TY - JOUR T1 - Strain-Specific Human Natural Killer Cell Recognition of Influenza A Virus JF - bioRxiv DO - 10.1101/148528 SP - 148528 AU - Lisa M. Kronstad AU - Christof Seiler AU - Rosemary Vergara AU - Susan P. Holmes AU - Catherine A. Blish Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/06/10/148528.abstract N2 - Abstract Innate Natural killer (NK) cells employ an array of surface receptors to detect ‘altered self’ induced by infection or malignancy. Despite their decisive role in early antiviral immunity, the cellular mechanisms governing if or how they discriminate between viral infections remain unresolved. Here, we demonstrate that while human NK cells are capable of reducing infection levels of distinct influenza A strains, the A/California/07/2009 (pH1N1) strain induces a significantly more robust IFN-γ response than A/Victoria/361/2011 (H3N2) and all other strains tested. This surprising degree of strain specificity results in part from the inability of the pH1N1 strain to downregulate the activating ligands CD112 (Nectin-2) and CD54 (ICAM-1) as efficiently as the H3N2 strain, leading to enhanced NK cell detection and IFN-γ secretion. A network analysis of differentially expressed transcripts identifies the interferon α/β receptor (IFNAR) pathway as an additional, critical determinant of this strain-specific response. Strain-specific downregulation of NK cell activating ligands and modulation of type I IFN production represents a previously unrecognized influenza immunoevasion tactic and could present new opportunities to modulate the quality and quantity of the innate antiviral response for therapeutic benefit.One Sentence Summary Human natural killer cells distinguish between Influenza A strains using a combinatorial cytokine priming and receptor-ligand signaling mechanism. ER -