Molecular basis of viral pathogenicity
Projects and grants
The emergence of new and re-emergence of already known viral diseases as zoonoses represents a major threat to human health. Modern trends in the evolution of our societies aggravate the chance of such emergencies. Deforestation and destruction of natural habitats increases the likelihood of encounters between humans and wild animals and of transmission of zoonotic infections to humans. The recent outbreak of Ebola virus in previously unaffected West African countries has led to the infection of over 28 000 people, approximately 11 000 deaths, and a breakdown of these countries’ economies. Over 800 health-care workers including those from developed countries have been infected during this epidemic and about 60% of them have died.
Filo- and Henipaviruses belong to a short list of viruses that can be seen as “loaded guns” primed to cause a deadly human pandemic and as such are classified as Biosafety Level-4 (BSL-4) pathogens. Both groups of viruses are very likely to emerge or re-emerge in the future from either wild animal reservoirs or after “conservation” in patients’ bodies upon primary infection. High error rates of the polymerases of these RNA-containing viruses provide them with the capacity to undergo rapid evolution, and adaptation to transmission within a new host. Our previous findings reveal a potential for such viruses to quickly enhance their replication rates in different animal hosts through acquirement of adaptive mutations. Of note, multiple transmissions of Ebola virus in humans during the West African outbreak also revealed the appearance of adaptive mutations.
Because there is a substantial risk that the virus spreads into urban areas of high population density, and because of the absence of a vaccine and a specific treatment approved for human use, a better understanding of the molecular basis of high pathogenicity has become a priority. Another pertinent question that remains to be answered is why humans are so vulnerable and incapable of confronting the infection.
Our scientific program will continue the research axes developed over the last period. The success in research made by our team, proven by a number of important publications, allows us to target the major bases of high pathogenicity such as (I) the capacity to replicate to high viral titers in multiple cell targets, (ii) escape host innate immune defenses through multiple virus-driven mechanisms, (iii) the ability to hijack host factors and mechanisms to facilitate virus replication and, (iv) damage to homeostasis within host defense systems, thereby potentially causing an excessive but inadequate host response to viral replication.
To provide new insights into the malfunction induced by these viruses we combine reverse genetic, with in vitro and in cellular experiments together with atomic description of selected viral proteins. A structure-based understanding of the mechanisms by which viral proteins affect and hijack host-cell mechanisms involved in antiviral defense will be combined with an in-depth analysis of samples collected from recently developed experimental animal models. It is expected that our efforts will increase the preparedness to fight these pathogens, and to create new opportunities for developing innovative therapeutic approaches.
The main research topics related to our concept of high pathogenicity will be centered as follows on:
a) Ebola virus and the role of the structural protein VP24; homeostasis of oxidative stress – antioxidative responses (ANR EboDisReg)
b) Structure-function analysis of the Nipah virus P gene-encoded proteins; the phenomenon of gene overprinting (ANR NIPAH-C)
1. “Structure and function of Nipah virus C protein”. ANR NIPAH-C 2018-2022. Consortium coordinator – M. Jamin, coordinator for INSERM -V.Volchkov.
2. “Molecular basis of disregulation in inflammatory responses during Ebola virus infection.” ANR, France. 2015-2020. Coordinator-V.Volchkov.
3. “ANTIcipating the Global Onset of Novel Epidemics (ANTIGONE)”. European Commission’s FP7 program 2012-2019. Consortium coordinator – T. Kuiken; Coordinator for INSERM –VE Volchkov.
4. “Development of anti EBOV antibodies in rabbits”. ABIVAX, France. 2016-2019. Coordinator: V.Volchkov.
5. “Structural and functional characterization of the replication machinery of Congo Crimean Hemorrhagic Fever virus”. FINOVI, France 2016-2018. Consortium coordinator M. Jamin, co-coordinator – V.Volchkov.
6. Axes transversal CCHF and Ebola. CIRI, INSERM 2015-2016. Coordinator- V.Volchkov.
7. “Development of polyclonal anti EBOV antibodies in xenogenic pigs” XENOTHERA, France. 2014-2016. Coordinator-V.Volchkov.
8. “Non-structural proteins of Henipaviruses and their role in extremely high pathogenicity: structure-function analysis.” FINOVI, France 2013-2015. Coordinator- M. Jamin, co-coordinator –V.Volchkov.
1. “Development of anti EBOV antibodies in rabbits” ABIVAX, France. 2016-2019. Coordinator: V.Volchkov.
2. “Development of polyclonal anti EBOV antibodies in xenogenic pigs” XENOTHERA, France. 2014-2016. Coordinator: V.Volchkov.
3. “Development of test system based on VSV replicons” SANOFI, France. 2019-2020. Coordinator: V.Volchkov.
Teaching and training through research
MBVP team is highly involved in University Claude Bernard Lyon 1, University Catholic Lyon and École Pratique des Hautes Études (EPHE) Master 1/Master 2 training programs. Furthermore, Viktor Volchkov, as a Prof UCBL1, is responsible for number of courses such as Fundamental Virology, Advances in Virology, Virus manipulation and diagnostic.