Cooperation and cheating orchestrate Vibrio assemblages and polymicrobial synergy in oysters infected with OsHV-1 virus.

Polymicrobial infections threaten the health of humans and animals but remain understudied in natural systems. We recently described the Pacific Oyster Mortality Syndrome (POMS), a polymicrobial disease affecting oyster production worldwide. In the French Atlantic coast, the disease involves coinfection with ostreid herpesvirus 1 (OsHV-1) and virulent Vibrio. However, it is unknown whether consistent Vibrio populations are associated with POMS in different regions, how Vibrio contribute to POMS, and how they interact with OsHV-1 during pathogenesis. By connecting field-based approaches in a Mediterranean ecosystem, laboratory infection assays and functional genomics, we uncovered a web of interdependencies that shape the structure and function of the POMS pathobiota. We show that Vibrio harveyi and Vibrio rotiferianus are predominant in OsHV-1-diseased oysters and that OsHV-1 drives the partition of the Vibrio community observed in the field. However only V. harveyi synergizes with OsHV-1 by promoting mutual growth and accelerating oyster death. V. harveyi shows high-virulence potential and dampens oyster cellular defenses through a type 3 secretion system, making oysters a more favorable niche for microbe colonization. In addition, V. harveyi produces a key siderophore called vibrioferrin. This important resource promotes the growth of V. rotiferianus, which cooccurs with V. harveyi in diseased oysters, and behaves as a cheater by benefiting from V. harveyi metabolite sharing. Our data show that cooperative behaviors contribute to synergy between bacterial and viral coinfecting partners. Additional cheating behaviors further shape the polymicrobial consortium. Controlling cooperative behaviors or countering their effects opens avenues for mitigating polymicrobial diseases.

Allergens grouping names on packaging: Are the substances similar enough to ensure safety? The worst case scenarios question this.

OBJECTIVE: European Commission Regulation (EU) n°2023/1545 introduced the concept of grouping names in the cosmetics sector in July 2023. These groups bring together allergenic substances with the same level of skin sensitization. Their purpose is to lighten the list of ingredients on cosmetic packaging, by grouping together substances deemed to be similar under the same name. As this classification is based on a single toxic effect - skin sensitization - the present study aims to analyse the relevance of these groupings with regard to other toxic effects of substances in the same group. METHODS: This study was carried out by consulting an available database, various reports from 5 committees, 2 books and 5 articles in order to complete the toxicological profile of each substance. Then, in order to highlight any discrepancies within the classification, the worst cases were identified. For this purpose, the data for each substance in a group were compared, and in the event of greater criticality for a toxic effect, this was qualified as a worst case. In addition, similar toxic effects between several substances within the same group were also recorded. The aim of this additional research was to validate the definition of the grouping name and the similarities between substances in the same group. RESULTS: From the 17 grouping names, 5 presented worst cases. Two groups had 2 worst cases and the others only one. In total, from the 7 worst cases detected, 3 were due to the toxic effect "skin irritation". In most cases, the substances in the groupings shared the presence or absence of risk. Only the degree of risk criticality varied. CONCLUSION: Classification by grouping names appears justified regarding the similarities between substances, particularly in terms of skin sensitization. However, the presence of worst cases qualifies it and highlights the importance of being vigilant when assessing the risk of cosmetic products including these grouping names in their list of ingredients.

OBJECTIF: Le règlement (UE) n°2023/1545 de la Commission européenne a introduit la notion de « grouping names ¼ dans le domaine des cosmétiques en juillet 2023. Ces groupes rassemblent des substances allergènes ayant le même niveau de sensibilisation cutanée. Ils ont pour objectif d'alléger la liste des ingrédients figurant sur les emballages des produits cosmétiques, en regroupant sous un même nom des substances jugées similaires. Cette classification étant fondée sur un seul effet toxique ­ la sensibilisation cutanée ­ la présente étude vise à analyser la pertinence de ces regroupements au regard des autres effets toxiques des substances d'un même groupe. MÉTHODES: Cette étude a été réalisée en consultant une base de données disponible, différents rapports de 5 comités, 2 livres et 5 articles afin de compléter le profil toxicologique de chaque substance. Ensuite, afin de mettre en évidence les divergences au sein de la classification, les cas de criticité plus importante ont été identifiés. Pour ce faire, les données de chaque substance d'un groupe ont été comparées, et en cas de criticité supérieure d'un effet toxique, celui­ci a été qualifié de « worst case ¼. En outre, les effets toxiques similaires entre plusieurs substances d'un même groupe ont également été enregistrés. L'objectif de cette recherche complémentaire était de valider la définition du « grouping name ¼ et les similitudes entre les substances d'un même groupe. RÉSULTATS: Sur les 17 « grouping names ¼, 5 présentaient des « worst cases ¼. Deux groupes présentaient deux « worst cases ¼ et les autres un seul. Au total, sur les 7 « worst cases ¼ détectés, 3 étaient dus à l'effet toxique "irritation cutanée". Dans la plupart des cas, les substances des groupes partagent la présence ou l'absence de risque. Seul le degré de criticité du risque variait. CONCLUSION: La classification par « grouping names ¼ semble justifiée au regard des similitudes entre les substances, notamment en termes de sensibilisation cutanée. Cependant, la présence de « worst cases ¼ la nuance et souligne l'importance d'être vigilant lors de l'évaluation du risque des produits cosmétiques incluant ces « grouping names ¼ dans leur liste d'ingrédients.

Development of an Objective Structured Clinical Examination (OSCE) to evaluate the diagnosis announcement of chronic neurological disease by residents in neurology.

BACKGROUND: There is little consensus on how to make a diagnosis announcement of severe chronic disease in neurology. Other medical specialties, such as oncology, have developed assessment methods similar to the Objective Structured Clinical Examination (OSCE) to address this issue. Here we report the implementation of an OSCE focused on the diagnosis announcement of chronic disease in neurology by residents. OBJECTIVE: We aimed to evaluate the acceptability, feasibility and validity in routine practice of an OSCE combined with a theoretical course focused on diagnosis announcement in neurology. METHOD: Eighteen neurology residents were prospectively included between 2019 and 2022. First, they answered a questionnaire on their previous level of training in diagnosis announcement. Second, in a practical session with a simulated patient, they made a 15-min diagnosis announcement and then had 5mins of immediate feedback with an expert observer, present in the room. The OSCE consisted of 4 different stations, with standardized scenarios dedicated to the announcement of multiple sclerosis (MS), Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Third, in a theory session, expert observers covered the essential theoretical points. All residents and expert observers completed an evaluation of the "practical session" and the "theory session". RESULTS: Residents estimated their previous level of diagnosis announcement training at 3.1/5. The most feared announcements were AD and ALS. The "practical session" was rated at a mean of 4.1/5 by the residents and 4.8/5 by the expert observers, and the "theory session" at a mean of 4.7/5 by the residents and 5/5 by the expert observers. After the OSCEs, 11 residents felt more confident about making an announcement. CONCLUSION: This study has shown a benefit of using an OSCE to learn how to make a diagnosis announcement of severe chronic disease in neurology. OSCEs could be used in many departments in routine practice and seem adapted to residents.

Emergence and clonal expansion of Vibrio aestuarianus lineages pathogenic for oysters in Europe.

Crassostrea gigas oysters represent a significant global food source with 4.7 million tons harvested per year. In 2001, the bacterium Vibrio aestuarianus subsp. francensis emerged as a pathogen that causes adult oyster mortality in France and Ireland. Its impact on oyster aquaculture has increased in Europe since its re-emergence in 2012. To better understand the evolutionary mechanisms leading to the emergence and persistence over time of this pathogen, we conducted a survey of mollusc diseases through national reference laboratories across Europe. We analysed 54 new genomes of Vibrio aestuarianus (Va) isolated from multiple environmental compartments since 2001, in areas with and without bivalve mortalities. We used a combination of comparative genomics and population genetics approaches and show that Va has a classical epidemic population structure from which the pathogenic Va francensis subspecies emerged and clonally expanded. Furthermore, we identified a specific cus-cop-containing island conferring copper resistance to Va francensis whose acquisition may have favoured the emergence of pathogenic lineages adapted and specialized to oysters.

Prevalence and polymorphism of a mussel transmissible cancer in Europe.

Transmissible cancers are parasitic malignant cell lineages that have acquired the ability to infect new hosts from the same species, or sometimes related species. First described in dogs and Tasmanian devils, transmissible cancers were later discovered in some marine bivalves affected by a leukaemia-like disease. In Mytilus mussels, two lineages of bivalve transmissible neoplasia (BTN) have been described to date (MtrBTN1 and MtrBTN2), both of which emerged in a Mytilus trossulus founder individual. Here, we performed extensive screening of genetic chimerism, a hallmark of transmissible cancer, by genotyping 106 single nucleotide polymorphisms of 5,907 European Mytilus mussels. Genetic analysis allowed us to simultaneously obtain the genotype of hosts - Mytilus edulis, M. galloprovincialis or hybrids - and the genotype of tumours of heavily infected individuals. In addition, a subset of 222 individuals were systematically genotyped and analysed by histology to screen for possible nontransmissible cancers. We detected MtrBTN2 at low prevalence in M. edulis, and also in M. galloprovincialis and hybrids although at a much lower prevalence. No MtrBTN1 or new BTN were found, but eight individuals with nontransmissible neoplasia were observed at a single polluted site on the same sampling date. We observed a diversity of MtrBTN2 genotypes that appeared more introgressed or more ancestral than MtrBTN1 and reference healthy M. trossulus individuals. The observed polymorphism is probably due to somatic null alleles caused by structural variations or point mutations in primer-binding sites leading to enhanced detection of the host alleles. Despite low prevalence, two sublineages divergent by 10% fixed somatic null alleles and one nonsynonymous mtCOI (mitochondrial cytochrome oxidase I) substitution are cospreading in the same geographical area, suggesting a complex diversification of MtrBTN2 since its emergence and host species shift.

Functional Diversification of Oyster Big Defensins Generates Antimicrobial Specificity and Synergy against Members of the Microbiota.

Big defensins are two-domain antimicrobial peptides (AMPs) that have highly diversified in mollusks. Cg-BigDefs are expressed by immune cells in the oyster Crassostrea gigas, and their expression is dampened during the Pacific Oyster Mortality Syndrome (POMS), which evolves toward fatal bacteremia. We evaluated whether Cg-BigDefs contribute to the control of oyster-associated microbial communities. Two Cg-BigDefs that are representative of molecular diversity within the peptide family, namely Cg-BigDef1 and Cg-BigDef5, were characterized by gene cloning and synthesized by solid-phase peptide synthesis and native chemical ligation. Synthetic peptides were tested for antibacterial activity against a collection of culturable bacteria belonging to the oyster microbiota, characterized by 16S sequencing and MALDI Biotyping. We first tested the potential of Cg-BigDefs to control the oyster microbiota by injecting synthetic Cg-BigDef1 into oyster tissues and analyzing microbiota dynamics over 24 h by 16S metabarcoding. Cg-BigDef1 induced a significant shift in oyster microbiota ß-diversity after 6 h and 24 h, prompting us to investigate antimicrobial activities in vitro against members of the oyster microbiota. Both Cg-BigDef1 and Cg-BigDef5 were active at a high salt concentration (400 mM NaCl) and showed broad spectra of activity against bacteria associated with C. gigas pathologies. Antimicrobial specificity was observed for both molecules at an intra- and inter-genera level. Remarkably, antimicrobial spectra of Cg-BigDef1 and Cg-BigDef5 were complementary, and peptides acted synergistically. Overall, we found that primary sequence diversification of Cg-BigDefs has generated specificity and synergy and extended the spectrum of activity of this peptide family.

Species-specific mechanisms of cytotoxicity toward immune cells determine the successful outcome of Vibrio infections.

Vibrio species cause infectious diseases in humans and animals, but they can also live as commensals within their host tissues. How Vibrio subverts the host defenses to mount a successful infection remains poorly understood, and this knowledge is critical for predicting and managing disease. Here, we have investigated the cellular and molecular mechanisms underpinning infection and colonization of 2 virulent Vibrio species in an ecologically relevant host model, oyster, to study interactions with marine Vibrio species. All Vibrio strains were recognized by the immune system, but only nonvirulent strains were controlled. We showed that virulent strains were cytotoxic to hemocytes, oyster immune cells. By analyzing host and bacterial transcriptional responses to infection, together with Vibrio gene knock-outs, we discovered that Vibrio crassostreae and Vibrio tasmaniensis use distinct mechanisms to cause hemocyte lysis. Whereas V. crassostreae cytotoxicity is dependent on a direct contact with hemocytes and requires an ancestral gene encoding a protein of unknown function, r5.7, V. tasmaniensis cytotoxicity is dependent on phagocytosis and requires intracellular secretion of T6SS effectors. We conclude that proliferation of commensal vibrios is controlled by the host immune system, preventing systemic infections in oysters, whereas the successful infection of virulent strains relies on Vibrio species-specific molecular determinants that converge to compromise host immune cell function, allowing evasion of the host immune system.

[Learnings from the use of CEdRIC strategy in the context of COVID-19 pandemic]. / Face à la COVID-19. Utilisation de la stratégie CEdRIC dans le contexte de la pandémie à coronavirus : retour d'expérience.

This article relates the experience of mobilisation of the CEdRIC strategy by health promotion staff of the Province of Liège, Belgium between June and September 2020. The perception of the beneficiaries is also approached. Four key messages are discussed in the article: the adjustment of a brief educational intervention strategy to the context of the pandemic and integration into primary care; the need for the citizen to be heard and accompanied in times of crisis; the need to go beyond information to health education embedded in a health promotion approach; the role that a structure such as the Province of Liège can play in the health promotion landscape. This article relates the experience of mobilisation of the CEdRIC strategy by health promotion staff of the Province of Liège, through the eyes of the beneficiaries (citizen) contacted by telephone in the days following the intervention. The results indicate an over-information concerning the rules to be respected and a good knowledge of preventive measures. The participants consider these measures useful, easy to apply and declare that they have a role to play in the fight against the pandemic. Nevertheless, not all of the recommendations made by the government are implemented by all participants. Future research should focus on adherence to preventive measures and the factors that can influence this adherence so that future and sustainable actions can be put in place.

La pandémie de coronavirus (COVID-19) a mis en évidence l'importance de développer des stratégies de prévention pour éviter la propagation du virus en adoptant des mesures d'autogestion sanitaires. La stratégie CEdRIC consiste en un protocole en 5 étapes visant à aider le personnel soignant des centres de dépistage à structurer leur communication afin d'éduquer brièvement les citoyens sur les conduites à tenir pour préserver leur santé et prévenir la propagation du virus. Dans cet article est relatée l'expérience de mobilisation de la stratégie CEdRIC menée entre juin et septembre 2020 par du personnel de promotion de la Santé de la Province de Liège. La perception des bénéficiaires est également approchée. Quatre messages clés sont discutés dans l'article : l'ajustement d'une stratégie d'intervention éducative brève au contexte de la pandémie et d'intégration en première ligne de soins; le besoin pour le citoyen d'être entendu et accompagné en temps de crise; la nécessité de dépasser l'information pour passer à de l'éducation en santé inscrite dans une approche de promotion de la santé; le rôle qu'une structure comme la Province de Liège peut tenir dans le paysage de la promotion de la Santé.

Therapeutic strategies for C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia.

PURPOSE OF REVIEW: An intronic G4C2 expansion mutation in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Although there are currently no treatments for this insidious, fatal disease, intense research has led to promising therapeutic strategies, which will be discussed here. RECENT FINDINGS: Therapeutic strategies for C9-ALS/FTD have primarily focused on reducing the toxic effects of mutant expansion RNAs or the dipeptide repeat proteins (DPRs). The pathogenic effects of G4C2 expansion transcripts have been targeted using approaches aimed at promoting their degradation, inhibiting nuclear export or silencing transcription. Other promising strategies include immunotherapy to reduce the DPRs themselves, reducing RAN translation, removing the repeats using DNA or RNA editing and manipulation of downstream disease-altered stress granule pathways. Finally, understanding the molecular triggers that lead to pheno-conversion may lead to opportunities that can delay symptomatic disease onset. SUMMARY: A large body of evidence implicates RAN-translated DPRs as a main driver of C9-ALS/FTD. Promising therapeutic strategies for these devastating diseases are being rapidly developed with several approaches already in or approaching clinical trials.

Sympatric versus allopatric evolutionary contexts shape differential immune response in Biomphalaria / Schistosoma interaction.

Selective pressures between hosts and their parasites can result in reciprocal evolution or adaptation of specific life history traits. Local adaptation of resident hosts and parasites should lead to increase parasite infectivity/virulence (higher compatibility) when infecting hosts from the same location (in sympatry) than from a foreign location (in allopatry). Analysis of geographic variations in compatibility phenotypes is the most common proxy used to infer local adaptation. However, in some cases, allopatric host-parasite systems demonstrate similar or greater compatibility than in sympatry. In such cases, the potential for local adaptation remains unclear. Here, we study the interaction between Schistosoma and its vector snail Biomphalaria in which such discrepancy in local versus foreign compatibility phenotype has been reported. Herein, we aim at bridging this gap of knowledge by comparing life history traits (immune cellular response, host mortality, and parasite growth) and molecular responses in highly compatible sympatric and allopatric Schistosoma/Biomphalaria interactions originating from different geographic localities (Brazil, Venezuela and Burundi). We found that despite displaying similar prevalence phenotypes, sympatric schistosomes triggered a rapid immune suppression (dual-RNAseq analyses) in the snails within 24h post infection, whereas infection by allopatric schistosomes (regardless of the species) was associated with immune cell proliferation and triggered a non-specific generalized immune response after 96h. We observed that, sympatric schistosomes grow more rapidly. Finally, we identify miRNAs differentially expressed by Schistosoma mansoni that target host immune genes and could be responsible for hijacking the host immune response during the sympatric interaction. We show that despite having similar prevalence phenotypes, sympatric and allopatric snail-Schistosoma interactions displayed strong differences in their immunobiological molecular dialogue. Understanding the mechanisms allowing parasites to adapt rapidly and efficiently to new hosts is critical to control disease emergence and risks of Schistosomiasis outbreaks.

Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders.

Repeat-associated non-AUG (RAN) translation was discovered in 2011 in spinocerebellar ataxia type 8 (SCA8) and myotonic dystrophy type 1 (DM1). This non-canonical form of translation occurs in all reading frames from both coding and non-coding regions of sense and antisense transcripts carrying expansions of trinucleotide to hexanucleotide repeat sequences. RAN translation has since been reported in 7 of the 53 known microsatellite expansion disorders which mainly present with neurodegenerative features. RAN translation leads to the biosynthesis of low-complexity polymeric repeat proteins with aggregating and cytotoxic properties. However, the molecular mechanisms and protein factors involved in assembling functional ribosomes in absence of canonical AUG start codons remain poorly characterised while secondary repeat RNA structures play key roles in initiating RAN translation. Here, we briefly review the repeat expansion disorders, their complex pathogenesis and the mechanisms of physiological translation initiation together with the known factors involved in RAN translation. Finally, we discuss research challenges surrounding the understanding of pathogenesis and future directions that may provide opportunities for the development of novel therapeutic approaches for this group of incurable neurodegenerative diseases.

Is adaptive therapy natural?

Research suggests that progression-free survival can be prolonged by integrating evolutionary principles into clinical cancer treatment protocols. The goal is to prevent or slow the proliferation of resistant malignant cell populations. The logic behind this therapy relies on ecological and evolutionary processes. These same processes would be available to natural selection in decreasing the probability of an organism's death due to cancer. We propose that organisms' anticancer adaptions include not only ones for preventing cancer but also ones for directing and retarding the evolution of life-threatening cancer cells. We term this last strategy natural adaptive therapy (NAT). The body's NAT might include a lower than otherwise possible immune response. A restrained immune response might forego maximum short-term kill rates. Restraint would forestall immune-resistant cancer cells and produce long-term durable control of the cancer population. Here, we define, develop, and explore the possibility of NAT. The discovery of NAT mechanisms could identify new strategies in tumor prevention and treatments. Furthermore, we discuss the potential risks of immunotherapies that force the immune system to ramp up the short-term kill rates of malignant cancer cells in a manner that undermines the body's NAT and accelerates the evolution of immune resistance.

[Quality of life in the medical field : a brief overview of its origin, semantics, measuring instruments and clinical use]. / La qualité de vie dans le champ médical. Bref aperçu de son origine, de sa sémantique, de ses instruments de mesure et de leur utilisation en clinique.

Since the early 1970s, the concept of quality of life has been the subject of increasing interest in the medical field, although no scientific consensus has emerged on how to define and measure it. The aim of this narrative review of the literature is to decrypt the notion of quality of life in the medical field, in order to enable clinicians-researchers and clinicians who use quality of life measurement instruments in clinical practice to form an informed and nuanced opinion on the issue. To do so, the paper is divided into three parts. Firstly, a brief overview of the origin of the concept in the medical field is given by exposing the main factors explaining its emergence and its rise in importance. Next, the plurality of definitions of quality of life and its derivatives (e.g. health-related quality of life), as well as its measurement instruments in the medical field, are explored. Finally, some benchmarks for the use of health-related quality of life instruments in clinical practice are presented.

Depuis le début des années 70, la notion de qualité de vie fait l'objet d'un intérêt croissant dans le champ médical, sans pour autant que n'émerge un consensus scientifique sur une manière de la définir et de la mesurer. L'objectif de cette revue narrative de la littérature consiste à décrypter la notion de qualité de vie dans le champ médical afin de permettre aux cliniciens-chercheurs et aux cliniciens, qui utilisent des instruments de mesure de la qualité de vie en pratique clinique, de se forger un avis éclairé et nuancé sur la question. Pour ce faire, le papier se décline en trois parties. Tout d'abord, il fait état d'un bref aperçu de l'origine de la notion dans le champ médical en exposant, notamment, les principaux facteurs expliquant son émergence et son importance grandissante. Ensuite, il explore la pluralité de définitions de la qualité de vie et de ses dérivés (e.g. qualité de vie liée à la santé), ainsi que ses instruments de mesure dans le champ médical. Enfin, il présente quelques repères pour l'utilisation d'instruments de mesure de la qualité de vie liée à la santé en pratique clinique.

The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy.

A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). C9orf72 encodes two C9orf72 protein isoforms of unclear function. Reduced levels of C9orf72 expression have been reported in C9ALS/FTD patients, and although C9orf72 haploinsufficiency has been proposed to contribute to C9ALS/FTD, its significance is not yet clear. Here, we report that C9orf72 interacts with Rab1a and the Unc-51-like kinase 1 (ULK1) autophagy initiation complex. As a Rab1a effector, C9orf72 controls initiation of autophagy by regulating the Rab1a-dependent trafficking of the ULK1 autophagy initiation complex to the phagophore. Accordingly, reduction of C9orf72 expression in cell lines and primary neurons attenuated autophagy and caused accumulation of p62-positive puncta reminiscent of the p62 pathology observed in C9ALS/FTD patients. Finally, basal levels of autophagy were markedly reduced in C9ALS/FTD patient-derived iNeurons. Thus, our data identify C9orf72 as a novel Rab1a effector in the regulation of autophagy and indicate that C9orf72 haploinsufficiency and associated reductions in autophagy might be the underlying cause of C9ALS/FTD-associated p62 pathology.

Vibrio-bivalve interactions in health and disease.

In the marine environment, bivalve mollusks constitute habitats for bacteria of the Vibrionaceae family. Vibrios belong to the microbiota of healthy oysters and mussels, which have the ability to concentrate bacteria in their tissues and body fluids, including the hemolymph. Remarkably, these important aquaculture species respond differently to infectious diseases. While oysters are the subject of recurrent mass mortalities at different life stages, mussels appear rather resistant to infections. Thus, Vibrio species are associated with the main diseases affecting the worldwide oyster production. Here, we review the current knowledge on Vibrio-bivalve interaction in oysters (Crassostrea sp.) and mussels (Mytilus sp.). We discuss the transient versus stable associations of vibrios with their bivalve hosts as well as technical issues limiting the monitoring of these bacteria in bivalve health and disease. Based on the current knowledge of oyster/mussel immunity and their interactions with Vibrio species pathogenic for oyster, we discuss how differences in immune effectors could contribute to the higher resistance of mussels to infections. Finally, we review the multiple strategies evolved by pathogenic vibrios to circumvent the potent immune defences of bivalves and how key virulence mechanisms could have been positively or negatively selected in the marine environment through interactions with predators.

Vibrio splendidus O-antigen structure: a trade-off between virulence to oysters and resistance to grazers.

A major debate in evolutionary biology is whether virulence is maintained as an adaptive trait and/or evolves to non-virulence. In the environment, virulence traits of non-obligatory parasites are subjected to diverse selective pressures and trade-offs. Here, we focus on a population of Vibrio splendidus that displays moderate virulence for oysters. A MARTX (Multifunctional-autoprocessing repeats-in-toxin) and a type-six secretion system (T6SS) were found to be necessary for virulence toward oysters, while a region (wbe) involved in O-antigen synthesis is necessary for resistance to predation against amoebae. Gene inactivation within the wbe region had major consequences on the O-antigen structure, conferring lower immunogenicity, competitive advantage and increased virulence in oyster experimental infections. Therefore, O-antigen structures that favour resistance to environmental predators result in an increased activation of the oyster immune system and a reduced virulence in that host. These trade-offs likely contribute to maintaining O-antigen diversity in the marine environment by favouring genomic plasticity of the wbe region. The results of this study indicate an evolution of V. splendidus towards moderate virulence as a compromise between fitness in the oyster as a host, and resistance to its predators in the environment.

Resistance of the oyster pathogen Vibrio tasmaniensis LGP32 against grazing by Vannella sp. marine amoeba involves Vsm and CopA virulence factors.

Vibrios are ubiquitous in marine environments and opportunistically colonize a broad range of hosts. Strains of Vibrio tasmaniensis present in oyster farms can thrive in oysters during juvenile mortality events and behave as facultative intracellular pathogen of oyster haemocytes. Herein, we wondered whether V. tasmaniensis LGP32 resistance to phagocytosis is specific to oyster immune cells or contributes to resistance to other phagocytes, like marine amoebae. To address this question, we developed an integrative study, from the first description of amoeba diversity in oyster farms to the characterization of LGP32 interactions with amoebae. An isolate of the Vannella genus, Vannella sp. AP1411, which was collected from oyster farms, is ubiquitous, and belongs to one clade of Vannella that could be found associated with Vibrionaceae. LGP32 was shown to be resistant to grazing by Vannella sp. AP1411 and this phenotype depends on some previously identified virulence factors: secreted metalloprotease Vsm and copper efflux p-ATPase CopA, which act at different steps during amoeba-vibrio interactions, whereas some other virulence factors were not involved. Altogether, our work indicates that some virulence factors can be involved in multi-host interactions of V. tasmaniensis ranging from protozoans to metazoans, potentially favouring their opportunistic behaviour.

Segregation of dopamine and glutamate release sites in dopamine neuron axons: regulation by striatal target cells.

Dopamine (DA) is a key regulator of circuits controlling movement and motivation. A subset of midbrain DA neurons has been shown to express the vesicular glutamate transporter (VGLUT)2, underlying their capacity for glutamate release. Glutamate release is found mainly by DA neurons of the ventral tegmental area (VTA) and can be detected at terminals contacting ventral, but not dorsal, striatal neurons, suggesting the possibility that target-derived signals regulate the neurotransmitter phenotype of DA neurons. Whether glutamate can be released from the same terminals that release DA or from a special subset of axon terminals is unclear. Here, we provide in vitro and in vivo data supporting the hypothesis that DA and glutamate-releasing terminals in mice are mostly segregated and that striatal neurons regulate the cophenotype of midbrain DA neurons and the segregation of release sites. Our work unveils a fundamental feature of dual neurotransmission and plasticity of the DA system.-Fortin, G. M., Ducrot, C., Giguère, N., Kouwenhoven, W. M., Bourque, M.-J., Pacelli, C., Varaschin, R. K., Brill, M., Singh, S., Wiseman, P. W., Trudeau, L.-E. Segregation of dopamine and glutamate release sites in dopamine neuron axons: regulation by striatal target cells.

Pathogen-derived effectors trigger protective immunity via activation of the Rac2 enzyme and the IMD or Rip kinase signaling pathway.

Although infections with virulent pathogens often induce a strong inflammatory reaction, what drives the increased immune response to pathogens compared to nonpathogenic microbes is poorly understood. One possibility is that the immune system senses the level of threat from a microorganism and augments the response accordingly. Here, focusing on cytotoxic necrotizing factor 1 (CNF1), an Escherichia coli-derived effector molecule, we showed the host indirectly sensed the pathogen by monitoring for the effector that modified RhoGTPases. CNF1 modified Rac2, which then interacted with the innate immune adaptors IMD and Rip1-Rip2 in flies and mammalian cells, respectively, to drive an immune response. This response was protective and increased the ability of the host to restrict pathogen growth, thus defining a mechanism of effector-triggered immunity that contributes to how metazoans defend against microbes with pathogenic potential.

Astrocyte adenosine deaminase loss increases motor neuron toxicity in amyotrophic lateral sclerosis.

As clinical evidence supports a negative impact of dysfunctional energy metabolism on the disease progression in amyotrophic lateral sclerosis, it is vital to understand how the energy metabolic pathways are altered and whether they can be restored to slow disease progression. Possible approaches include increasing or rerouting catabolism of alternative fuel sources to supplement the glycolytic and mitochondrial pathways such as glycogen, ketone bodies and nucleosides. To analyse the basis of the catabolic defect in amyotrophic lateral sclerosis we used a novel phenotypic metabolic array. We profiled fibroblasts and induced neuronal progenitor-derived human induced astrocytes from C9orf72 amyotrophic lateral sclerosis patients compared to normal controls, measuring the rates of production of reduced nicotinamide adenine dinucleotides from 91 potential energy substrates. This approach shows for the first time that C9orf72 human induced astrocytes and fibroblasts have an adenosine to inosine deamination defect caused by reduction of adenosine deaminase, which is also observed in induced astrocytes from sporadic patients. Patient-derived induced astrocyte lines were more susceptible to adenosine-induced toxicity, which could be mimicked by inhibiting adenosine deaminase in control lines. Furthermore, adenosine deaminase inhibition in control induced astrocytes led to increased motor neuron toxicity in co-cultures, similar to the levels observed with patient derived induced astrocytes. Bypassing metabolically the adenosine deaminase defect by inosine supplementation was beneficial bioenergetically in vitro, increasing glycolytic energy output and leading to an increase in motor neuron survival in co-cultures with induced astrocytes. Inosine supplementation, in combination with modulation of the level of adenosine deaminase may represent a beneficial therapeutic approach to evaluate in patients with amyotrophic lateral sclerosis.