STUDY OF THE EARLY PATHOGENIC EVENTS DURING LASSA FEVER IN CYNOMOLGUS MONKEYS AND IDENTIFICATION OF BIOLOGICAL MARKERS OF INFECTION – PRECOLAS

Among emerging infectious diseases, viral hemorrhagic fevers (VHF) constitute a perfect example of the threat represented by these diseases for the civil but also military societies. Because of their increasing incidence, dramatic severity, lack of treatment or vaccine, complicated diagnosis, misreading of the pathogenesis, and need for a maximum containment, these diseases constitute a major public health problem, exacerbated by the possible use of these viruses as biological weapons. There is therefore an urgent need to further study VHF to understand the pathogenesis of the severe disease and the host responses involved in their control or in the dramatic damages. This will allow to develop therapeutic and prophylactic approaches but also to identify early biological markers of infection and improve the early diagnosis to optimize the management of outbreaks in the field and increase the survival rate in patients. Among VHF, Lassa fever (LF) is probably the most worrying one because of its endemicity and the large number of cases. LF is caused by the Old-World arenavirus Lassa virus (LASV). It is endemic to West Africa and is responsible for 300,000 cases and 5,000 to 6,000 deaths each year. We propose here to study the pathogenesis of VHF by using LF in cynomolgus monkeys as a paradigm, with a particular emphasis on the very early events. The viral tropism, pathophysiological mechanisms, and immune responses will be studied during the course of infection, including the incubation period. Powerful transcriptomic, proteomic, immunohistological, and immunological approaches will be used to (1), identify early biological markers of infection, to be able to confirm infection, isolate patients and provide appropriate care; (2), determine the viral tropism and dynamics during the course of infection, to improve diagnosis, understand the natural history of virus into its host and help to design new therapeutic approaches; (3), characterize the early pathogenic events that lead to the severe hemorrhagic syndrome, the multivisceral failure and the terminal shock, to fully understand the pathophysiogenesis of VHF, identify new therapeutic targets and optimize the use of existing symptomatic therapeutics; (4), identify the immune responses involved in the control of infection or in the fatal outcome, to reveal the involvement of immunopathological mechanisms and propose therapeutic approaches based on immune system modulation and help to design a vaccine approach. This ambitious and unprecedented project realized by a consortium that is highly competitive and unique in Europe will lead to a significant breakthrough in the field of VHF because of the important advances in the knowledge of events common to these diseases and because of the priceless perspectives for a therapeutic development. In addition, the ability to early confirm the infection will also represent an immediate and important benefit by allowing to isolate patients and contain viral spreading and outbreak, but also by optimizing the patient’s care and improving survival rate. This project clearly fits with the priorities of the ANR-ASTRID call. Indeed, it will lead to a better understanding of pathogens that represent an important threat for civil and military societies and will be helpful for epidemiological survey and health monitoring. The new ways of diagnosis, prevention and therapeutics that will result will represent important medical counter-measure, as well as the identification of biomarkers of exposition for pre-symptomatic diagnosis. Moreover, our project fully matches with the priority of the Délégation Générale pour l’Armement by providing the French Army Forces with tools to manage the important risk represented by VHF.