Metabolic landscape of the male mouse gut identifies different niches determined by microbial activities.

Distinct niches of the mammalian gut are populated by diverse microbiota, but the contribution of spatial variation to intestinal metabolism remains unclear. Here we present a map of the longitudinal metabolome along the gut of healthy colonized and germ-free male mice. With this map, we reveal a general shift from amino acids in the small intestine to organic acids, vitamins and nucleotides in the large intestine. We compare the metabolic landscapes in colonized versus germ-free mice to disentangle the origin of many metabolites in different niches, which in some cases allows us to infer the underlying processes or identify the producing species. Beyond the known impact of diet on the small intestinal metabolic niche, distinct spatial patterns suggest specific microbial influence on the metabolome in the small intestine. Thus, we present a map of intestinal metabolism and identify metabolite-microbe associations, which provide a basis to connect the spatial occurrence of bioactive compounds to host or microorganism metabolism

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Etude des réseaux de régulation chez Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic human pathogen and a leading cause of nosocomial infections. This Gram-negative bacterium possesses one of the most complex regulatory networks, which allows it to sense and adapt to a wide variety of environmental conditions. In this work, several aspects of P. aeruginosa regulation were investigated. A new transcription factor (TF), ErfA, was found involved in the regulation of the ExlBA-dependent virulence in the PA7-like lineage of P. aeruginosa strains. The study of exlBA regulation in several Pseudomonas species revealed a diversity of regulatory mechanisms for this virulence factor due to differences in promoter cis-regulatory elements, which illustrated a mechanism of regulatory network evolution between closely related species. This type of promoter diversity was further investigated at a genome-wide scale and was found to be very common across all genes. Additionally, the characterization of all regulators sharing ErfA domain architecture allowed the definition of this family of TFs as comprising local, specialized regulators involved in the inhibition of small metabolic pathways. To go further into P. aeruginosa transcriptional regulation, the genome-wide determination of the regulons of all DNA-binding response regulators allowed the delineation of the two-component systems regulatory network, which comprises more than half of all genes of the bacterium. Finally, the investigation of post-transcriptional regulation through the comparative determination of RNA interactomes of Hfq between strains and growth phases identified numerous new common or specific regulatory interactions.Pseudomonas aeruginosa est un pathogène opportuniste pour l’humain et une des premières causes d’infections nosocomiales. Cette bactérie Gram-négative possède un des réseaux de régulation les plus complexes, ce qui lui permet de s’adapter à un grand nombre d’environnements différents. Durant cette thèse, différents aspects de la régulation chez P. aeruginosa ont été investigués. Un nouveau facteur de transcription (FT), ErfA, a été identifié comme impliqué dans la régulation de la virulence dépendante d’ExlBA dans le groupe phylogénétique des souches PA7-like de P. aeruginosa. L’étude de la régulation d’exlBA dans plusieurs espèces de Pseudomonas a révélé une diversité de mécanismes de régulation pour ce facteur de virulence due à des différences de séquences régulatrices dans les promoteurs, ce qui illustre un mécanisme d’évolution de la régulation entre espèce proches. La diversité de promoteurs a été étudiée à l’échelle du génome et s’est révélée être relativement commune parmi tous les gènes. De plus, la caractérisation de tous les régulateurs qui possèdent la même architecture protéique que ErfA a permis d’identifier ces FTs comme des régulateurs locaux et spécialisés dans l’inhibition de voies métaboliques. Pour aller plus loin dans l’exploration de la régulation transcriptionnelle, la détermination des régulons de tous les régulateurs de réponses qui sont des FTs a permis la définition du réseau de régulation des systèmes à deux composantes, qui comprend plus de la moitié des gènes de P. aeruginosa. Enfin, l’étude de la régulation post-transcriptionnelle au travers de la caractérisation des interactomes de Hfq dans trois phases de croissance de différentes souches a permis d’identifier de nombreuses nouvelles interactions régulatrices communes ou spécifiques

Insights into the regulatory networks of Pseudomonas aeruginosa

Pseudomonas aeruginosa est un pathogène opportuniste pour l’humain et une des premières causes d’infections nosocomiales. Cette bactérie Gram-négative possède un des réseaux de régulation les plus complexes, ce qui lui permet de s’adapter à un grand nombre d’environnements différents. Durant cette thèse, différents aspects de la régulation chez P. aeruginosa ont été investigués. Un nouveau facteur de transcription (FT), ErfA, a été identifié comme impliqué dans la régulation de la virulence dépendante d’ExlBA dans le groupe phylogénétique des souches PA7-like de P. aeruginosa. L’étude de la régulation d’exlBA dans plusieurs espèces de Pseudomonas a révélé une diversité de mécanismes de régulation pour ce facteur de virulence due à des différences de séquences régulatrices dans les promoteurs, ce qui illustre un mécanisme d’évolution de la régulation entre espèce proches. La diversité de promoteurs a été étudiée à l’échelle du génome et s’est révélée être relativement commune parmi tous les gènes. De plus, la caractérisation de tous les régulateurs qui possèdent la même architecture protéique que ErfA a permis d’identifier ces FTs comme des régulateurs locaux et spécialisés dans l’inhibition de voies métaboliques. Pour aller plus loin dans l’exploration de la régulation transcriptionnelle, la détermination des régulons de tous les régulateurs de réponses qui sont des FTs a permis la définition du réseau de régulation des systèmes à deux composantes, qui comprend plus de la moitié des gènes de P. aeruginosa. Enfin, l’étude de la régulation post-transcriptionnelle au travers de la caractérisation des interactomes de Hfq dans trois phases de croissance de différentes souches a permis d’identifier de nombreuses nouvelles interactions régulatrices communes ou spécifiques.Pseudomonas aeruginosa is an opportunistic human pathogen and a leading cause of nosocomial infections. This Gram-negative bacterium possesses one of the most complex regulatory networks, which allows it to sense and adapt to a wide variety of environmental conditions. In this work, several aspects of P. aeruginosa regulation were investigated. A new transcription factor (TF), ErfA, was found involved in the regulation of the ExlBA-dependent virulence in the PA7-like lineage of P. aeruginosa strains. The study of exlBA regulation in several Pseudomonas species revealed a diversity of regulatory mechanisms for this virulence factor due to differences in promoter cis-regulatory elements, which illustrated a mechanism of regulatory network evolution between closely related species. This type of promoter diversity was further investigated at a genome-wide scale and was found to be very common across all genes. Additionally, the characterization of all regulators sharing ErfA domain architecture allowed the definition of this family of TFs as comprising local, specialized regulators involved in the inhibition of small metabolic pathways. To go further into P. aeruginosa transcriptional regulation, the genome-wide determination of the regulons of all DNA-binding response regulators allowed the delineation of the two-component systems regulatory network, which comprises more than half of all genes of the bacterium. Finally, the investigation of post-transcriptional regulation through the comparative determination of RNA interactomes of Hfq between strains and growth phases identified numerous new common or specific regulatory interactions

Etude des réseaux de régulation chez Pseudomonas aeruginosa

Pseudomonas aeruginosa is an opportunistic human pathogen and a leading cause of nosocomial infections. This Gram-negative bacterium possesses one of the most complex regulatory networks, which allows it to sense and adapt to a wide variety of environmental conditions. In this work, several aspects of P. aeruginosa regulation were investigated. A new transcription factor (TF), ErfA, was found involved in the regulation of the ExlBA-dependent virulence in the PA7-like lineage of P. aeruginosa strains. The study of exlBA regulation in several Pseudomonas species revealed a diversity of regulatory mechanisms for this virulence factor due to differences in promoter cis-regulatory elements, which illustrated a mechanism of regulatory network evolution between closely related species. This type of promoter diversity was further investigated at a genome-wide scale and was found to be very common across all genes. Additionally, the characterization of all regulators sharing ErfA domain architecture allowed the definition of this family of TFs as comprising local, specialized regulators involved in the inhibition of small metabolic pathways. To go further into P. aeruginosa transcriptional regulation, the genome-wide determination of the regulons of all DNA-binding response regulators allowed the delineation of the two-component systems regulatory network, which comprises more than half of all genes of the bacterium. Finally, the investigation of post-transcriptional regulation through the comparative determination of RNA interactomes of Hfq between strains and growth phases identified numerous new common or specific regulatory interactions.Pseudomonas aeruginosa est un pathogène opportuniste pour l’humain et une des premières causes d’infections nosocomiales. Cette bactérie Gram-négative possède un des réseaux de régulation les plus complexes, ce qui lui permet de s’adapter à un grand nombre d’environnements différents. Durant cette thèse, différents aspects de la régulation chez P. aeruginosa ont été investigués. Un nouveau facteur de transcription (FT), ErfA, a été identifié comme impliqué dans la régulation de la virulence dépendante d’ExlBA dans le groupe phylogénétique des souches PA7-like de P. aeruginosa. L’étude de la régulation d’exlBA dans plusieurs espèces de Pseudomonas a révélé une diversité de mécanismes de régulation pour ce facteur de virulence due à des différences de séquences régulatrices dans les promoteurs, ce qui illustre un mécanisme d’évolution de la régulation entre espèce proches. La diversité de promoteurs a été étudiée à l’échelle du génome et s’est révélée être relativement commune parmi tous les gènes. De plus, la caractérisation de tous les régulateurs qui possèdent la même architecture protéique que ErfA a permis d’identifier ces FTs comme des régulateurs locaux et spécialisés dans l’inhibition de voies métaboliques. Pour aller plus loin dans l’exploration de la régulation transcriptionnelle, la détermination des régulons de tous les régulateurs de réponses qui sont des FTs a permis la définition du réseau de régulation des systèmes à deux composantes, qui comprend plus de la moitié des gènes de P. aeruginosa. Enfin, l’étude de la régulation post-transcriptionnelle au travers de la caractérisation des interactomes de Hfq dans trois phases de croissance de différentes souches a permis d’identifier de nombreuses nouvelles interactions régulatrices communes ou spécifiques

The regulation of bacterial two‐partner secretion systems

Two-partner secretion (TPS) systems, also known as Type Vb secretion systems, allow the translocation of effector proteins across the outer membrane of Gram-negative bacteria. By secreting different classes of effectors, including cytolysins and adhesins, TPS systems play important roles in bacterial pathogenesis and host interactions. Here, we review the current knowledge on TPS systems regulation and highlight specific and common regulatory mechanisms across TPS functional classes. We discuss in detail the specific regulatory networks identified in various bacterial species and emphasize the importance of understanding the context-dependent regulation of TPS systems. Several regulatory cues reflecting host environment during infection, such as temperature and iron availability, are common determinants of expression for TPS systems, even across relatively distant species. These common regulatory pathways often affect TPS systems across subfamilies with different effector functions, representing conserved global infection-related regulatory mechanisms

The core and accessory Hfq interactomes across Pseudomonas aeruginosa lineages

International audienceAbstract The major RNA-binding protein Hfq interacts with mRNAs, either alone or together with regulatory small noncoding RNAs (sRNAs), affecting mRNA translation and degradation in bacteria. However, studies tend to focus on single reference strains and assume that the findings may apply to the entire species, despite the important intra-species genetic diversity known to exist. Here, we use RIP-seq to identify Hfq-interacting RNAs in three strains representing the major phylogenetic lineages of Pseudomonas aeruginosa . We find that most interactions are in fact not conserved among the different strains. We identify growth phase-specific and strain-specific Hfq targets, including previously undescribed sRNAs. Strain-specific interactions are due to different accessory gene sets, RNA abundances, or potential context- or sequence- dependent regulatory mechanisms. The accessory Hfq interactome includes most mRNAs encoding Type III Secretion System (T3SS) components and secreted toxins in two strains, as well as a cluster of CRISPR guide RNAs in one strain. Conserved Hfq targets include the global virulence regulator Vfr and metabolic pathways involved in the transition from fast to slow growth. Furthermore, we use rGRIL-seq to show that RhlS, a quorum sensing sRNA, activates Vfr translation, thus revealing a link between quorum sensing and virulence regulation. Overall, our work highlights the important intra-species diversity in post-transcriptional regulatory networks in Pseudomonas aeruginosa

The core and accessory Hfq interactomes across Pseudomonas aeruginosa lineages

The major RNA-binding protein Hfq interacts with mRNAs, either alone or together with regulatory small noncoding RNAs (sRNAs), affecting mRNA translation and degradation in bacteria. However, studies tend to focus on single reference strains and assume that the findings may apply to the entire species, despite the important intra-species genetic diversity known to exist. Here, we use RIP-seq to identify Hfq-interacting RNAs in three strains representing the major phylogenetic lineages of Pseudomonas aeruginosa. We find that most interactions are in fact not conserved among the different strains. We identify growth phase-specific and strain-specific Hfq targets, including previously undescribed sRNAs. Strain-specific interactions are due to different accessory gene sets, RNA abundances, or potential context- or sequence- dependent regulatory mechanisms. The accessory Hfq interactome includes most mRNAs encoding Type III Secretion System (T3SS) components and secreted toxins in two strains, as well as a cluster of CRISPR guide RNAs in one strain. Conserved Hfq targets include the global virulence regulator Vfr and metabolic pathways involved in the transition from fast to slow growth. Furthermore, we use rGRIL-seq to show that RhlS, a quorum sensing sRNA, activates Vfr translation, thus revealing a link between quorum sensing and virulence regulation. Overall, our work highlights the important intra-species diversity in post-transcriptional regulatory networks in Pseudomonas aeruginosa.ISSN:2041-172

Probabilistic Logic Graph Attention Networks for Reasoning.

Deep Learning for Graphs Workshop at the Web Conference (WWW 2020)669-67

Transcription Inhibitors with XRE DNA-Binding and Cupin Signal-Sensing Domains Drive Metabolic Diversification in Pseudomonas

International audienc