RESUMEN
Prokaryotes have evolved a multitude of defense systems to protect against phage predation. Some of these resemble eukaryotic genes involved in antiviral responses. Here, we set out to systematically project the current knowledge of eukaryotic-like antiviral defense systems onto prokaryotic genomes, using Pseudomonas aeruginosa as a model organism. Searching for phage defense systems related to innate antiviral genes from vertebrates and plants, we uncovered over 450 candidates. We validated six of these phage defense systems, including factors preventing viral attachment, R-loop-acting enzymes, the inflammasome, ubiquitin pathway, and pathogen recognition signaling. Collectively, these defense systems support the concept of deep evolutionary links and shared antiviral mechanisms between prokaryotes and eukaryotes.
Asunto(s)
Pseudomonas aeruginosa , Pseudomonas aeruginosa/genética , Pseudomonas aeruginosa/inmunología , Pseudomonas aeruginosa/virología , Inmunidad Innata , Bacteriófagos/genética , Bacteriófagos/fisiología , Interacciones Huésped-Patógeno/inmunología , Interacciones Huésped-Patógeno/genética , Animales , Evolución Molecular , Inflamasomas/inmunología , Inflamasomas/genética , Eucariontes/virología , Eucariontes/genética , Eucariontes/inmunología , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Evolución Biológica , Plantas/inmunología , Plantas/virología , Plantas/microbiologíaRESUMEN
Dozens of new antiviral systems have been recently characterized in bacteria. Some of these systems are present in eukaryotes and appear to have originated in prokaryotes, but little is known about these defense mechanisms in archaea. Here, we explore the diversity and distribution of defense systems in archaea and identify 2610 complete systems in Asgardarchaeota, a group of archaea related to eukaryotes. The Asgard defense systems comprise 89 unique systems, including argonaute, NLR, Mokosh, viperin, Lassamu, and CBASS. Asgard viperin and argonaute proteins have structural homology to eukaryotic proteins, and phylogenetic analyses suggest that eukaryotic viperin proteins were derived from Asgard viperins. We show that Asgard viperins display anti-phage activity when heterologously expressed in bacteria. Eukaryotic and bacterial argonaute proteins appear to have originated in Asgardarchaeota, and Asgard argonaute proteins have argonaute-PIWI domains, key components of eukaryotic RNA interference systems. Our results support that Asgardarchaeota played important roles in the origin of antiviral defense systems in eukaryotes.
Asunto(s)
Archaea , Proteínas Arqueales , Filogenia , Archaea/genética , Archaea/inmunología , Archaea/virología , Proteínas Arqueales/metabolismo , Proteínas Arqueales/genética , Proteínas Argonautas/metabolismo , Proteínas Argonautas/genética , Eucariontes/genética , Eucariontes/inmunología , Bacteriófagos/genética , Bacteriófagos/fisiología , Evolución MolecularRESUMEN
Immune defence mechanisms exist across the tree of life in such diversity that prokaryotic antiviral responses have historically been considered unrelated to eukaryotic immunity. Mechanisms of defence in divergent eukaryotes were similarly believed to be largely clade specific. However, recent data indicate that a subset of modules (domains and proteins) from prokaryote defence systems are conserved in eukaryotes and populate many stages of innate immune pathways. In this Essay, we propose the notion of ancestral immunity, which corresponds to the set of immune modules conserved between prokaryotes and eukaryotes. After offering a typology of ancestral immunity, we speculate on the selective pressures that could have led to the differential conservation of specific immune modules across domains of life. The exploration of ancestral immunity is in its infancy and appears full of promises to illuminate immune evolution, and also to identify and decipher immune mechanisms of economic, ecological, and therapeutic importance.
Asunto(s)
Inmunidad Innata , Animales , Células Procariotas/inmunología , Filogenia , Humanos , Evolución Biológica , Eucariontes/inmunología , Evolución MolecularRESUMEN
Monoclonal antibody biologics have significantly transformed the therapeutic landscape within the biopharmaceutical industry, partly due to the utilisation of discovery technologies such as the hybridoma method and phage display. While these established platforms have streamlined the development process to date, their reliance on cell transformation for antibody identification faces limitations related to library diversification and the constraints of host cell physiology. Cell-free systems like ribosome display offer a complementary approach, enabling antibody selection in a completely in vitro setting while harnessing enriched cellular molecular machinery. This review aims to provide an overview of the fundamental principles underlying the ribosome display method and its potential for advancing antibody discovery and development.
Asunto(s)
Anticuerpos Monoclonales , Biblioteca de Péptidos , Ribosomas , Ribosomas/inmunología , Humanos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/genética , Animales , Técnicas de Visualización de Superficie Celular , Descubrimiento de Drogas , Eucariontes/inmunología , Eucariontes/genéticaRESUMEN
Pathogens are ubiquitous and a constant threat to their hosts, which has led to the evolution of sophisticated immune systems in bacteria, archaea and eukaryotes. Bacterial immune systems encode an astoundingly large array of antiviral (antiphage) systems, and recent investigations have identified unexpected similarities between the immune systems of bacteria and animals. In this Review, we discuss advances in our understanding of the bacterial innate immune system and highlight the components, strategies and pathogen restriction mechanisms conserved between bacteria and eukaryotes. We summarize evidence for the hypothesis that components of the human immune system originated in bacteria, where they first evolved to defend against phages. Further, we discuss shared mechanisms that pathogens use to overcome host immune pathways and unexpected similarities between bacterial immune systems and interbacterial antagonism. Understanding the shared evolutionary path of immune components across domains of life and the successful strategies that organisms have arrived at to restrict their pathogens will enable future development of therapeutics that activate the human immune system for the precise treatment of disease.
Asunto(s)
Bacterias , Eucariontes , Inmunidad Innata , Humanos , Bacterias/inmunología , Animales , Eucariontes/inmunología , Interacciones Huésped-Patógeno/inmunología , Bacteriófagos/inmunología , Bacteriófagos/fisiología , Evolución BiológicaRESUMEN
In both prokaryotic and eukaryotic innate immune systems, TIR domains function as NADases that degrade the key metabolite NAD+ or generate signaling molecules. Catalytic activation of TIR domains requires oligomerization, but how this is achieved varies in distinct immune systems. In the Short prokaryotic Argonaute (pAgo)/TIR-APAZ (SPARTA) immune system, TIR NADase activity is triggered upon guide RNA-mediated recognition of invading DNA by an unknown mechanism. Here, we describe cryo-EM structures of SPARTA in the inactive monomeric and target DNA-activated tetrameric states. The monomeric SPARTA structure reveals that in the absence of target DNA, a C-terminal tail of TIR-APAZ occupies the nucleic acid binding cleft formed by the pAgo and TIR-APAZ subunits, inhibiting SPARTA activation. In the active tetrameric SPARTA complex, guide RNA-mediated target DNA binding displaces the C-terminal tail and induces conformational changes in pAgo that facilitate SPARTA-SPARTA dimerization. Concurrent release and rotation of one TIR domain allow it to form a composite NADase catalytic site with the other TIR domain within the dimer, and generate a self-complementary interface that mediates cooperative tetramerization. Combined, this study provides critical insights into the structural architecture of SPARTA and the molecular mechanism underlying target DNA-dependent oligomerization and catalytic activation.
Asunto(s)
Inmunidad Innata , Células Procariotas , Sistema Inmunológico , NAD+ Nucleosidasa , Células Procariotas/inmunología , ARN Guía de Sistemas CRISPR-Cas , Transducción de Señal , Eucariontes/inmunologíaRESUMEN
Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages1-3. Similar to how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns4 (PAMPs), many bacterial immune systems that respond to bacteriophage infection require phage-specific triggers to be activated. However, the identities of such triggers and the sensing mechanisms remain largely unknown. Here we identify and investigate the anti-phage function of CapRelSJ46, a fused toxin-antitoxin system that protects Escherichia coli against diverse phages. Using genetic, biochemical and structural analyses, we demonstrate that the C-terminal domain of CapRelSJ46 regulates the toxic N-terminal region, serving as both antitoxin and phage infection sensor. Following infection by certain phages, newly synthesized major capsid protein binds directly to the C-terminal domain of CapRelSJ46 to relieve autoinhibition, enabling the toxin domain to pyrophosphorylate tRNAs, which blocks translation to restrict viral infection. Collectively, our results reveal the molecular mechanism by which a bacterial immune system directly senses a conserved, essential component of phages, suggesting a PAMP-like sensing model for toxin-antitoxin-mediated innate immunity in bacteria. We provide evidence that CapRels and their phage-encoded triggers are engaged in a 'Red Queen conflict'5, revealing a new front in the intense coevolutionary battle between phages and bacteria. Given that capsid proteins of some eukaryotic viruses are known to stimulate innate immune signalling in mammalian hosts6-10, our results reveal a deeply conserved facet of immunity.
Asunto(s)
Bacteriófagos , Proteínas de la Cápside , Escherichia coli , Inmunidad Innata , Animales , Antitoxinas/inmunología , Bacteriófagos/inmunología , Proteínas de la Cápside/inmunología , Escherichia coli/inmunología , Escherichia coli/virología , Eucariontes/inmunología , Moléculas de Patrón Molecular Asociado a Patógenos/inmunologíaRESUMEN
Legionella pneumophila is an intracellular bacterial pathogen that can cause a severe form of pneumonia in humans, a phenotype evolved through interactions with aquatic protozoa in the environment. Here, we show that L. pneumophila uses extracellular vesicles to translocate bacterial small RNAs (sRNAs) into host cells that act on host defence signalling pathways. The bacterial sRNA RsmY binds to the UTR of ddx58 (RIG-I encoding gene) and cRel, while tRNA-Phe binds ddx58 and irak1 collectively reducing expression of RIG-I, IRAK1 and cRel, with subsequent downregulation of IFN-ß. Thus, RsmY and tRNA-Phe are bacterial trans-kingdom regulatory RNAs downregulating selected sensor and regulator proteins of the host cell innate immune response. This miRNA-like regulation of the expression of key sensors and regulators of immunity is a feature of L. pneumophila host-pathogen communication and likely represents a general mechanism employed by bacteria that interact with eukaryotic hosts.
Asunto(s)
Eucariontes/inmunología , Interacciones Huésped-Patógeno/inmunología , Legionella pneumophila/metabolismo , Enfermedad de los Legionarios/inmunología , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Bacterianas/metabolismo , Línea Celular , Proteína 58 DEAD Box , Eucariontes/genética , Vesículas Extracelulares , Humanos , Inmunidad Innata , Quinasas Asociadas a Receptores de Interleucina-1 , Enfermedad de los Legionarios/microbiología , Receptores Inmunológicos , Transducción de SeñalRESUMEN
Bioinformatics programs have been developed that exploit informative signals encoded within protein sequences to predict protein characteristics. Unfortunately, there is no program as yet that can predict whether a protein will induce a protective immune response to a pathogen. Nonetheless, predicting those pathogen proteins most likely from those least likely to induce an immune response is feasible when collectively using predicted protein characteristics. Vacceed is a computational pipeline that manages different standalone bioinformatics programs to predict various protein characteristics, which offer supporting evidence on whether a protein is secreted or membrane -associated. A set of machine learning algorithms predicts the most likely pathogen proteins to induce an immune response given the supporting evidence. This chapter provides step by step descriptions of how to configure and operate Vacceed for a eukaryotic pathogen of the user's choice.
Asunto(s)
Antígenos/inmunología , Biología Computacional/métodos , Mapeo Epitopo/métodos , Eucariontes/inmunología , Interacciones Huésped-Patógeno/inmunología , Programas Informáticos , AlgoritmosRESUMEN
The proper function of the innate immune system depends on an intricate network of regulation that promotes effective responses to pathogens while avoiding autoimmunity. Circular RNAs (circRNAs), a class of RNAs that lack 5' and 3' ends, have emerged as key actors in these networks. Recent studies have demonstrated that endogenous circRNAs in eukaryotes regulate the activation of innate immune proteins and cells through diverse modes of action. Some DNA viruses also encode circRNAs, and foreign circRNAs have been found to stimulate an innate immune response. This review summarizes recent investigations that reveal the critical roles that circRNAs play in innate immunity and points to future areas of study in this emerging field.
Asunto(s)
Inmunidad Innata/inmunología , ARN Circular/inmunología , Eucariontes/inmunología , HumanosRESUMEN
Nucleotide-activated effector deployment, prototyped by interferon-dependent immunity, is a common mechanistic theme shared by immune systems of several animals and prokaryotes. Prokaryotic versions include CRISPR-Cas with the CRISPR polymerase domain, their minimal variants, and systems with second messenger oligonucleotide or dinucleotide synthetase (SMODS). Cyclic or linear oligonucleotide signals in these systems help set a threshold for the activation of potentially deleterious downstream effectors in response to invader detection. We establish such a regulatory mechanism to be a more general principle of immune systems, which can also operate independently of such messengers. Using sensitive sequence analysis and comparative genomics, we identify 12 new prokaryotic immune systems, which we unify by this principle of threshold-dependent effector activation. These display regulatory mechanisms paralleling physiological signaling based on 3'-5' cyclic mononucleotides, NAD+-derived messengers, two- and one-component signaling that includes histidine kinase-based signaling, and proteolytic activation. Furthermore, these systems allowed the identification of multiple new sensory signal sensory components, such as a tetratricopeptide repeat (TPR) scaffold predicted to recognize NAD+-derived signals, unreported versions of the STING domain, prokaryotic YEATS domains, and a predicted nucleotide sensor related to receiver domains. We also identify previously unrecognized invader detection components and effector components, such as prokaryotic versions of the Wnt domain. Finally, we show that there have been multiple acquisitions of unidentified STING domains in eukaryotes, while the TPR scaffold was incorporated into the animal immunity/apoptosis signal-regulating kinase (ASK) signalosome.IMPORTANCE Both prokaryotic and eukaryotic immune systems face the dangers of premature activation of effectors and degradation of self-molecules in the absence of an invader. To mitigate this, they have evolved threshold-setting regulatory mechanisms for the triggering of effectors only upon the detection of a sufficiently strong invader signal. This work defines general templates for such regulation in effector-based immune systems. Using this, we identify several previously uncharacterized prokaryotic immune mechanisms that accomplish the regulation of downstream effector deployment by using nucleotide, NAD+-derived, two-component, and one-component signals paralleling physiological homeostasis. This study has also helped identify several previously unknown sensor and effector modules in these systems. Our findings also augment the growing evidence for the emergence of key animal immunity and chromatin regulatory components from prokaryotic progenitors.
Asunto(s)
Bacterias/genética , Bacterias/inmunología , Proteínas Bacterianas/inmunología , Eucariontes/inmunología , Secuencia de Aminoácidos , Bacterias/química , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Eucariontes/genética , Genómica , Sistema Inmunológico , Nucleótidos/química , Nucleótidos/inmunología , Alineación de SecuenciaRESUMEN
Inflammasomes are cytosolic complexes that assemble in response to cellular stress or upon sensing microbial molecules, culminating in cytokine processing and an inflammatory form of cell death called pyroptosis. Inflammasomes are usually composed of a sensor molecule, an adaptor protein, and an inflammatory caspase, such as Caspase-1, which cleaves and activates multiple substrates, including Gasdermin-D, pro-IL-1ß, and pro-IL-18. Ultimately, inflammasome activation promotes inflammation and restriction of the microbial infection. In recent years, many studies have addressed the role of inflammasomes during fungal, bacterial, viral, and parasitic diseases, revealing sophisticated aspects of the host-pathogen interaction. In this review, we summarize recent advances on inflammasome activation in response to intracellular parasites, including Leishmania spp., Plasmodium spp., Trypanosoma cruzi, and Toxoplasma gondii.
Asunto(s)
Interacciones Huésped-Patógeno/inmunología , Inflamasomas/inmunología , Infecciones por Protozoos/inmunología , Animales , Eucariontes/inmunología , Humanos , Leishmaniasis/inmunología , Leishmaniasis/parasitología , Malaria/inmunología , Malaria/parasitología , Infecciones por Protozoos/parasitología , Investigación/tendencias , Toxoplasmosis/inmunología , Toxoplasmosis/parasitología , Tripanosomiasis/inmunología , Tripanosomiasis/parasitologíaRESUMEN
CRISPR/Cas evolved as an adaptive immune system in bacteria and archaea to inactivate foreign viral and plasmid DNA. However, the capacities of various CRISPR/Cas systems for precise genome editing based on sequence homology also allow their use as tools for genomic and epigenomic modification in eukaryotes. Indeed, these genetic characteristics have proven useful for disease modeling and testing the specific functions of target genes under pathological conditions. Moreover, recent studies provide compelling evidence that CRISPR/Cas systems could be useful therapeutic tools against human diseases, including cancer, monogenic disorders, and autoimmune disorders.HighlightsCRISPR/Cas evolved as an adaptive immune system in bacteria and archaea.CRISPR/Cas systems are nowadays used as tools for genomic modification.CRISPR/Cas systems could be useful therapeutic tools against human disease, including autoimmune conditions.
Asunto(s)
Archaea/inmunología , Enfermedades Autoinmunes/terapia , Bacterias/inmunología , Sistemas CRISPR-Cas , Eucariontes/inmunología , Neoplasias/terapia , Inmunidad Adaptativa/genética , Inmunidad Adaptativa/inmunología , Archaea/genética , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/microbiología , Bacterias/genética , Eucariontes/metabolismo , Edición Génica/métodos , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Neoplasias/genética , Neoplasias/microbiologíaRESUMEN
Herd immunity, a process in which resistant individuals limit the spread of a pathogen among susceptible hosts has been extensively studied in eukaryotes. Even though bacteria have evolved multiple immune systems against their phage pathogens, herd immunity in bacteria remains unexplored. Here we experimentally demonstrate that herd immunity arises during phage epidemics in structured and unstructured Escherichia coli populations consisting of differing frequencies of susceptible and resistant cells harboring CRISPR immunity. In addition, we develop a mathematical model that quantifies how herd immunity is affected by spatial population structure, bacterial growth rate, and phage replication rate. Using our model we infer a general epidemiological rule describing the relative speed of an epidemic in partially resistant spatially structured populations. Our experimental and theoretical findings indicate that herd immunity may be important in bacterial communities, allowing for stable coexistence of bacteria and their phages and the maintenance of polymorphism in bacterial immunity.
Asunto(s)
Bacteriófagos/fisiología , Evolución Molecular , Inmunidad Colectiva/inmunología , Modelos Teóricos , Animales , Bacterias/genética , Bacterias/inmunología , Bacteriófagos/genética , Epidemias , Escherichia coli/genética , Eucariontes/genética , Eucariontes/inmunología , Humanos , Inmunidad Colectiva/genéticaRESUMEN
Enterohemorrhagic Escherichia coli (EHEC) or other attaching/effacing pathogen infections often cause host intestinal inflammation and pathology, which is thought to result in part from a host aggressive innate immune response. However, few effectors that play an important role in this pathology change have been reported. In this study, we discovered a previously unknown EHEC effector, Stk (putative serine/threonine kinase), which induces host aggressive inflammatory response during EHEC infection. Interestingly, homologous proteins of Stk are widely distributed in many pathogens. After translocating into the infected host cells, Stk efficiently phosphorylates IκBα and activates the NF-κB pathway. In EHEC-infected mice, Stk increases serum keratinocyte-derived cytokine (KC) levels and hyperactivates the inflammatory response of the colon, intensifying pathological injury of the colon. The virulence of Stk is based on its eukaryotic-like kinase activity. In conclusion, our data suggest that Stk is a new effector that induces the host aggressive inflammatory response during EHEC infection.
Asunto(s)
Escherichia coli Enterohemorrágica/inmunología , Escherichia coli Enterohemorrágica/metabolismo , Infecciones por Escherichia coli/inmunología , Infecciones por Escherichia coli/metabolismo , Interacciones Huésped-Patógeno/inmunología , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Eucariontes/inmunología , Eucariontes/metabolismo , Humanos , Inflamación/inmunología , Inflamación/metabolismoRESUMEN
According to experimental data, eukaryote unicellulars are able to learn, have immunity and memory. Learning is carried out in a very primitive form, and the memory is not neural but an epigenetic one. However, this epigenetic memory, which is well justified by the presence and manifestation of hormonal imprinting, is strong and permanent in the life of cell and also in its progenies. This memory is epigenetically executed by the alteration and fixation of methylation pattern of genes without changes in base sequences. The immunity of unicellulars is based on self/non-self discrimination, which leads to the destruction of non-self invaders and utilization of them as nourishment (by phagocytosis). The tools of learning, memory, and immunity of unicellulars are uniformly found in plasma membrane receptors, which formed under the effect of dynamic receptor pattern generation, suggested by Koch et al., and this is the basis of hormonal imprinting, by which the encounter between a chemical substance and the cell is specifically memorized. The receptors and imprinting are also used in the later steps of evolution up to mammals (including man) in each mentioned functions. This means that learning, memory, and immunity can be deduced to a unicellular eukaryote level.
Asunto(s)
Eucariontes/inmunología , Eucariontes/fisiología , Animales , Eucariontes/genética , Humanos , Aprendizaje , MemoriaRESUMEN
Prokaryotes and eukaryotes evolved relatively similar RNA-based molecular mechanisms to fight potentially deleterious nucleic acids coming from phages, transposons, or viruses. Short RNAs guide effector complexes toward their targets to be silenced or eliminated. These short immunity RNAs are transcribed from clustered loci. Unexpectedly and strikingly, bacterial and eukaryotic immunity RNA clusters share substantial functional and mechanistic resemblances in fighting nucleic acid intruders.
Asunto(s)
Proteínas Argonautas/inmunología , Sistemas CRISPR-Cas/inmunología , Eucariontes/inmunología , Células Procariotas/inmunología , ARN Interferente Pequeño/inmunología , Proteínas Argonautas/genética , Bacteriófagos/genética , Bacteriófagos/patogenicidad , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/inmunología , Elementos Transponibles de ADN/inmunología , Eucariontes/genética , Eucariontes/virología , Plásmidos/química , Plásmidos/inmunología , Células Procariotas/virología , ARN Guía de Kinetoplastida/genética , ARN Guía de Kinetoplastida/inmunología , ARN Interferente Pequeño/genéticaRESUMEN
Genome editing by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated gene 9) system has been transformative in biology. Originally discovered as an adaptive prokaryotic immune system, CRISPR/Cas9 has been repurposed for genome editing in a broad range of model organisms, from yeast to mammalian cells. Protist parasites are unicellular organisms producing important human diseases that affect millions of people around the world. For many of these diseases, such as malaria, Chagas disease, leishmaniasis and cryptosporidiosis, there are no effective treatments or vaccines available. The recent adaptation of the CRISPR/Cas9 technology to several protist models will be playing a key role in the functional study of their proteins, in the characterization of their metabolic pathways, and in the understanding of their biology, and will facilitate the search for new chemotherapeutic targets. In this work we review recent studies where the CRISPR/Cas9 system was adapted to protist parasites, particularly to Apicomplexans and trypanosomatids, emphasizing the different molecular strategies used for genome editing of each organism, as well as their advantages. We also discuss the potential usefulness of this technology in the green alga Chlamydomonas reinhardtii.
Asunto(s)
Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/genética , Eucariontes/genética , Edición Génica , Inmunidad Adaptativa/genética , Animales , Apicomplexa/genética , Chlamydomonas reinhardtii/genética , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/inmunología , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas/fisiología , Cryptosporidium parvum/genética , Eucariontes/inmunología , Eucariontes/patogenicidad , Leishmania/genética , Modelos Biológicos , Plasmodium/genética , Toxoplasma/genética , Trypanosoma cruzi/genética , Trypanosomatina/genéticaRESUMEN
Professor Declan McKeever, a much-loved colleague and friend who died in January 2014, devoted much of his professional life to developing vaccines against tick-borne diseases of cattle. A conference was held at Hatfield House on the 21st October, 2014, bringing together colleagues from across the world to discuss the challenges of parasite control and to celebrate Declan's contributions and achievements.