Pascal Dujardin, AgroParisTech, UMR Virologie Maisons-Alfort

Pascal Dujardin (1), Marine Lemesle (1), Aurore Fablet (1), Grégory Caignard (1), Damien Vitour (1) (1) UMR Virologie, École Nationale Vétérinaire d’Alfort, Anses, Inrae. 94700 Maisons-Alfort, France

Pathogenesis and Immunity

African horse sickness virus (AHSV) is an arbovirus that infects equids, causing a hemorrhagic fever with a case fatality rate of up to 95%. It belongs to the Orbivirus genus (Sedoreoviridae family) with 9 serotypes described. AHSV is transmitted by Culicoides midges, and its spread to non-endemic regions due to global warming has raised concerns among animal health authorities. Despite its severe clinical manifestations, little is known about the molecular mechanisms behind AHSV infection, particularly how it modulates the type 1 interferon (IFN-I) response. This project aims to identify AHSV proteins that inhibit the IFN-I pathway and investigate the molecular mechanisms behind their antagonistic effects. Using reporter gene assays with Firefly luciferase expression driven by IFN-β or ISRE promoters, we screened the entire AHSV ORFeome to identify proteins that inhibit the IFN-I signaling cascade. Results revealed that NS4 is the primary antagonist of the IFN-I induction pathway, acting upstream of IRF3 activation. Furthermore, NS4 also blocks the JAK/STAT signaling pathway, highlighting its role as a key proviral factor in the viral replication cycle. To further elucidate the molecular mechanisms of NS4 antagonistic action, interactomic analyses through mass spectrometry approaches are currently in progress. These analyses will help identify cellular partners of NS4 providing insights into how it modulates the IFN-I pathway and potentially other cellular signaling pathways affected by AHSV.