Abstract
Natural killer (NK) cells are part of the innate immunity repertoire, and function in the recognition and destruction of tumorigenic and pathogen-infected cells. Engagement of NK cell activating receptors can lead to functional activation of NK cells, resulting in lysis of target cells. NK cell activating receptors specific for non-major histocompatibility complex ligands are NKp46, NKp44, NKp30, NKG2D, and CD16 (also known as FcγRIII). The natural cytotoxicity receptors (NCRs), NKp46, NKp44, and NKp30, have been implicated in functional activation of NK cells following influenza virus infection via binding with influenza virus hemagglutinin (HA). In this review we describe NK cell and influenza A virus biology, and the interactions of influenza A virus HA and other pathogen lectins with NK cell natural cytotoxicity receptors (NCRs). We review concepts which intersect viral immunology, traditional virology and glycobiology to provide insights into the interactions between influenza virus HA and the NCRs. Furthermore, we provide expert opinion on future directions that would provide insights into currently unanswered questions.
Highlights
Natural killer (NK) cells are considered an ancient cytotoxic immune effector cell involved in the innate immune response
A delicate balance of signals relayed through activating and inhibitory receptors on NK cells is important to determine the outcome of the interaction; whether target cells will be killed via the release of cytotoxic granules, via death receptors that cause direct lysis, or spared [24,25,26]
We describe NK cell functional biology, NK cell natural cytotoxicity receptors (NCRs) glycobiology, the role of NK cells in influenza disease outcomes, influenza virus biology with a particular focus on HA structure and function, and the interactions of influenza virus
Summary
Natural killer (NK) cells are considered an ancient cytotoxic immune effector cell involved in the innate immune response. Mice lacking a key NK cell activating receptor, natural cytotoxicity receptor (NCR) 1, are highly susceptible to influenza infection [21,22,23]. Interactions between NCRs and bacterial and parasitic pathogens have been described for Mycobacterium [48,49,50], Plasmodium falciparum [51], Enterococcus faecium [50], and Fusobacterium nucleatum [33] (Table 1). Of these pathogens, the interactions between the IAV hemagglutinin (HA) glycoprotein and human NCRs has been the most extensively studied. We summarize current knowledge regarding the carbohydratemediated interactions of influenza virus HA with the NK cell NCRs, currently unanswered questions, and provide discussion as to future directions
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