Project

Discipline

Cell Entry; Membrane fusion; Host cell surface receptor; Viral glycoproteins ; Dynamics of viral entry; Paramyxovirus

Lead
Despite the availability of efficient vaccines, measles virus (MeV) and canine distemper virus (CDV) are still associated with major impacts on human and animal health. Global eradication of MeV is considered feasible if 95% herd immunity would be achieved. However, increasing anxiety concerning the vaccine’s safety in industrialized countries and sub-optimal delivery in developing countries continue to foster measles outbreaks. Meanwhile, CDV exhibits an ever-increasing host range in animals with recent threatening outbreaks in monkeys, hence raising concerns about its adaptation to humans. In this project, we aim at refining our knowledge on the mechanistic and structural framework that defines MeV and CDV cell entry systems. We then plan to extract “druggable” microdomains from these mechanistic studies and subject them to a structure-based drug discovery campaign.
Lay summary
La famille des virus Paramyxoviridae comprend un grand nombre de virus qui peuvent avoir des effets critiques sur la santé humaine et animale. Parmi ceux-ci, se trouve le virus de la rougeole qui continue de tuer plus de 120’000 personnes par année, malgré le fait qu’un vaccin très efficace soit disponible. En parallèle, le virus de la maladie de Carré (Canine Distemper Virus; CDV), la version animale du virus de la rougeole, possède la caractéristique unique d’infecter non seulement les chiens, mais aussi un nombre toujours plus important d’animaux carnivores. Récemment, il a été démontré que CDV a évolué et infecte maintenant de nouvelles espèces telles que le singe, des épidémies très sévères ayant été signalées. Ces épidémies confirment la capacité inquiétante de CDV à acquérir rapidement les modifications moléculaires nécessaires à l’infection de nouvelles espèces, devenant une menace potentielle pour la santé humaine. Ainsi, le projet proposé s’articule tout d’abord autour de la compréhension de l’entrée du virus de la rougeole et de CDV dans les cellules hôtes puis, dans un deuxième temps, autour du développement d’antiviraux à large spectre. Au-delà du potentiel d’améliorer et de protéger de manière significative la santé humaine et animale, nous pensons que de tels inhibiteurs pourraient également jouer un rôle essentiel dans la campagne mondiale visant à éradiquer le virus de la rougeole de la planète. En effet, malgré l’efficacité excellente du vaccin et le travail remarquable des services de santé humaine, le seuil fatidique de 95% de couverture vaccinale, qui mènerait à une éradication complète du virus de la rougeole, n’est toujours pas atteint. Par conséquent, l’approche qui consisterait à combiner la vaccination avec des traitements antiviraux pourrait se révéler cruciale pour atteindre l’objectif de l’OMS, à savoir l’éradication globale du virus de la rougeole.

Direct link to Lay Summary

Last update: 02.04.2014

Number	Title	Start	Funding scheme

Paramyxoviruses include infectious agents of humans and animals, such as respiratory syncytial virus, the measles and canine distemper morbilliviruses (MeV and CDV), or the henipaviruses, with significant global health and economic impacts. While MeV is still associated with more than 120’000 human death per year, CDV remains one of the major infectious pathogen of dogs and wild carnivores worldwide. The latter exhibits an ever-increasing host range with recently reported severe outbreaks in primates raising concerns about adaptation of CDV to humans with potential dramatic consequences. To date, no effective treatment exists against any of these viruses.Fusion of the viral envelope with cellular membranes is critical for all enveloped viruses to enter target cells. Membrane fusion constitutes a first essential step to infection by this large group of viruses, leading to a wide range of pathologies such as respiratory illnesses and/or persistent neurological infections. The paramyxovirus entry machinery is composed of two distinct envelope glycoproteins: the attachment and fusion proteins that tightly co-operate to execute membrane fusion. Despite recent structural and mechanistic studies, how precisely these two envelope glycoproteins interact and move to merge viral and cellular membranes for cell entry remains largely unknown. In this context, our recent studies addressed mechanistic and thermodynamic aspects of specific domains of the morbillivirus cell entry machinery, which shed new light on the viral membrane fusion process. My aim in the present proposal is to extend our fundamental molecular and structural understanding of the membrane fusion process mediated by morbilliviruses, the model system used in my laboratory to study paramyxovirus cell entry. Two complementary approaches will be used: I. The highly dynamic process that controls morbillivirus-mediated membrane fusion will be investigated in detail. Established state-of-the-art molecular, cellular, biochemical and functional techniques combined with structure-based design of mutants through reverse genetics will be used to: i) identify new functional microdomains of the F and H glycoproteins, ii) the site(s) of interaction between these proteins and iii) the critical role of the receptor in the fine regulation of the extent of the membrane fusion process. II. The impact of membrane fusion on viral entry, spread and ensuing pathogenesis will be assessed using i) cell lines expressing different well-known receptors (mutated or not) and ii) a unique primary brain cell culture system (putatively expressing a yet unidentified receptor), that will be inoculated with neurovirulent recombinant viruses (carrying mutations identified in approach I). I believe that this research proposal will lead to a better fundamental understanding of the morbillivirus membrane fusion process, which not only is a key contributing factor determining the initial phase of the infection but also the type of pathology that these viruses may induce (immune dysfunctions, respiratory illnesses and brain disorders). I expect that the achieved molecular insights combined with bioinformatics and functional genomics will help set the stage for the rational design of effective viral entry inhibitors. Because increasing evidence suggests that the entry mechanism is highly conserved among different members of the paramyxovirus family, newly identified antivirals targeting the morbillivirus membrane fusion machinery may also be effective against other paramyxoviruses. The wider context of this research is the general understanding of the interaction of enveloped viruses with their host cells involving membrane fusion events.