day. There are plenty of places to eat nearby if you would prefer to purchase food offsite. Participants are welcome to bring their own lunch to the meeting

Enquiries: contact the Scientific Programmes team

Image credit: Dr Anna Olina

Organisers

  • Dr Edze Westra, University of Exeter, UK

    After his PhD in the lab of Prof. John van der Oost at Wageningen University on the molecular mechanism and regulation of CRISPR-Cas immune systems (2009-2013), Dr. Westra started to explore the evolutionary ecology of CRISPR-Cas immune systems as a Marie-Curie Fellow in the lab of Prof. Angus Buckling, University of Exeter (2013-2015). He then received a NERC Independent Research Fellowship in 2015 to set up his own lab at the University of Exeter, and received further funding from NERC, BBSRC, Wellcome Trust, Leverhulme Trust and ERC.

  • Professor Stineke van Houte, University of Exeter, UK

    Professor Stineke van Houte, University of Exeter, UK

    Stineke is a microbiologist at the Environment and Sustainability Institute of the University of Exeter who is interested in the molecular and evolutionary interplay between bacteria and their parasites, particularly bacteriophages and plasmids. In her work she integrates molecular, genetic and evolutionary approaches. Although the majority of her work addresses fundamental research questions, she also applies this fundamental knowledge to tackle real-world challenges, e.g. the spread of antibiotic resistance, the potential for microbiome engineering and the development of phage therapy as an alternative to antibiotics.

  • Professor Rotem Sorek, Weizmann Institute, Israel

    Professor Rotem Sorek, Weizmann Institute of Science

    Professor Rotem Sorek conducted his undergraduate and graduate studies at Tel Aviv University, earning a PhD with distinction in human genetics in 2006. After conducting postdoctoral studies in the Lawrence Berkeley National Lab in Berkeley, CA, he joined the Weizmann Institute in 2008. Sorek is a Professor at the Department of Molecular Genetics, and in 2019 became the Director of the Knell Family Center for Microbiology. 

    Professor Sorek investigates the molecular mechanisms providing bacteria with protection against phages, collectively known as the "immune system" of bacteria. He is an elected fellow of the American Academy of Microbiology, the European Academy of Microbiology, EMBO, and the German National Academy of Sciences Leopoldina. He received multiple awards to acknowledge his work, including recently the Humboldt Award (2023) the HFSP Nakasone award (2023) and the Rothschild Prize.

  • Professor Uri Gophna, Tel Aviv University, Israel

    Professor Uri Gophna, Tel Aviv University, Israel

    Professor Uri Gophna's research in TAU is focused on understanding the evolutionary processes behind microbial adaptation that have contributed to both the medical community and evolutionary theory. His research group's interests revolve around two related topics: the role of lateral gene transfer (LGT) and selfish DNA in the evolution of microorganisms, and the study of host-microbe interactions, focusing on the human gut microbiome in health and disease.

    The work spans the whole spectrum of evolutionary biology, from environmental and comparative population genomics all the way to the testing of specific hypotheses by engineering strains and performing competition experiments under ecologically relevant conditions. Genetic manipulation allows the dissection of the contribution of specific genetic components, such as defence systems (CRISPR-Cas and additional recently discovered systems), the recombination machinery, and selfish mobile DNA, to genome diversity within microbial populations.

Schedule

Chair

Dr Simon Jackson, University of Otago, New Zealand

Dr Simon Jackson, University of Otago, New Zealand

09:00-09:05 Welcome by the Royal Society
09:05-09:30 The immune system of bacteria: progress and challenges

The arms race between bacteria and phages led to the development of sophisticated anti-phage defence systems. A flurry of recent discoveries showed that the microbial pan-genome contains over 100 defence systems whose functions are just beginning to be elucidated. The talk will present progress in understanding the mechanisms of action of new defence systems, will highlight cases in which bacterial defence from phage gave rise to key components in the eukaryotic innate immune system, and will demonstrate how phages evolved to overcome bacterial immunity.

Professor Rotem Sorek, Weizmann Institute of Science

Professor Rotem Sorek, Weizmann Institute of Science

09:30-09:45 Discussion
09:45-10:15 Importance of bacterial defence systems in shaping the host range of phages

The range of bacterial strains that a phage can infect primarily depends on its capacity to bind one or several specific structures at the host cell surface. Upon adsorption and genome injection, the phage lifecycle can begin. In the case of lytic phages, a series of temporally-regulated steps follow, consisting in hijacking the host metabolism, producing new phage particles and eventually lysing the host cell. Recent work suggested that phages often bind to a larger diversity of hosts than they can kill and proposed that this is likely due to the multiplicity and diversity of defence systems encoded by the host. The search for correlations between the composition of the bacterial antiphage arsenal and the level of phage resistance yielded contrasting results. We explore the contribution of bacterial defence systems in defining phage resistance profile, using two different approaches in different model systems. First, we quantitatively measure the infectivity of 9 phages on a panel of 125 clinical isolates of Pseudomonas aeruginosa, determine their ability to adsorb on each strain and compare these data to the composition of defence systems in the isolates. Second, we use a genetic approach and test how systematic knock-out of predicted defence genes affect the phage resistance phenotype in an Escherichia coli clinical isolate. Our results suggest that the contribution of defence systems to phage resistance likely depends on environmental parameters.

Dr Anne Chevallereau, Molecular Microbiology and Structural Biochemistry (MMSB), France

Dr Anne Chevallereau, Molecular Microbiology and Structural Biochemistry (MMSB), France

10:15-10:30 Discussion
10:30-11:00 Break
11:00-11:30 The ecological distribution of defences

The diversity of bacterial defence systems is vast and such systems are mobilised between bacteria frequently. Despite their prevalence and mobility, the distribution of defence systems is not uniform across prokaryotic taxa or environments. Selection from viruses and other mobile genetic elements is assumed to drive the acquisition and maintenance of defence systems in natural environments. To test this assumption, we use a diverse collection of metagenomes to measure the abundance of defence systems and the role of the viral community in shaping defence abundance. We first focus on CRISPR defence systems, followed by more recently described defence systems, across diverse microbial ecosystems. We find that viral abundance is key predictor of CRISPR abundance, but that this relationship is more complex when the genomic origin of the arrays is known. We then use metagenomic data from a soil disturbance experiment to evaluate how both the viral community and defence system composition changes following environmental perturbation. We find that the viral community is more strongly determined by geographical location than the disturbance regime. However, within site disturbances substantially shape viral abundances, which we link to changes in defence composition. Taken together, these results highlight how microbial ecology shapes the defence system composition across multiple scales.

Dr Sean Meaden, University of York, UK

Dr Sean Meaden, University of York, UK

11:30-11:45 Discussion
11:45-12:15 Genomic analyses to infer defence system interactions among global Pseudomonas aeruginosa populations
Professor Kate Baker, University of Cambridge, UK

Professor Kate Baker, University of Cambridge, UK

12:15-12:30 Discussion

Chair

Dr Franz Baumdicker, University of Tuebingen, Germany

Dr Franz Baumdicker, University of Tuebingen, Germany

13:30-14:00 RNAs in phage counter-defence and regulation

Bacteria have evolved ‘immune systems’ as a result of their constant exposure to foreign mobile genetic elements, including bacteriophages and plasmids. In response, phages have evolved different strategies to evade these immune mechanisms. These include RNAs that inhibit CRISPR-Cas and other defence systems. RNA-based regulation is also important for the anti-immune deployment by phages. In this talk I will discuss how RNA contributes to phage counter-defence strategies and their regulation.

Associate Professor Peter Fineran, University of Otago, New Zealand

Associate Professor Peter Fineran, University of Otago, New Zealand

14:00-14:15 Discussion
14:15-14:45 "All the world's a phage": exploring phage-host interactions

Bacteriophages (phages) outnumber bacteria by ten to one, with an estimated 10^30 phages causing infections at a rate of 10^25 a second. This huge selection pressure has led to the evolution of bacterial defence systems that protect from phage predation. Many of these defence systems have already proven useful to biochemists; the restriction-modification and CRISPR-Cas systems underpin the recombinant DNA and genome editing revolutions. Defence systems are commonly found grouped into “islands”, but functionality has not previously been systematically tested. We have isolated a ten-gene phage-defence island from a multidrug-resistant plasmid of Escherichia fergusonii and demonstrated that it encodes both a BacteRiophage Exclusion (BREX) locus, and a highly promiscuous type IV restriction enzyme. Using phages isolated by Durham undergraduates we are exploring the complementary biochemistry of these two defence systems, which together provide a highly effective “belt-and-braces” approach to phage defence. Furthermore, we have identified a new widespread family of transcriptional regulators controlling phage defence. Finally, comparative studies between BREX defence systems are helping to identify anti-BREX genes that are used by phages to circumvent host defence.

Professor Tim Blower, Durham University, UK

Professor Tim Blower, Durham University, UK

14:45-15:00 Discussion
15:00-15:30 Break
15:30-16:00 Probing the diversity of Type III CRISPR antiviral defence

CRISPR-Cas systems provide adaptive immunity against mobile genetic elements in prokaryotes. Type III CRISPR is arguably the most diverse and mechanistically complex of all prokaryotic defence systems. On detecting invading RNA, the type III CRISPR effector activates its catalytic Cas10 domain, generating a nucleotide second messenger that activates ancillary defence proteins. Known examples include nucleases, proteases, hydrolases, membrane channels and transcription factors. This talk will focus on the results of a comprehensive bioinformatic analysis of type III CRISPR loci in prokaryotes. The distribution, frequency and co-occurrence pattern of each effector family are mapped, allowing the prediction of some general rules for type III CRISPR defence. By focussing on gaps where no known effectors are present, we predict new classes of type III CRISPR ancillary proteins, confirming one of these predictions biochemically. Finally, I will focus on the prevalence of enzymatic ring nuclease “off-switches” in type III CRISPR loci, which has implications for cell fates on viral infection.

Professor Malcolm White, University of St Andrews, UK

Professor Malcolm White, University of St Andrews, UK

16:00-16:15 Discussion
16:15-16:45 Collective immunity: how groups of bacteria sense and respond to danger

Quorum sensing (QS), is the bacterial cell-to-cell communication process that promotes the collective undertaking of group behaviours. In addition to regulating bacterial virulence programmes, it shapes the outcomes of encounters between bacteria and the bacteriophage (phage) viruses that prey on them. 

Since phages require a host to proliferate, at low cell density, bacteria rarely encounter a phage. Conversely, at high cell density, phage infection can spread rapidly in a dense microbial environment. We have shown that Pseudomonas aeruginosa uses elevated QS levels at high cell density to launch its CRISPR-Cas anti-phage defense system when the risk of phage infection is highest. If phages successfully infect P. aeruginosa, despite defenses, it emits the PQS QS signal, warning and redirecting healthy neighboring bacterial swarms away from the infected cells. Not only does phage infection activate QS in wild type cells, it also restores PQS signaling in a lasI QS mutant, in which the PQS system is otherwise mute. Hereby, we demonstrate that a P. aeruginosa lasI mutant can bypass the otherwise hierarchal QS organisation in response to phage infection, further underscoring the importance of QS in regulating phage defences. Thus, QS is an Achilles heel in phage defences. 

Intriguingly, some phages have evolved the ability to inhibit QS, potentially aiding them in their battle with bacteria. 

Dr Nina Molin Høyland-Kroghsbo, University of Copenhagen, Denmark

Dr Nina Molin Høyland-Kroghsbo, University of Copenhagen, Denmark

16:45-17:00 Discussion

Chair

Dr Tanita Wein, Weizmann Institute, Israel

Dr Tanita Wein, Weizmann Institute, Israel

09:00-09:30 Real-time arms race: coevolution of phages and vibrio in natural populations
Professor Frederique Le Roux, University de Montreal, Canada

Professor Frederique Le Roux, University de Montreal, Canada

09:30-09:45 Discussion
09:45-10:15 Fighting with phages: how vibrio cholerae defends against viral attack

The evolution of all forms of life is a history of the relentless conflict between hosts and parasites. Viral parasites of bacteria, known as phages, are key components of all ecosystems and profoundly influence the biology of their bacterial hosts. Phages select for bacteria that evade phage predation by deploying elaborate and mechanistically diverse defence systems, the full breadth of which is only beginning to be realised. Phages also drive the mobilisation and dissemination of genetic material. Yet, despite the central role of phages in microbial evolution and ecology, molecular insight into the reciprocal dynamics of phage-bacterial adaptations in nature is lacking, particularly in clinical contexts. As a direct consequence, the discovery of phage-encoded defence inhibitors dramatically lags behind the known arsenal of bacterial defences. In partnership with international collaborators, my lab has established a longitudinal collection focused on the diarrheal pathogen, Vibrio cholerae, and the lytic phages that prey on this pathogen as it causes disease in humans. Leveraging genomic and mechanistic approaches, we use this tractable platform to gain an in-depth understanding of how these interacting microbes coevolve within the context of human infection. I will discuss mechanisms of defence in epidemic V cholerae mediated by parasitic mobile genetic elements and how phage-encoded mechanisms countering these elements have driven their diversification in epidemic V cholerae

Dr Kim Seed, University of California, USA

Dr Kim Seed, University of California, USA

10:15-10:30 Discussion
10:30-11:00 Break
11:00-11:30 The phage anti-restriction induced system (PARIS)

The PARIS defense system was first identified within hotspots of anti-phage defense systems carried by satellites of the P4 family. There it acts as an anti-anti-restriction system by blocking the infection of phages carrying anti-restriction proteins such as the T7 Ocr. PARIS is composed of a 53 kDa ABC ATPase (AriA) and a 35 kDa TOPRIM nuclease (AriB) that assemble into a 425 kDa supramolecular immune complex. We used cryo-EM to determine the structure of this complex which explains how six molecules of AriA assemble into a propeller-shaped scaffold that coordinates three subunits of AriB. ATP-dependent detection of foreign proteins triggers the release of AriB, which assembles into a homodimeric nuclease that blocks infection by cleaving the host tRNALys. Phage T5 subverts PARIS immunity through expression of a tRNALys variant that prevent PARIS-mediated cleavage, and thereby restores viral infection. PARIS is one of an emerging set of immune systems that target tRNA to trigger translational arrest. It also belongs to a broader family of systems that employ ABC ATPases to sense viral infections. 

Professor David Bikard, Institut Pasteur, France

Professor David Bikard, Institut Pasteur, France

11:30-11:45 Discussion
11:45-12:15 How do microbial immune systems spread in nature?

Microbial immune systems play a crucial role in protecting microbes from foreign mobile genetic elements (MGEs) such as bacteriophages, satellites, and plasmids. These defence mechanisms can be readily acquired or lost by bacteria, facilitating their adaptation to various threats. Interestingly, many microbial immune systems are themselves encoded by MGEs, linking their distribution directly to the movement of these MGEs. However, not all immune systems are associated with MGEs; some are integrated into different regions of bacterial chromosomes. This raises intriguing questions about the transfer mechanisms of these chromosomally encoded immune systems between bacterial strains. 

In this talk, we will explore the roles of lateral transduction and lateral cotransduction in the mobility of chromosomal defence islands that harbour multiple immune systems. Lateral transduction, a robust gene transfer process mediated by bacteriophages, enables the transfer of large segments of bacterial DNA from one bacterium to another. Lateral cotransduction, a more recently described mechanism, further expands our understanding of gene mobilisation facilitated by phage-inducible chromosomal islands (PICIs). 

We will examine how these processes contribute to the horizontal gene transfer of immune systems across bacterial populations, and their impact on bacterial adaptation and evolutionary dynamics. Our findings will illuminate the complex interactions between phages and bacteria, revealing how these interactions govern the genetic flow and diversity of immune systems within microbial communities. Understanding these mechanisms is vital for gaining insights into the spread of resistance traits and the ongoing evolutionary arms race between microbes and their viral predators.

Professor José Penades, Imperial College London, UK

Professor José Penades, Imperial College London, UK

12:15-12:30 Discussion

Chair

Dr Rafael Pinilla Redondo, University of Copenhagen, Denmark

Dr Rafael Pinilla-Redondo, University of Copenhagen, Denmark

13:30-14:00 New phage defence systems in 7th pandemic Vibrio cholerae strains

The Latin American cholera epidemic, which originated in Peru in 1991, was driven by the West African South American (WASA) lineage of the 7th pandemic O1 El Tor Vibrio cholerae. This lineage is characterized by two genetic signatures: the WASA-1 prophage and a novel set of genes on the Vibrio seventh pandemic island II (VSP-II). 

Our study reveals that these elements encode diverse anti-phage defence systems. Particularly noteworthy is the WASA-1 prophage, which contains a two-gene system termed WASA OLD-ABC-ATPase REase – WorAB, providing resistance against the major predatory phage of pandemic V. cholerae, phage ICP1. We demonstrate that the WorAB system is activated early during infection and functions through abortive infection by halting translation. Furthermore, we uncover that the WASA-specific genes carried on VSP-II encode two additional defense systems: a modification-dependent restriction system targeting bacteriophages with modified genomes, and a novel variant of the Shedu defense system. 

Our findings shed new light on the evolution of pandemic cholera strains and suggest that anti-phage defence systems may have contributed to the success of this major epidemic lineage, which caused more than 1.2 million disease cases in South America in the 1990s.

Professor Melanie Blokesch, Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland

Professor Melanie Blokesch, Swiss Federal Institute of Technology Lausanne (EPFL), Switzerland

14:00-14:15 Discussion
14:15-14:45 When does it pay to encode CRISPR-Cas immunity?

Bacterial genomes vary extensively in the defence systems they encode, including CRISPR-Cas systems which are present in only ~50% of Pseudomonas aeruginosa genomes. The selective drivers of this variation are not fully understood. Using a large panel of diverse lytic phages we show that the fitness benefit of CRISPR-Cas adaptive immunity varies according to phage identity and function in predictable ways unlinked to known anti-CRISPR systems. The fitness effect of CRISPR immunity was positively associated with the presence of spacers targeting the phage but was negatively associated with the probability of evolving resistance via mutations that provide escape from phage predation. The probability of resistance mutations enabling escape was predicted by sequence differences in tail structural genes between otherwise closely related lipopolysaccharide-binding phages. These short-term fitness differences of CRISPR-Cas immunity control longer-term dynamics of bacteria-phage communities with implications for phage therapy and understanding the role and distribution of CRISPR-Cas immunity in nature.

Professor Michael Brockhurst, University of Manchester, UK

Professor Michael Brockhurst, University of Manchester, UK

14:45-15:00 Discussion
15:00-15:30 Break
15:30-16:00 Phage communication-defence interactions
Professor Avigdor Eldar, Tel Aviv University, Israel

Professor Avigdor Eldar, Tel Aviv University, Israel

16:00-16:15 Discussion
16:15-16:45 Evolution of anti-viral immunity across domains of life

Immune defence mechanisms exist across the tree of life in such a wide diversity that the antiviral response of bacteria was considered unrelated to immunity of eukaryotes. Mechanisms of defence in divergent eukaryotes were similarly believed to be largely clade-specific.  However, recent data indicate that a subset of prokaryotic defence systems are conserved in eukaryotes and populate every stage of immune pathways. I will discuss the evolutionary dynamics of immunity across domains of life and how the conservation of immune modules can lead to discoveries in prokaryotes and eukaryotes. 

Dr Aude Bernheim, Institut Pasteur, France

Dr Aude Bernheim, Institut Pasteur, France

16:45-17:00 Discussion and future directions