Decoding Antiviral Restriction, Immune Modulation, and Risk Assessment of Influenza A Viruses.

Objetivo

Influenza A viruses (IAVs) originating from wild waterfowl reservoirs are zoonotic pathogens that pose a constant public health threat. Human spill-over infections occur directly from birds or indirectly through intermediate mammalian hosts and are typically confined to individuals. However, viruses with pandemic potential occasionally emerge, if they overcome the human species barriers. The human innate immune restriction factor Mx1 (known as MxA) is a key interspecies barrier. Previous studies showed that human-adapted IAVs evade MxA restriction through a full set of adaptive amino acids in the viral nucleoprotein (NP). Yet, the mechanisms leading to MxA resistance in NP remain poorly understood. Partial MxA resistance may be acquired in intermediate hosts that express an antivirally active Mx1 or emerge de novo upon viral circulation in humans, as seen in past pandemic IAVs. However, because MxA efficiently suppresses growth of zoonotic IAV with partial MxA resistance, early pandemic IAVs must have evolved additional mechanisms that counteracted MxA restriction. I hypothesize that pre-pandemic IAVs overcome MxA restriction through a combination of (i) an NP pre-shaped by Mx1-driven selection in intermediate hosts, and (ii) by effective measures to dampen the host’s innate immune response, via the viral innate immune antagonist NS1. In FLU-ARMOR, we will reveal how pre-pandemic IAVs evade MxA restriction. Using a forward evolutionary screen, we will explore the adaptive plasticity of NP under Mx1 selection pressure, followed by a component-level analysis of pandemic NS1 proteins, including their cellular interactome and immunosuppressive capabilities. Finally, we will integrate these insights into an AI-based horizon scanning approach to detect circulating IAVs with pre-pandemic characteristics. By unraveling the molecular adaptation processes and virus-host interactions that precede MxA evasion, FLU-ARMOR will set a new benchmark for pandemic preparedness.