Molecular basis of viral pathogenicity
Although it is somewhat remarkable that certain viruses are able to carry out all of the essential elements of the viral life cycle, namely cellular infection, viral replication and host immune evasion, with such a limited range of structural and non-structural proteins, it is perhaps even more remarkable that some viruses are so highly pathogenic whilst others are much less so. The key to this high viral pathogenicity lies within the viral genome and the intense and vital interplay that occurs between both viral and host cell proteins as well as between the viral proteins themselves, in order to orchestrate host cell sequestration and the balance between regulation of viral replication kinetics and innate immune evasion. However despite apparent genetic and structural similarities between viral protein types and replication mechanisms for viruses of the same family, the extreme lethality of certain members or indeed of certain virus families, suggests the existence of particular properties that distinguish these pathogens from their less pathogenic relatives.
That is why our research goals center around the exploration of the molecular basis of viral pathogenicity for several highly pathogenic viruses, including the Filoviruses; Ebola and Marburg and the Paramyxoviridae Hendra and Nipah. These pathogens have recently emerged as human pathogens and demonstrate a potential for transmission to different animal hosts, causing highly pathogenic diseases in man. Currently there is no vaccine or treatment available against these dangerous pathogens. Human-to-human transmission and the threat of intercontinental spread identify these infections as an important human health concern. The main goal of our research program is to understand the molecular mechanisms leading to the high pathogenicity of Ebola, Marburg and Nipah viruses with particular emphasis on virus-host interactions during viral replication and mechanisms of viral emergence. The identification of cellular partners for the viral proteins and an understanding of the mechanisms viruses exploit to avoid different cell defence barriers as well as identification of the molecular basis of an excessive and inadequate host response to viral replication will bring to light novel information pertaining to viral pathogenesis and will ultimately lead to the development of novel antiviral drugs. For these viruses we are able to employ viral gene products as well as full length virus by molecular virology and reserve genetic approaches in order to study parameters including replication kinetics, host cell receptor usage and range and the role of viral proteins in innate immune evasion.
Discovery of molecular mechanisms revealing how Marburg virus hijacks the Nrf2-dependent cellular pathway and induces damage to homeostasis within the cellular oxidative stress–antioxidative response system. (Page, Cell reports, 2014)
Based on crystal structure data and molecular reverse genetic modelling of the interactions involved in the replication of Nipah virus we demonstrated that binding of the N-terminal region of P blocks the polymerization of N thus keeping N in an open conformation, ready to grasp an RNA molecule. (Yabukarski, Nat Struct Mol Biol, 2014).
Identification of a mechanism exploited by Ebola virus (Shed GP) to induce excessive and dysregulated inflammatory host reactions and damage to endothelial cell function which ultimately leads to cytokine storm-like syndrome and vascular permeability, thus contributing to high pathogenicity. (Escudero-Perez, PLos Pathog 2014; Dolnik, JID 2015).
Identification of the Ebola virus editing site as an important mechanism controlling expression of a single surface glycoprotein GP and a pathogenicity factor. (Volchkova, JID 2015).
INSERM, UCBL1, ANR, European FP, FINOVI, CIRI