Fundamental properties of the mammalian innate immune system revealed by multispecies comparison of type I interferon responses

The host innate immune response mediated by type I interferon (IFN) and the resulting up-regulation of hundreds of interferon-stimulated genes (ISGs) provide an immediate barrier to virus infection. Studies of the type I ‘interferome’ have mainly been carried out at a single species level, often lacking the power necessary to understand key evolutionary features of this pathway. Here, using a single experimental platform, we determined the properties of the interferomes of multiple vertebrate species and developed a webserver to mine the dataset. This approach revealed a conserved ‘core’ of 62 ISGs, including genes not previously associated with IFN, underscoring the ancestral functions associated with this antiviral host response. We show that gene expansion contributes to the evolution of the IFN system and that interferomes are shaped by lineage-specific pressures. Consequently, each mammal possesses a unique repertoire of ISGs, including genes common to all mammals and others unique to their specific species or phylogenetic lineages. An analysis of genes commonly down-regulated by IFN suggests that epigenetic regulation of transcription is a fundamental aspect of the IFN response. Our study provides a resource for the scientific community highlighting key paradigms of the type I IFN response

We are what we eat, plus some per mill: Using stable isotopes to estimate diet composition in Gyps vultures over space and time

This research article published by John Wiley & Sons, Ltd, 20221. Dietary studies in birds of prey involve direct observation and examination of food remains at resting and nesting sites. Although these methods accurately identify diet in raptors, they are time-consuming, resource-intensive, and associated with biases from the feeding ecology of raptors like Gyps vultures. Our study set out to estimate diet composition in Gyps vultures informed by stable isotopes that provide a good representation of assimilated diet from local systems. 2. We hypothesized that differences in Gyps vulture diet composition is a function of sampling location and that these vultures move between Serengeti National Park and Selous Game Reserve to forage. We also theorized that grazing ungulates are the principal items in Gyps vulture diet. 3. Through combined linear and Bayesian modeling, diet derived from δ13C in Gyps vultures consisted of grazing herbivores across sites, with those in Serengeti National Park consuming higher proportions of grazing herbivores (>87%). δ13C differences in vulture feather subsets did not indicate shifts in vulture diet and combined with blood δ13C, vultures fed largely on grazers for ~159 days before they were sampled. Similarly, δ15N values indicated Gyps vultures fed largely on herbivores. δ34S ratios separated where vultures fed when the two sites were compared. δ34S variation in vultures across sites resulted from baseline differences in plant δ34S values, though it is not possible to match δ34S to specific locations. 4. Our findings highlight the relevance of repeated sampling that considers tissues with varying isotopic turnover and emerging Bayesian techniques for dietary studies using stable isotopes. Findings also suggested limited vulture movement between the two local systems. However, more sampling coupled with environmental data is required to fully comprehend this observation and its implication to Gyps vulture ecology and conservation

Predicting the presence and titre of rabies virus‐neutralizing antibodies from low‐volume serum samples in low‐containment facilities

Serology is a core component of the surveillance and management of viral zoonoses. Virus neutralization tests are a gold standard serological diagnostic, but requirements for large volumes of serum and high biosafety containment can limit widespread use. Here, focusing on Rabies lyssavirus, a globally important zoonosis, we developed a pseudotype micro‐neutralization rapid fluorescent focus inhibition test (pmRFFIT) that overcomes these limitations. Specifically, we adapted an existing micro‐neutralization test to use a green fluorescent protein‐tagged murine leukaemia virus pseudotype in lieu of pathogenic rabies virus, reducing the need for specialized reagents for antigen detection and enabling use in low‐containment laboratories. We further used statistical models to generate rapid, quantitative predictions of the probability and titre of rabies virus‐neutralizing antibodies from microscopic imaging of neutralization outcomes. Using 47 serum samples from domestic dogs with neutralizing antibody titres estimated using the fluorescent antibody virus neutralization test (FAVN), pmRFFIT showed moderate sensitivity (78.79%) and high specificity (84.62%). Despite small conflicts, titre predictions were correlated across tests repeated on different dates both for dog samples (r = 0.93) and in a second data set of sera from wild common vampire bats (r = 0.72, N = 41), indicating repeatability. Our test uses a starting volume of 3.5 µl of serum, estimates titres from a single dilution of serum rather than requiring multiple dilutions and end point titration, and may be adapted to target neutralizing antibodies against alternative lyssavirus species. The pmRFFIT enables high‐throughput detection of rabies virus‐neutralizing antibodies in low‐biocontainment settings and is suited to studies in wild or captive animals where large serum volumes cannot be obtained

Transmission ecology of canine parvovirus in a multi-host, multi-pathogen system

Understanding multi-host pathogen maintenance and transmission dynamics is critical for disease control. However, transmission dynamics remain enigmatic largely because they are difficult to observe directly, particularly in wildlife. Here, we investigate the transmission dynamics of canine parvovirus (CPV) using state-space modelling of 20-years of CPV serology data from domestic dogs and African lions in the Serengeti ecosystem. We show that, although vaccination reduces the probability of infection in dogs, and despite indirect enhancement of population seropositivity as a result of vaccine shedding, the vaccination coverage achieved has been insufficient to prevent CPV from becoming widespread. CPV is maintained by the dog population and has become endemic with ~3.5-year cycles and prevalence reaching ~80%. While the estimated prevalence in lions is lower, peaks of infection consistently follow those in dogs. Dogs exposed to CPV are also more likely to become infected with a second multihost pathogen, canine distemper virus. However, vaccination can weaken this coupling raising questions about the value of monovalent versus polyvalent vaccines against these two pathogens. Our findings highlight the need to consider both pathogen- and host-level community interactions when seeking to understand the dynamics of multi-host pathogens and their implications for conservation, disease surveillance and control programmes

Inference of the interactions between evolutionary processes

Au cours de cette thèse, nous avons développé un outil pour détecter la coévolution, c'est à dire l'évolution conjointe de différentes entités biologiques (nucléotides, acides aminés, fonctions biologiques), à différentes échelles (moléculaire, organe). Cet outil s'applique sur des arbres phylogénétiques sur lesquels des évènements évolutifs (mutations, gains/pertes de fonctions biologiques) sont placés. Nous nous plaçons dans un cadre abstrait dans le but de travailler sur les processus conduisant à l'apparition d'évènements évolutifs au sens large le long des lignées d'un arbre phylogénétique. Cet outil est constitué de deux parties distinctes, chacune ayant ses propres spécificités.D'une part, nous avons produit une première méthode simple, très efficace, permettant de détecter parmi un très grand nombre de tels processus, quelles paires d'évènements semblent apparaître de manière conjointe dans l'arbre. Grâce à un formalisme mathématique utilisant les propriétés de l'algèbre bilinéaire, des calculs exacts d'espérance, de variance et même de distributions de probabilités sont possibles et permettent d'associer à ces paires détectées des p-values exactes, rendant cette méthode très précise.D'autre part, nous avons développé un modèle de coévolution entre de tels processus évolutifs. Ce modèle mathématique limite considérablement le nombre de paramètres utilisés et nous a permis de calculer et d'optimiser une fonction de vraisemblance. Cette optimisation revient à rechercher les paramètres du modèles expliquant au mieux les données contemporaines observées, et nous permet ainsi, toujours selon notre modèle, d'établir le scénario le plus probable ayant mené aux données observées.Cette seconde méthode est plus gourmande en temps de calcul, ce qui invite à associer les deux méthodes dans un pipeline nous permettant de traiter efficacement un grand nombre de paires avant d'aller plus loin dans notre étude et tester les paires les plus encourageantes à l'aide de notre modèle mathématique, dans le but de décrire un scénario interprétable dans un contexte biologique. Nous avons testé cet outil à l'aide de simulations, avant de l'appliquer à deux exemples biologiques très différents : le lien entre intracellularité et perte de flagelle chez Escherichia coli, et l'étude de toutes les paires de nucléotides dans des séquences d'ARNr 16S d’un échantillon de gamma-entérobactéries.In this thesis, we have developed a tool to detect co-evolution, ie the joined evolution of different biological entities (nucleotides, amino acids, organic functions), on different scales (molecular, organ). This tool is applied to phylogenetic trees on which evolutionary events (mutations, gain / loss of biological functions) are placed. We consider an abstract framework in order to work on the processes leading to the emergence of evolutionary events along the lineages of a phylogenetic tree. This tool consists of two separate parts, each with its own specificities.On the one hand, we have produced a first simple, highly effective method to detect from a very large number of such processes, which pairs events seem to appear jointly in the tree. Using a mathematical formalism using the properties of the bilinear algebra, exact calculations of expectancy, variance and even probability distributions are possible and allow to associate exact p-values to these pairs, making this method very precise.On the other hand, we have developed a model of coevolution between such evolutionary processes. This mathematical model severely limits the number of parameters used and allows us to calculate and maximize a likelihood function. This optimization is similar to searching the parameters of a model explaining the best the observed contemporary data, and allows us as well, according to our model, to determine the most likely scenario that led to the observed data.This second method requires more computing time, which invites to combine the two methods in a pipeline allowing us to efficiently process a large number of pairs before proceeding further in our study and test the most promising pairs using our mathematical model in order to describe a scenario interpreted in a biological context. We have tested this tool by using simulations, before applying it to two very different biological examples: the link between intracellularity and loss of flagellum in Escherichia coli, and the study of all the pairs of nucleotides in sequences 16S rRNA of a sample of gamma-Enterobacteria

Inference of the interactions between evolutionary processes

Au cours de cette thèse, nous avons développé un outil pour détecter la coévolution, c'est à dire l'évolution conjointe de différentes entités biologiques (nucléotides, acides aminés, fonctions biologiques), à différentes échelles (moléculaire, organe). Cet outil s'applique sur des arbres phylogénétiques sur lesquels des évènements évolutifs (mutations, gains/pertes de fonctions biologiques) sont placés. Nous nous plaçons dans un cadre abstrait dans le but de travailler sur les processus conduisant à l'apparition d'évènements évolutifs au sens large le long des lignées d'un arbre phylogénétique. Cet outil est constitué de deux parties distinctes, chacune ayant ses propres spécificités.D'une part, nous avons produit une première méthode simple, très efficace, permettant de détecter parmi un très grand nombre de tels processus, quelles paires d'évènements semblent apparaître de manière conjointe dans l'arbre. Grâce à un formalisme mathématique utilisant les propriétés de l'algèbre bilinéaire, des calculs exacts d'espérance, de variance et même de distributions de probabilités sont possibles et permettent d'associer à ces paires détectées des p-values exactes, rendant cette méthode très précise.D'autre part, nous avons développé un modèle de coévolution entre de tels processus évolutifs. Ce modèle mathématique limite considérablement le nombre de paramètres utilisés et nous a permis de calculer et d'optimiser une fonction de vraisemblance. Cette optimisation revient à rechercher les paramètres du modèles expliquant au mieux les données contemporaines observées, et nous permet ainsi, toujours selon notre modèle, d'établir le scénario le plus probable ayant mené aux données observées.Cette seconde méthode est plus gourmande en temps de calcul, ce qui invite à associer les deux méthodes dans un pipeline nous permettant de traiter efficacement un grand nombre de paires avant d'aller plus loin dans notre étude et tester les paires les plus encourageantes à l'aide de notre modèle mathématique, dans le but de décrire un scénario interprétable dans un contexte biologique. Nous avons testé cet outil à l'aide de simulations, avant de l'appliquer à deux exemples biologiques très différents : le lien entre intracellularité et perte de flagelle chez Escherichia coli, et l'étude de toutes les paires de nucléotides dans des séquences d'ARNr 16S d’un échantillon de gamma-entérobactéries.In this thesis, we have developed a tool to detect co-evolution, ie the joined evolution of different biological entities (nucleotides, amino acids, organic functions), on different scales (molecular, organ). This tool is applied to phylogenetic trees on which evolutionary events (mutations, gain / loss of biological functions) are placed. We consider an abstract framework in order to work on the processes leading to the emergence of evolutionary events along the lineages of a phylogenetic tree. This tool consists of two separate parts, each with its own specificities.On the one hand, we have produced a first simple, highly effective method to detect from a very large number of such processes, which pairs events seem to appear jointly in the tree. Using a mathematical formalism using the properties of the bilinear algebra, exact calculations of expectancy, variance and even probability distributions are possible and allow to associate exact p-values to these pairs, making this method very precise.On the other hand, we have developed a model of coevolution between such evolutionary processes. This mathematical model severely limits the number of parameters used and allows us to calculate and maximize a likelihood function. This optimization is similar to searching the parameters of a model explaining the best the observed contemporary data, and allows us as well, according to our model, to determine the most likely scenario that led to the observed data.This second method requires more computing time, which invites to combine the two methods in a pipeline allowing us to efficiently process a large number of pairs before proceeding further in our study and test the most promising pairs using our mathematical model in order to describe a scenario interpreted in a biological context. We have tested this tool by using simulations, before applying it to two very different biological examples: the link between intracellularity and loss of flagellum in Escherichia coli, and the study of all the pairs of nucleotides in sequences 16S rRNA of a sample of gamma-Enterobacteria

Inférence des interactions entre processus évolutifs

In this thesis, we have developed a tool to detect co-evolution, ie the joined evolution of different biological entities (nucleotides, amino acids, organic functions), on different scales (molecular, organ). This tool is applied to phylogenetic trees on which evolutionary events (mutations, gain / loss of biological functions) are placed. We consider an abstract framework in order to work on the processes leading to the emergence of evolutionary events along the lineages of a phylogenetic tree. This tool consists of two separate parts, each with its own specificities.On the one hand, we have produced a first simple, highly effective method to detect from a very large number of such processes, which pairs events seem to appear jointly in the tree. Using a mathematical formalism using the properties of the bilinear algebra, exact calculations of expectancy, variance and even probability distributions are possible and allow to associate exact p-values to these pairs, making this method very precise.On the other hand, we have developed a model of coevolution between such evolutionary processes. This mathematical model severely limits the number of parameters used and allows us to calculate and maximize a likelihood function. This optimization is similar to searching the parameters of a model explaining the best the observed contemporary data, and allows us as well, according to our model, to determine the most likely scenario that led to the observed data.This second method requires more computing time, which invites to combine the two methods in a pipeline allowing us to efficiently process a large number of pairs before proceeding further in our study and test the most promising pairs using our mathematical model in order to describe a scenario interpreted in a biological context. We have tested this tool by using simulations, before applying it to two very different biological examples: the link between intracellularity and loss of flagellum in Escherichia coli, and the study of all the pairs of nucleotides in sequences 16S rRNA of a sample of gamma-Enterobacteria.Au cours de cette thèse, nous avons développé un outil pour détecter la coévolution, c'est à dire l'évolution conjointe de différentes entités biologiques (nucléotides, acides aminés, fonctions biologiques), à différentes échelles (moléculaire, organe). Cet outil s'applique sur des arbres phylogénétiques sur lesquels des évènements évolutifs (mutations, gains/pertes de fonctions biologiques) sont placés. Nous nous plaçons dans un cadre abstrait dans le but de travailler sur les processus conduisant à l'apparition d'évènements évolutifs au sens large le long des lignées d'un arbre phylogénétique. Cet outil est constitué de deux parties distinctes, chacune ayant ses propres spécificités.D'une part, nous avons produit une première méthode simple, très efficace, permettant de détecter parmi un très grand nombre de tels processus, quelles paires d'évènements semblent apparaître de manière conjointe dans l'arbre. Grâce à un formalisme mathématique utilisant les propriétés de l'algèbre bilinéaire, des calculs exacts d'espérance, de variance et même de distributions de probabilités sont possibles et permettent d'associer à ces paires détectées des p-values exactes, rendant cette méthode très précise.D'autre part, nous avons développé un modèle de coévolution entre de tels processus évolutifs. Ce modèle mathématique limite considérablement le nombre de paramètres utilisés et nous a permis de calculer et d'optimiser une fonction de vraisemblance. Cette optimisation revient à rechercher les paramètres du modèles expliquant au mieux les données contemporaines observées, et nous permet ainsi, toujours selon notre modèle, d'établir le scénario le plus probable ayant mené aux données observées.Cette seconde méthode est plus gourmande en temps de calcul, ce qui invite à associer les deux méthodes dans un pipeline nous permettant de traiter efficacement un grand nombre de paires avant d'aller plus loin dans notre étude et tester les paires les plus encourageantes à l'aide de notre modèle mathématique, dans le but de décrire un scénario interprétable dans un contexte biologique. Nous avons testé cet outil à l'aide de simulations, avant de l'appliquer à deux exemples biologiques très différents : le lien entre intracellularité et perte de flagelle chez Escherichia coli, et l'étude de toutes les paires de nucléotides dans des séquences d'ARNr 16S d’un échantillon de gamma-entérobactéries

Testing for independence between evolutionary processes

International audienceEvolutionary events co-occurring along phylogenetic trees usually point to complex adaptive phenomena, sometimes implicating epistasis. While a number of methods have been developed to account for co-occurrence of events on the same internal or external branch of an evolutionary tree, there is a need to account for the larger diversity of possible relative positions of events in a tree. Here we propose a method to quantify to what extent two or more evolutionary events are associated on a phylogenetic tree. The method is applicable to any discrete character, like substitutions within a coding sequence or gains/losses of a biological function. Our method uses a general approach to statistically test for significant associations between events along the tree, which encompasses both events inseparable on the same branch, and events genealogically ordered on different branches. It assumes that the phylogeny and themapping of branches is known without errors. We address this problem from the statistical viewpoint by a linear algebra representation of the localization of the evolutionary events on the tree.We compute the full probability distribution of the number of paired events occurring in the same branch or in different branches of the tree, under a null model of independence where each type of event occurs at a constant rate uniformly inthephylogenetic tree. The strengths andweaknesses of themethodare assessed via simulations;we then apply the method to explore the loss of cell motility in intracellular pathogens