Innovative metabolic therapy against pathogenic airborne viruses, including Nipah and H5N1 influenza – ViroMetaBlock

With an average of over 4 million deaths per year, respiratory infections are the third-leading cause of death in the world. At the top of the list of the airborne viruses responsible for serious respiratory infections, and besides SARS-CoV-2, are influenza viruses in the orthomyxovirus family and several paramyxoviruses, such as Nipah virus and measles virus.
While the 1918 "Spanish Flu" is still remembered for killing nearly 50 million people, the 21st century has already seen several major health crises caused by the H1N1 and H3N2 seasonal influenza viruses. Since 2003, the highly pathogenic H5N1 avian influenza virus has been responsible for outbreaks outside Asia where it is now endemic. Due to its high mortality rate and the risks of bio-terrorism, the authorities have recommended its handling only in highly secured biosafety level 4 laboratories.
Among the Paramyxoviridae that are fatal to humans, measles virus remains the most contagious airborne virus with an R0 close to 18. This virus kills more than 140,000 people each year due to insufficient vaccination coverage and there is a risk that vaccine-resistant mutants will emerge. In addition, Henipaviruses such as Nipah virus which emerged from fruit bats 20 years ago are among the deadliest pathogens in the world (40 to 100% mortality). Due to the absence of a vaccine that can be used in humans, its ability to infect most mammals and its inter-species and inter-individual transmission, Nipah virus has also joined the list of biosafety level 4 pathogens. It has also been included by the World Health Organization in the "blue print" list of viruses for which the research of treatments and vaccines is a top priority.
In addition to their natural hazard, all these viruses could be grown in cell culture by skilled individuals and can be adapted or genetically manipulated to increase their transmission and virulence. Such modifications can even result in higher resistance to vaccines, e.g. in the case of measles. In this context, these airborne viral infections represent a pervasive threat for civilians and for the military personnel against which immediately available countermeasures are extremely limited. Therefore, there is an urgent need for innovative antiviral therapies.
Interactions between metabolism and immunity was recently (re)discovered thanks to "omics" approaches and transdisciplinary research that led to the concept of “immunometabolism”. For several years, teams from the ViroMetaBlock consortium have been studying the metabolic pathways involved in the control of both the innate antiviral immune response and the replication of viruses in general. This work has led to the identification of 3 candidate molecules with antiviral activity that target the same metabolic pathway in the cell: the succinate/HIF-1a axis.
The ViroMetaBlock project aims at validating within the next 24 months the antiviral properties of these candidate molecules against the highly pathogenic Nipah and H5N1 influenza viruses as well as measles virus and seasonal H3N2 and H1N1 influenza viruses, which are still a threat for human populations. First, we will validate in vitro the antiviral properties of our candidate molecules against these different viruses. We will then characterize the molecular mechanisms of the antiviral action of these molecules and their impact on the innate immune response. Finally, we will validate the efficacy and the absence of toxicity of those molecules, alone or in combination, in relevant three-dimensional models known as pulmonary organotypic cultures. Results will pave the way for future in vivo evaluations in preclinical models and the development of these innovative metabolic therapies against viruses representing a major threat for human health.