Smell and taste changes are early indicators of the COVID-19 pandemic and political decision effectiveness

In response to the COVID-19 pandemic, many governments have taken drastic measures to avoid an overflow of intensive care units. Accurate metrics of disease spread are critical for the reopening strategies. Here, we show that self-reports of smell/taste changes are more closely associated with hospital overload and are earlier markers of the spread of infection of SARS-CoV-2 than current governmental indicators. We also report a decrease in self-reports of new onset smell/taste changes as early as 5 days after lockdown enforcement. Cross-country comparisons demonstrate that countries that adopted the most stringent lockdown measures had faster declines in new reports of smell/taste changes following lockdown than a country that adopted less stringent lockdown measures. We propose that an increase in the incidence of sudden smell and taste change in the general population may be used as an indicator of COVID-19 spread in the population

Modélisation moléculaire des récepteurs chimiosensoriels

The perpetual struggle of living organisms to maintain their homeostasis despite an ever-changing environment has pushed evolution towards ever greater complexity. Even early in evolution, organisms were able to analyze their chemical environment through chemoperception and respond accordingly with specific behavior. The wide variety of chemicals has given rise to an equally diverse array of chemoreceptors to detect them. This evolution has resulted in the creation of specific and complex sensory organs as diverse as the antenna of Drosophila, the vomeronasal organ of the mouse, or the taste buds and olfactory epithelium of humans. There is a general organization of the olfactory system found in the animal kingdom, but the olfaction of insects and mammals is totally different at the level of receptors. In insects, ions channels are responsible for initiating signal transduction, whereas metabotropic G protein coupled receptors play this role in mammals. This work focuses on understanding the molecular basis of chemoreception at the level of olfactory receptors (ORs) in insects and mammals.Humans possess about 400 subtypes of ORs able to sense a virtually infinite number of odorants, and 6 trace amine-associated receptors (TAARs) that bind specifically to volatile amines. Deciphering the combinatorial code of odorants is the first step in understanding olfaction and predicting the odor of a molecule based on its structure, but data are scarce. First, to accelerate the deorphanization process of mammalian olfaction, we implement machine learning models powered by in vitro and structural data and found 66 novel odorant-receptor pairs. Today, more than 50% of human ORs are deorphanized, allowing a finer understanding of the combinatorial code. Second, we predict the impact of a mutation in the activation process of the human receptor TAAR5, responsible for the detection of the trimethylamine rotten fish odor. This demonstrates how a joint approach combining molecular dynamic simulations combined and in vitro functional assays can decipher OR structure-function relationships. We then apply a similar protocol to get new insights into the importance of OR extracellular loops 2 and 3. We finally describe the ligand diffusion pathway from the extracellular medium into the insect olfactory co-receptor (Orco) binding site. This work paves the way for the rational design of broad-spectrum insect repellents.This thesis illustrates that computational approaches coupled to experimental ones, are powerful tools to study the sequence-structure-function relationships of olfactory receptors.La lutte perpétuelle des organismes vivants pour maintenir leur homéostasie malgré un environnement en perpétuelle transformation a poussé l'évolution vers une complexité toujours plus grande. Dès le début de l'évolution, les organismes étaient capables d'analyser leur environnement chimique grâce à la chémoperception et de réagir en conséquence par un comportement spécifique. La grande variété de substances chimiques a donné lieu à un éventail tout aussi diversifié de chémorécepteurs pour les détecter. Cette évolution a abouti à la création d'organes sensoriels spécifiques et complexes aussi divers que l'antenne de la drosophile, l'organe voméronasal de la souris, ou les papilles gustatives et l'épithélium olfactif de l'homme.Il existe une organisation générale des systèmes olfactifs que l'on retrouve dans le règne animal, mais l'olfaction des insectes et des mammifères est totalement différente au niveau des récepteurs. Chez les insectes, des canaux ioniques sont responsables de l'initiation de la transduction du signal, alors que des récepteurs métabotropiques couplés aux protéines G jouent ce rôle chez les mammifères. Ce travail vise à comprendre les bases moléculaires de la chémoréception au niveau des récepteurs olfactifs (RO) chez les insectes et les mammifères.L'homme possède environ 400 sous-types de ROs capables de détecter un nombre virtuellement infini d'odorants, et 6 récepteurs associés aux amines traces (TAARs) qui se lient spécifiquement aux amines volatiles. Déchiffrer le code combinatoire des odorants est la première étape pour comprendre l'olfaction et prédire l'odeur d'une molécule à partir de sa structure, mais les données sont rares. Dans un premier temps, pour accélérer le processus de déorphanisation de l'olfaction des mammifères, nous mettons en œuvre des modèles d'apprentissage automatique alimentés par des données in vitro et structurales et découvrons 66 nouvelles paires odorant-récepteur. Aujourd'hui, plus de 50% des ORs humains sont déorphanisés, permettant une compréhension plus fine du code combinatoire. Deuxièmement, nous prédisons l'impact d'une mutation dans le processus d'activation du récepteur humain TAAR5, responsable de la détection de l'odeur de poisson pourri de la triméthylamine. Ceci démontre comment une approche conjointe combinant des simulations de dynamique moléculaire et des essais fonctionnels in vitro peut déchiffrer les relations structure-fonction des ROs. Nous appliquons ensuite un protocole similaire pour obtenir de nouvelles informations sur l'importance des boucles extracellulaires 2 et 3 dans la fonction des ROs. Nous décrivons enfin le chemin de diffusion du ligand depuis le milieu extracellulaire jusqu'au site de liaison du corécepteur olfactif (Orco) des insectes. Ce travail ouvre la voie à la conception rationnelle de répulsifs pour insectes à large spectre.Cette thèse illustre que les approches computationnelles, couplées aux approches expérimentales, sont des outils puissants pour étudier les relations séquence-structure-fonction des récepteurs olfactifs

Molecular modeling of chemosensory receptors

La lutte perpétuelle des organismes vivants pour maintenir leur homéostasie malgré un environnement en perpétuelle transformation a poussé l'évolution vers une complexité toujours plus grande. Dès le début de l'évolution, les organismes étaient capables d'analyser leur environnement chimique grâce à la chémoperception et de réagir en conséquence par un comportement spécifique. La grande variété de substances chimiques a donné lieu à un éventail tout aussi diversifié de chémorécepteurs pour les détecter. Cette évolution a abouti à la création d'organes sensoriels spécifiques et complexes aussi divers que l'antenne de la drosophile, l'organe voméronasal de la souris, ou les papilles gustatives et l'épithélium olfactif de l'homme.Il existe une organisation générale des systèmes olfactifs que l'on retrouve dans le règne animal, mais l'olfaction des insectes et des mammifères est totalement différente au niveau des récepteurs. Chez les insectes, des canaux ioniques sont responsables de l'initiation de la transduction du signal, alors que des récepteurs métabotropiques couplés aux protéines G jouent ce rôle chez les mammifères. Ce travail vise à comprendre les bases moléculaires de la chémoréception au niveau des récepteurs olfactifs (RO) chez les insectes et les mammifères.L'homme possède environ 400 sous-types de ROs capables de détecter un nombre virtuellement infini d'odorants, et 6 récepteurs associés aux amines traces (TAARs) qui se lient spécifiquement aux amines volatiles. Déchiffrer le code combinatoire des odorants est la première étape pour comprendre l'olfaction et prédire l'odeur d'une molécule à partir de sa structure, mais les données sont rares. Dans un premier temps, pour accélérer le processus de déorphanisation de l'olfaction des mammifères, nous mettons en œuvre des modèles d'apprentissage automatique alimentés par des données in vitro et structurales et découvrons 66 nouvelles paires odorant-récepteur. Aujourd'hui, plus de 50% des ORs humains sont déorphanisés, permettant une compréhension plus fine du code combinatoire. Deuxièmement, nous prédisons l'impact d'une mutation dans le processus d'activation du récepteur humain TAAR5, responsable de la détection de l'odeur de poisson pourri de la triméthylamine. Ceci démontre comment une approche conjointe combinant des simulations de dynamique moléculaire et des essais fonctionnels in vitro peut déchiffrer les relations structure-fonction des ROs. Nous appliquons ensuite un protocole similaire pour obtenir de nouvelles informations sur l'importance des boucles extracellulaires 2 et 3 dans la fonction des ROs. Nous décrivons enfin le chemin de diffusion du ligand depuis le milieu extracellulaire jusqu'au site de liaison du corécepteur olfactif (Orco) des insectes. Ce travail ouvre la voie à la conception rationnelle de répulsifs pour insectes à large spectre.Cette thèse illustre que les approches computationnelles, couplées aux approches expérimentales, sont des outils puissants pour étudier les relations séquence-structure-fonction des récepteurs olfactifs.The perpetual struggle of living organisms to maintain their homeostasis despite an ever-changing environment has pushed evolution towards ever greater complexity. Even early in evolution, organisms were able to analyze their chemical environment through chemoperception and respond accordingly with specific behavior. The wide variety of chemicals has given rise to an equally diverse array of chemoreceptors to detect them. This evolution has resulted in the creation of specific and complex sensory organs as diverse as the antenna of Drosophila, the vomeronasal organ of the mouse, or the taste buds and olfactory epithelium of humans. There is a general organization of the olfactory system found in the animal kingdom, but the olfaction of insects and mammals is totally different at the level of receptors. In insects, ions channels are responsible for initiating signal transduction, whereas metabotropic G protein coupled receptors play this role in mammals. This work focuses on understanding the molecular basis of chemoreception at the level of olfactory receptors (ORs) in insects and mammals.Humans possess about 400 subtypes of ORs able to sense a virtually infinite number of odorants, and 6 trace amine-associated receptors (TAARs) that bind specifically to volatile amines. Deciphering the combinatorial code of odorants is the first step in understanding olfaction and predicting the odor of a molecule based on its structure, but data are scarce. First, to accelerate the deorphanization process of mammalian olfaction, we implement machine learning models powered by in vitro and structural data and found 66 novel odorant-receptor pairs. Today, more than 50% of human ORs are deorphanized, allowing a finer understanding of the combinatorial code. Second, we predict the impact of a mutation in the activation process of the human receptor TAAR5, responsible for the detection of the trimethylamine rotten fish odor. This demonstrates how a joint approach combining molecular dynamic simulations combined and in vitro functional assays can decipher OR structure-function relationships. We then apply a similar protocol to get new insights into the importance of OR extracellular loops 2 and 3. We finally describe the ligand diffusion pathway from the extracellular medium into the insect olfactory co-receptor (Orco) binding site. This work paves the way for the rational design of broad-spectrum insect repellents.This thesis illustrates that computational approaches coupled to experimental ones, are powerful tools to study the sequence-structure-function relationships of olfactory receptors

Trace amine associated receptors (TAARs) response to amines are largely affected by sequences variants

International audienc

Trace amine associated receptors (TAARs) response to amines are largely affected by sequences variants

International audienc

Integrative structural modeling reveals functional molecular switches of human G protein-coupled bittertaste receptors

On the human tongue, the bitter taste depends on a large family of 25 taste receptors type 2 (TAS2R) belonging to the G protein-coupled receptor (GPCR) family and classified distantly related to class A GPCR. To date, the experimental structures have not been determined for any TAS2R and key residues controlling their function are still under debate. Here we streamline the modeling of these receptors using an integrative approach combining sequence analysis, molecular modeling and site-directed mutagenesis followed by functional assays. We provide a general approach for modeling all mammal TAS2R and identify functional motifs or residues which are central to understand how we perceive bitterness. Above the protocol which is transposable to all TAS2R, the identification of functional molecular switches lays the groundwork for the rational design of chemical modulators of bitter taste receptors. Such ligands will be of broad interest beyond food science since bitter-taste receptors are ectopically expressed in other parts of the human body besides the tongue. Topin et al. Functional molecular switches of mammalian G protein-coupled bitter-taste receptors. Cell. Mol. Life Sci., 2021, 78, 7605-7615. Funding Acknowledgments: This work was supported by the French Ministry of Higher Education and Research [PhD Fellowship], by GIRACT (Geneva, Switzerland) [9th European PhD in Flavor Research Bursaries for first year students] and the Gen Foundation (Registered UK Charity No. 1071026) [a charitable trust which principally provides grants to students/researchers in natural sciences, in particular food sciences/technology]. This work has also been supported by the French government, through the UCAJEDI Investments in the Future project managed by the National Research Agency (ANR) with the reference number ANR15-IDEX-01. The authors are grateful to the OPAL infrastructure from Universite Cote drAzur and the Universite Cote drAzurrs Center for High-Performance Computing for providing resources and support. FCOI Declarations: Non

What is the function of ECL3, the shortest loop of the odorant receptor?

[No Abstract Available]FALS

Machine learning decodes chemical features to identify novel agonists of a moth odorant receptor

International audienceOdorant receptors expressed at the peripheral olfactory organs are key proteins for animal volatile sensing. Although they determine the odor space of a given species, their functional characterization is a long process and remains limited. To date, machine learning virtual screening has been used to predict new ligands for such receptors in both mammals and insects, using chemical features of known ligands. In insects, such approach is yet limited to Diptera, whereas insect odorant receptors are known to be highly divergent between orders. Here, we extend this strategy to a Lepidoptera receptor, SlitOR25, involved in the recognition of attractive odorants in the crop pest Spodoptera littoralis larvae. Virtual screening of 3 million molecules predicted 32 purchasable ones whose function has been systematically tested on SlitOR25, revealing 11 novel agonists with a success rate of 28%. Our results show that Support Vector Machine optimizes the discovery of novel agonists and expands the chemical space of a Lepidoptera OR. More, it opens up structure-function relationship analyses through a comparison of the agonist chemical structures. This proof-of-concept in a crop pest could ultimately enable the identification of OR agonists or antagonists, capable of modifying olfactory behaviors in a context of biocontrol

The Third Extracellular Loop of Mammalian Odorant Receptors Is Involved in Ligand Binding

Mammals recognize chemicals in the air via G protein-coupled odorant receptors (ORs). In addition to their orthosteric binding site, other segments of these receptors modulate ligand recognition. Focusing on human hOR1A1, which is considered prototypical of class II ORs, we used a combination of molecular modeling, site-directed mutagenesis, and in vitro functional assays. We showed that the third extracellular loop of ORs (ECL3) contributes to ligand recognition and receptor activation. Indeed, site-directed mutations in ECL3 showed differential effects on the potency and efficacy of both carvones, citronellol, and 2-nonanone

Elucidation of the structural basis for ligand binding and translocation in conserved insect odorant receptor co-receptors

International audienceIn numerous insects, the olfactory receptor family forms a unique class of heteromeric cation channels. Recent progress in resolving the odorant receptor structures offers unprecedented opportunities for deciphering their molecular mechanisms of ligand recognition. Unexpectedly, these structures in apo or ligand-bound states did not reveal the pathway taken by the ligands between the extracellular space and the deep internal cavities. By combining molecular modeling with electrophysiological recordings, we identified amino acids involved in the dynamic entry pathway and the binding of VUAA1 to Drosophila melanogaster ’s odorant receptor co-receptor (Orco). Our results provide evidence for the exact location of the agonist binding site and a detailed and original mechanism of ligand translocation controlled by a network of conserved residues. These findings would explain the particularly high selectivity of Orcos for their ligands