Marion Cannac, Centre Armand Frappier Santé Biotechnologie (INRS)

Marion Cannac1,2,3, Jim Zoladek1, Inès Bribes1, Mathis Fresneau--Resende1, Alexandre Legrand4, Rémi Demeure4, Eva Zusinaite5, Andres Merits5, Lucie Etienne4, Sébastien Nisole1,3 1. Institut de Recherche en Infectiologie de Montpellier (IRIM), Univ Montpellier, CNRS UMR9004, INSERM, Montpellier, France 2. Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), INSERM, Etablissement Français du Sang, Univ Montpellier, Montpellier, France 3. Centre Armand-Frappier Santé Biotechnologie, Institut National de la Recherche Scientifique, Laval, Québec, Canada 4. Centre international de recherche en infectiologie (CIRI), Inserm U1111, Université Claude-Bernard Lyon 1, CNRS UMR5308, École normale supérieure de Lyon, Lyon, France 5. Institute of Bioengineering, University of Tartu, Tartu, Estonia

Fighting & Responding

The Orthoflavivirus genus includes major mosquito-borne human pathogens such as dengue, Zika, West Nile, and Usutu viruses. Flavivirus replication is strongly inhibited by type I interferon, IFN-I, which induces hundreds of interferon-stimulated genes, ISGs. Yet, the specific ISGs that restrict flavivirus replication in physiologically relevant target cells remain incompletely defined. To identify cellular factors that inhibit flavivirus replication, we performed a large-scale overexpression screen of human ISGs. Among the top hits, we identified SAMD9L, a member of the SAMD9/SAMD9L family recently shown to act as translation-repressive antiviral effectors. Both proteins restrict poxvirus, rotavirus, and reoviruses, but only SAMD9L inhibits HIV-1 and other lentiviruses. We show that overexpression of SAMD9L, but not SAMD9, strongly inhibits the replication of multiple mosquito-borne flaviviruses. Conversely, knockdown of SAMD9L in human microglial cells and primary macrophages significantly impairs IFN-I–mediated antiviral activity, establishing SAMD9L as a key antiviral ISG in primary flavivirus target cells. Using a catalytically inactive mutant, we demonstrate that restriction relies on the Schlafen-like domain of SAMD9L, consistent with previous findings in HIV-1 and poxviruses. Mechanistic studies reveal that SAMD9L inhibits flavivirus replication at the level of viral genome translation. Although both SAMD9 and SAMD9L activate innate immune signaling, this function is dispensable for SAMD9L-mediated restriction. Together, these results identify SAMD9L as a novel anti-flaviviral effector that targets viral translation and highlight its central role in interferon-mediated defenses in myeloid cells.