G5 Research Project, call 2017 : Evolutionary genomics of RNA viruses
Emerging infectious diseases represent an increasing threat and burden worldwide, and an improved knowledge of these pathogen is crucial to prepare against the epidemic risk. RNA viruses are over-represented among human pathogens, and their rapid evolution constitutes a challenge for the control of these infectious agents, in addition to likely contributing to their emergence risk. In parallel, there is a wide variation in both animal and human risk and outcome of infection, generally encompassing asymptomatic, to more severe and sometimes lethal cases.
This junior group aims to explore the basis of the large differences of sensitivity to infection and severe disease in human from a novel, virological and evolutionary perspective. Specifically, the strategy of this junior group will be to combine phylodynamics studies of natural viral infections to an original in vitro system of evolution that includes the genetic and immune diversity of the host. Understanding how the various ecosystem in which a virus might multiply (here different human populations), can influence the evolutionary trajectories and composition of viral populations, notably with respect to pathogenicity and transmissibility, will open to new models of disease emergence and spread, and to functional studies on both the host and virus side.
D2I Research Project, call 2017 : Jérémy CHOIN (PhD Fellow) - Lluis Quintana Unit, Antoine Gessain Unit (IP)
Population genetic approaches to understand common diseases: adaptation and maladaptation to new environments in Melanesia.
Adopting an evolutionary perspective has become highly complementary to clinical and epidemiological genetic studies, as population genetics can provide new insights into the genetic architecture of human disease. Specifically, the advent of high-throughput sequencing, combined with cutting-edge statistical and mathematical frameworks, provide useful information on the way in which selection removes deleterious mutations from human populations and their potential to adapt to a broad range of climatic, nutritional, and pathogenic environments. Melanesia, a sub-region of Oceania, provides with an excellent model to test important hypotheses in population and medical genomics. Specifically, this project aims to (i) reconstruct the demographic history of Melanesian islanders, (ii) understand how such changes in human demography and environments have affected the efficacy of natural selection to remove deleterious mutations in the human genome and (iii) obtain insight into biological functions having participated in human adaptation and maladaptation, thereby affecting human health. Finally, an integrated epidemiological approach will be used to investigate the genetic basis of a common infection in Melanesia caused by the herpes virus 8 (HHV-8) and to explore the co-evolution of the host and the virus. Together, this study will increase our understanding of how human populations have genetically adapted to the different environments they have encountered, as well as detect events of “maladaptation”, thus increasing knowledge on the genetic architecture of human pathologies.
D2I Research Project, call 2017 : Jonathan Bastard (PhD fellow) - Lulla Opatowski (Didier Guillemot Unit, IP), Laura Temime (Cnam)
Better understand and control the spread of antibiotics resistant bacteria in livestock and at the human-livestock interface
The main objective of the SARAH project is to study the determinants of antibiotic resistant bacteria dissemination in livestock and at the animal-human interface. We develop a methodological research based on mathematical modelling and the analysis of epidemiological, microbiological and demographic data to:
- Better understand the role played by the different subpopulations in the temporal spread of the bacteria;
- Quantify the risks of diffusion of resistant bacteria from one population to another;
- Determine factors associated with the spread of resistant bacteria;
- Assess the impact of different control strategies on such diffusion.
Our focus is on several multi-resistant bacteria, in distinct contexts and in different livestock productions:
- Methicillin resistant Staphylococcus aureus (MRSA) in pig production in France
- ESBL producing Enterobacteriaceae in calves production in France
- Colistin resistant and other multidrug-resistant Enterobacteriaceae in pig and chicken productions in Vietnam
P2I Research Project, call 2017 : Understanding whooping cough resurgence in Europe by combining genomic, epidemiological and sociological approaches
Sylvain Brisse, Simon Cauchemez, Annick Opinel, Nadia Fernandes (postdoc fellow)
Whooping cough, caused by the bacterium Bordetella pertussis (Bp), can lead to lethal infections in neonates. Although largely controlled by vaccination, the infection is resurging in several parts of the world, including Europe. To understand the causes of resurgence, it is essential to define B. pertussis population composition and evolutionary changes. This has so far been impossible because of a lack of good genetic data of Bp at the European level. The objectives of the project are to decipher pertussis re-emergence by a population genomics approach complemented by epidemiological modelling and social sciences. We will initiate genomic sequencing within EupertStrain, the European network of national reference centers, leading to the first large-scale genomic sequence dataset of Bp isolates at European scale, and will analyze this unique resource (~2500 genomes and epidemiological surveillance data) to define inter-country dependencies in epidemiological patterns, strain transmission, evolutionary changes and vaccination strategies. We will also investigate historical or sociological factors, such as vaccine hesitancy (leveraging the ResiVax network), that may influence vaccination policy making. The integration of knowledge on pertussis epidemiology and population evolution with public health strategy build-up will contribute to a more efficient answer to the challenges of pertussis resurgence.
P2I Research Project, call 2017 : Microbial and viral circulations among people and wild and domesticated animals in an ecotone, Democratic Republic of Congo (MICROTONE)
IP: Tamara Giles-Vernick, Sean Kennedy, Etienne Simon-Lorière, Victor Narat, Romain Duda (postdoc fellow)
médialab, Sciences Po : Guillaume Lachenal
Zoonotic transmissions are a major global health risk, with human-animal contact frequently raised as a driver of emergence. Studies of zoonotic transmission risks are often piecemeal, targeting bushmeat, specific animal reservoirs, or single pathogens. Our study will examine ecological pathways and networks facilitating microbial and viral flows between people and animals and why these flows occur. Our primary objective is to conduct comparative metagenomic analyses of virome and gut microbiome among people and selected wild and domesticated animals along a gradient of ecological change in a forest-savanna mosaic in Democratic Republic of Congo, an epicenter of zoonotic disease emergence. We will analyze potential viral and bacterial overlap among humans and animals and explain this overlap (or not) through analyses of human and animal mobilities, practices and contacts.
We mobilize social sciences, animal ecology, and metagenomics tools to evaluate microbial dynamics among humans, domesticated animals (cows, goats, dogs, poultry) and wild animals (bonobos, other nonhuman primates, bats, rodents, antelopes). This multi-disciplinary, multi-species investigation in an ecotone (a transitional ecological zone linked to zoonotic emergence) will offer a “pre-history” of spillover and emergence, tracing an ecological web of virome and microbial sharing among humans and animals, and elucidating why such flows occur.
Inception Workshops, call 2018 : SinCellTE
Marie-Agnès Dillies, Institut Pasteur, Paris
Antonio Rausell, Akira Cortal, Institut Imagine, Paris Morgane Thomas-Chollier, Nathalie Lehmann, IBENS, Paris Marc Deloger, Nicolas Servant, Institut Curie, Paris
Agnès Paquet, Kevin Lebrigand, IPMC, Nice Sophia Antipolis
This school addresses the challenge of studying heterogeneous cell populations from a genomics, transcriptomics and epigenomics point of view. Technologies now allow to characterize tissues and biological samples at the single cell level. These technologies evolve very rapidly, requiring the constant development of bioinformatics and biostatistics methods adapted to these new types of data. The objective of this school is to explain and disseminate these new methods among practitioners involved in functional genomics projects at the single cell level. It offers a comprehensive training that provides an overview of the different technologies and their possible applications, and covers all the bioinformatics and biostatistics analysis steps, including experimental design, quality control, processing of the raw sequences, visualization and interpretation of the data.
The school is intended for engineers and researchers involved in single cell data analysis projects, as well as PhD students and post docs in computational biology. Attendees must have a previous knowledge of bulk high throughput data analysis (RNA-seq, ChIP-seq, ATAC-seq, Hi-C, ...) and befamiliar with unix command lines and the R language.
Inception Workshops, call 2018 : SaMMBA seminars (Statistical Mathematical Modeling in Biological Applications)
Lulla Opatowski - Pharmacoepidemiology and Infectious Disease Unit, Institut Pasteur
Epidémiologie des Madaies émergentes et Unité Pacri (Cnam / Institut Pasteur)
UR1404, Unité MaIAGE, INRA
Since September 2011, the SaMMBA seminars (Statistical and Mathematical Modeling in Biological Applications) have been organized monthly at Institut Pasteur with the aim to (1) gather the Ile-de-France modelling community monthly, to promote fruitful exchanges between researchers using mathematical methods in different fields of biology and medicine; and (2) enhance the visibility of this community and to provide opportunities for Ile-de-France researchers to meet high-level international scientists for potential collaborations.
Since 2011, >60 seminars have taken place (10 per year), featuring speakers from USA, Europe and France. The annual budget of the seminars includes travel and accommodation of speakers and also catering, as one specificity of this seminar series is the opportunity for the researchers and students to stay and have a light lunch (buffet) together with the speaker before going back to their different laboratories in the Paris region.
Inception Workshops, call 2018 : Science and society seminars
François Bontems - Structural Virology Unit
Cycle of conferences at the Pasteur Institute devoted to the interactions between science and society.
Herve Chneiweiss - 25 Octobre 2018
Catherine Tessier - 18 Mars 2019
Inception Workshops, call 2018 : Neural Networks - from machines to brain
Jean-Baptiste Masson - Decision and Bayesian computation
Continuous advances in machine learning have enabled groundbreaking progress in diverse fields such as computer vision or strategy games by making use of artificial neural networks. In parallel, novel technologies for recording and manipulating biological neural networks allow us to probe the behavioural function of neuronal activity in unprecedented detail. By bringing together leading experts in the fields of biology, applied mathematics and physics, this symposium aims to bridge our current understanding of how biological and artificial neural networks operate.
Inception Workshops, call 2018 : Pasteur Weizmann meeting - Integrative Biology to battle emerging diseases
Christophe Zimmer - Imaging and Modeling
For four decades l'Institut Pasteur and the Weizmann Institute of Science have established close ties, which have led to numerous collaborative projects sponsored by the Pasteur-Weizmann Council. Furthermore, a series of symposia have brought together scientists from both institutions with the goal of deepening the scientific exchange and friendship. In this spirit, the 26th Pasteur-Weizmann Symposium will be held at the Institut Pasteur in Paris, in the historic Duclaux amphitheatre from November 21st to 22nd, 2018.
The focus of the symposium will be on: “Integrative biology to battle emerging diseases” and will be structured in four thematic sessions:
1. Methods for integrative biology, genetis and omics
2. Signaling, organelle biology and development
3. Molecular basis of diseases, environment and global health
4. Social, behavioural and neurosciences
D2I Research Project, call 2018 : Marie Morel (PhD Fellow) - Olivier Gascuel Unit, Etienne Simon Loriere G5 (IP)
Evolutionary Trajectories of Viruses : Adaptation, Convergence and Dynamics.
The combination of large population sizes, high replication rates, short generation time and the error-prone nature of their replication lead to the vast genetic diversity observed for RNA viruses in nature. Within their hosts, these viruses generally exist as a population of mutants with genomic sequences that are genetically related but distinct. These features allow them to quickly adapt to new environments which contribute to their high emergence risk.
The aim of this project is to understand how the various environments in which a virus might multiply, can influence its evolutionary trajectories. These evolutionary mechanisms can be studied under two angles: at the sequence and at the population levels. To do so, during my PhD project, I develop new tools to study particular evolutionary mechanisms that result mainly from environmental pressure: convergent and parallel mutations or positive selection. Using existing tools, I also study potential changes in intrahost diversity when viruses are submitted to drug treatment.
This work presents the interest of studying basic evolutionary processes of viral evolution through a multiscale approach (population and sequence), with the development of bioinformatics tools, and this for viruses that impose an increasing burden on the public health and economy of many countries.
D2I Research Project, call 2018 : Robin Chalumeau (PhD Fellow) - Jean-Christophe Olivo-Marin Unit, Jost Eninnga Unit (IP)
Next-generation structured illumination microscopy for biological imaging.
Fluorescence microscopy is one of the most used tools in modern experimental biology, but classical microscopes (wide field and confocal) cannot image objects smaller than 200 nanometers because they are limited by the diffraction of light. To overcome this limit, several super-resolution techniques have emerged during the last few decades. One of them, called Structured Illumination Microscopy (SIM), is especially well suited for live imaging on living samples, because it provides wide field images with a resolution of 100 nanometers, at a relatively good framerate without degrading neither fluorophores nor cells. In this method, nine wide field images are acquired with specific illuminations patterns, then an algorithmic reconstruction returns the super-resolved image. Jean-Christophe Olivo-Marin’s Bioimage Analysis unit has been working over the last few years with ESPCI-Paristech and Centrale-Supelec on an alternative reconstruction algorithm that aims to improve the speed of SIM by reducing the number of required images from nine to four.
The main axes of the project will be firstly to push this new reconstruction to its limits, to adapt the method to 3D imaging and then to reduce the amount of required data by the implementation of compressive sensing protocols. This new structured illumination microscopy technique, with improved image quality and acquisition time, will be applied to relevant biological questions such as the host-pathogen interaction. In particular, providing new data about the intrusion of pathogenic bacteria like Shigella or Salmonella in human epithelial cells should lead to huge improvements in this field of research.
P2I Research Project, call 2018 : Machine learning to get at the heart of diagnostic cardiology
Sigolène Meilhac, G5 (IP/Imagine), Timothy Wai, G5 (IP), Christophe Zimmer Unit (IP), Francesca Raimondi (APHP/INSERM)
Congenital heart diseases are devastating developmental disorders that include severe cases characterized by complex anatomical abnormalities. Diagnosis remains a significant challenge that requires high-level expertise in imaging techniques and access to sophisticated equipment. Advances in cardiac biology and medicine have been hampered by an absence of tools and methods able to deliver accurate, quantitative descriptions of cardiac abnormalities at the cellular and organ level. Our objective is to develop deep learning approaches to address these unmet medical needs in cardiology and to accelerate fundamental research in congenital heart diseases by leveraging annotated images in clinical and research archives. From images in patients, mouse models and cellular models, we will address both the anatomical defects and the cellular mechanisms associated with congenital heart diseases. This collaborative project combines interdisciplinary expertise in heart development, cardiac metabolism, paediatric cardiology and image analysis by machine learning to provide novel insight into the origin of heart diseases and to develop novel diagnostic aides to facilitate the dissemination of expertise beyond specialized cardiology reference centres.
P2I Research Project, call 2018 : HOST AND BACTERIAL FACTORS INVOLVED IN INVASIVE LISTERIOSIS
Marc Lecuit Unit (IP/INSERM), Lluis Quintana Unit (IP/CNRS), Hugues Aschard, G5 (IP)
Listeriosis is a severe foodborne infection caused by the bacterium Listeria monocytogenes (Lm), a ubiquitous bacterium mainly found in dairy products and processed meat. It manifests as septicemia, central nervous system or maternal-fetal infection. Its overall mortality is very high, above of 25%, and death frequently occurs in patients under antimicrobial therapy. While human exposure to Lm is common, only few patients develop listeriosis, suggesting a role of host and bacterial genetics in this ifnection. Bacterial genomic analyses have identified putative virulence factors that were confirmed experimentally, yet these factors are only partly predictive of the virulence of Lm strains. This project aimed to study the host and bacterial genomes of ~1,000 patients from the MONALISA cohort, in order to identify host and bacterial genetic factors involved in the different forms of listeriosis. Using innovative statistical methods, we perform a human genome-wide association study (GWAS) of Lm infection, a bacterial GWAS of disease severity and clinical presentation, and a genome-to-genome analysis that combines the genomes of both organisms to detect host-pathogen interactions. Our analyses have already identified a genetic host factor that increases by ~3.5 the odds of developing maternal-fetal Lm infection. The identification of host and bacterial risk factors for listeriosis will shed light on the molecular mechanisms underlying listeriosis pathophysiology, and pave the way for preventive measures for at-risk individuals, which may result in reduced disease incidence.
G5 Research Project, call 2018 : Sequence Bioinformatics, Rayan Chikhi (IP, C3BI)
We are a new computational team that researches algorithms for big biological data, such as next-generation sequencing data. Our research roots are close to Computer Science, but the primary goal of the group is to apply research products to bioinformatics and biology. Our biological interests include genomics, metagenomics, pan-genomics, transcriptomics and proteomics. The group develops and implements algorithms and data structures into software tools, and also collaborates with biology groups. Some examples of recent projects are the development of data structures to index large collections of sequencing datasets, methods for improving bacterial genome assemblies with long reads, and genome assemblies (giraffe, gorilla Y, mountain goat). Our ongoing projects include the analysis of variants in Alzheimer’s disease whole-genome sequencing data, the development of algorithms on linked-reads sequencing data, and a search engine for all previously sequenced human RNA-seq experiments.
D2I Research Project, call 2019 : Vincent Mallet (PhD Fellow) - Michael Nilges Unit (IP), Jean-Philippe Vert Unit (Mines Paris Tech)
The current state of imaging techniques produces massive amounts of structural biological data. The structure of compounds plays a key role in structure based drug discovery. However most of the computational usage of this structure neglects the amount of data available and mostly relies on deterministic, physics-based tools.
The success of Machine Learning and Deep Learning in the exploitation of a growing amount of available data in other fields is now established. The main successful applications lie in computer vision and natural language processing, were computers skills now exceed humans’. The goal of this project is to adapt these algorithms for structural 3D data.
Common learning algorithms have limitations that make them less efficient for the data at hand. The underlying properties of a 3D shape must be taken into account for improved efficiency of these methods. The goal of this PhD project is thus to leverage recent advances in this direction and to extend them further for structural biology data. In the meantime, we want to apply such new methods to data used at IP to help the data processing and drug discovery process.
D2I Research Project, call 2019 : Armin Shoushtarizadeh (PhD Fellow) - Thomas Gregor Unit (IP), Pablo Navarro-Gil Unit (IP)
D2I Research Project, call 2019 : Chiara Figazzolo (PPU-PhD Fellow) - Marcel Hollenstein G5 (IP)
D2I Research Project, call 2019 : Mariana Gonzalez (PPU-PhD Fellow) - Arnaud Blondel Unit (IP)
Nicotinic acetylcholine receptors (nAChRs), are members of a superfamily of ligand-gated ion channels that regulate fast signal transmission at synapses. In order to achieve this, these receptors go through a number of conformational states, as acetylcholine binds to them after being released from presynaptic neurons. At the resting state, the ion channel remains closed. Upon binding of an agonist, the open channel conformation is stabilized allowing the conduction of ions and inducing depolarization of the cell membrane. Prolonged or repetitive agonist administration stabilizes the channel in a desensitized state with reduced response. nAChRs are potential therapeutic targets for central nervous system disorders such as schizophrenia, Alzheimer's disease, Parkinson’s disease and nicotine addiction. To date, 17 different nAChR subunits have been identified (a1-a10 and b1-b4). The subunit composition of each receptor determines its localization, function, agonist sensitivity as well as channel kinetics. The main goal of this project is to gain a more comprehensive understanding of the structure and molecular mechanisms regulating the function and behavior of nAChRs containing the a5 subunit. This will allow to propose positive allosteric modulators for the α4β2α5 receptor to treat nicotine addiction. The a5 subunit is relevant to treat nicotine addiction since a single nucleotide polymorphism (SNP) (D398N) in this subunit has been found to increase lung cancer and nicotine dependence susceptibility. Large genomewide association studies have found that the maximal response of the protein with the conserved amino acids was two times higher with respect to the variant.
Inception Workshops, call 2019 : International conference on Cilia, Flagella and Centrosomes
The International conference on Cilia, Flagella and Centrosomes was held on the 27-29th November 2019 at the Institut Imagine (Paris, France). It was dedicated to the emergence of ciliopathies, which are severe and pleiotropic diseases caused by a dysfunction of an organelle, the cilium. This meeting has provided a framework for an integrative approach to study ciliopathies from the molecular level to individuals and populations. The high genetic heterogeneity, as well as the phenotypic variations associated with ciliopathies are still poorly understood. A major aim of the meeting was to foster the multidisciplinary interactions that are required to decipher the emergence of ciliopathies. The meeting has highlighted the multi-scale analyses of cilium structure, function and cell-specific role during homeostasis and development, using a spectrum of model organisms, while also providing examples of omics dataset analyses from cohorts of patients with ciliopathies. The meeting was co-organised by two INCEPTION Pasteur teams and teams from two other INCEPTION partner institutions (ENS-PSL, CNRS). With a small number of invited speakers (4), it has promoted contributions of young researchers (students/post-docs).
Details of the conference can be found at https://www.cilianetwork.org.uk/events/frenchukcilia/
P2I Research Project, call 2019 : Identifying Tunneling Nanotube-like Structures in the Developing Cerebellum
Chiara Zurzolo Unit (IP), Jean-Baptiste Masson G5 (IP)
P2I Research Project, call 2019 : Path2Resistance: Deciphering evolutionary trajectories to characterize emergence and dissemination of multidrug resistant Escherichia coli
Eduardo Rocha Unit (IP/CNRS), Philippe Glaser Unit (IP/CNRS/APHP), Amaury Lambert & Guillaume Achaz - SMILE, CIRB (Collège de France)
The bacteria from the species Escherichia coli are some of the most frequent causes of infectious diseases in the community and in the hospital. These ubiquitous and versatile pathogens are, by their capacity to disseminate antibiotic resistance in the community, major public health threats. Selection for resistance results from transient repeated rounds of exposure to different antibiotics in humans, animals and external environments. Our preliminary data on E. coli carbapenemase producing isolates suggests that resistance is more frequent in certain genetic contexts. Here, we will integrate public data with a broad private collection of sequenced multi drug resistant isolates to characterize how evolution of the genetic context shapes the emergence of multidrug resistant strains.
POC Research Project, call 2019 : Aptamer-labeling as a strategy to determine the structure of macromolecular assemblies
Marcel Hollenstein G5 (IP), Ricardo Pellarin Unit (IP/CNRS)
Electron Microscopy (EM) is invaluable for structural determination since it allows visualization of large macromolecular complexes. However, the resolution of EM maps is often too low for a direct determination of the spatial arrangement of the subunits. To address this issue, we propose an aptamer-based labeling strategy combined with integrative modeling to improve the localization accuracy of individual components of the bacterial type VI secretion system (T6SS), a major virulence factor of many Gram-negative bacteria. The aim of the proposed project is to develop a hybrid pipeline for the generation of protein-specific aptamer-labels that will significantly improve the localization accuracy of individual components within the EM density map of protein complexes.
P2I Research Project, call 2019 : Computational analysis of 3D cell architecture : application in quantifying myocardium orientation at the cellular and tissue levels
Sigolène Meilhac Unit (IP/INSERM), Jean-Christophe Olivo-Marin Unit (IP/CNRS)
Inception Workshops, call 2020 : Single-Cell Transcriptomics and Epigenetics: Theory and Practice (sincellTE)
Scientific coordination: Marie-Agnès Dillies, C3BI (USR 3756 IP CNRS), Morgane Thomas-Chollier, IBENS (CNRS UMR8197, ENS, INSERM U1024), Agnès Paquet, SYNEOS Health (Sophia-Antipolis), Antonio Rausell (Institut Imagine, INSERM UMR-1163)
Technical coordination : Erwan Corre (ABIMS FR2424 CNRS-UPMC, Station Biologique de Roscoff)
Administrative management : Département de Biologie Computationnelle, Institut Pasteur
22 - 27 March 2020, Station Biologique, Roscoff, France
This workshop focuses on the large-scale study of heterogeneity across individual cells from a genomic, transcriptomic and epigenomic point of view. New technological developments enable the characterization of molecular information at a single cell resolution for large numbers of cells. The high dimensional omics data that these technologies produce come with novel methodological challenges for the analysis. In this regard, specific bioinformatics and statistical methods have been developed in order to extract robust information. The workshop aims to provide such methods for engineers and researchers directly involved in functional genomics project making use of single-cell. A wide range of single cell topics will be covered in lectures, demonstrations and practical classes. Among others, the areas and issues to be addressed will include the choice of the most appropriate single-cell sequencing technology, the experimental design and the bioinformatics and statistical methods and pipelines.