Cell Entry; Membrane fusion; Host cell surface receptor; Viral glycoproteins ; Dynamics of viral entry; Paramyxovirus
Plattet Philippe, Alves Lisa, Herren Michael, Aguilar Hector C (2016), Measles Virus Fusion Protein: Structure, Function and Inhibition., in Viruses
, 8(4), 1-30.
Avila Mislay, Khosravi Mojtaba, Alves Lisa, Ader-Ebert Nadine, Bringolf Fanny, Zurbriggen Andreas, Plemper Richard K, Plattet Philippe (2015), Canine distemper virus envelope protein interactions modulated by hydrophobic residues in the fusion protein globular head., in Journal of virology
, 89(2), 1445-51.
Khosravi Mojtaba, Bringolf Fanny, Röthlisberger Silvan, Bieringer Maria, Schneider-Schaulies Jürgen, Zurbriggen Andreas, Origgi Francesco, Plattet Philippe (2015), Canine Distemper Virus Fusion Activation: Critical Role of Residue E123 of CD150/SLAM., in Journal of virology
, 90(3), 1622-37.
Ader-Ebert Nadine, Khosravi Mojtaba, Herren Michael, Avila Mislay, Alves Lisa, Bringolf Fanny, Örvell Claes, Langedijk Johannes P, Zurbriggen Andreas, Plemper Richard K, Plattet Philippe (2015), Sequential conformational changes in the morbillivirus attachment protein initiate the membrane fusion process., in PLoS pathogens
, 11(5), 1004880-1004880.
Alves Lisa, Khosravi Mojtaba, Avila Mislay, Ader-Ebert Nadine, Bringolf Fanny, Zurbriggen Andreas, Vandevelde Marc, Plattet Philippe (2015), SLAM- and Nectin-4-Independent Noncytolytic Spread of Canine Distemper Virus in Astrocytes., in Journal of virology
, 89(10), 5724-33.
Brindley Melinda A, Plattet Philippe, Plemper Richard Karl (2014), Efficient replication of a paramyxovirus independent of full zippering of the fusion protein six-helix bundle domain., in Proceedings of the National Academy of Sciences of the United States of America
, 111(36), 3795-804.
Sattler Ursula, Khosravi Mojtaba, Avila Mislay, Pilo Paola, Langedijk Johannes P, Ader-Ebert Nadine, Alves Lisa A, Plattet Philippe, Origgi Francesco C (2014), Identification of amino acid substitutions with compensational effects in the attachment protein of canine distemper virus., in Journal of virology
, 88(14), 8057-64.
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.