MRC AMED - The HDAC6/USP7 axis in enveloped RNA viral infection

甲型流感病毒（IAV）每年都会引起流行，偶尔也会引起大流行，并且由于与禽流感或猪流感病毒重新组合而产生的新毒株和潜在致命毒株持续存在威胁。除了开发通用流感疫苗外，还需要更深入地了解IAV感染的细胞生物学，以发现针对细胞蛋白和途径的抗病毒策略。病毒脱壳是感染的早期步骤，但我们对其了解甚少，但我们认为宿主细胞因子可以作为一种有效的抗病毒策略。与许多包膜RNA病毒相比，IAV的进入和剥膜得到了很好的研究。脱衣需要一个泛素介导的错误折叠的蛋白质降解途径，称为聚合体加工。在这里，关键的宿主角色，细胞质组蛋白去乙酰化酶6 (HDAC6)，感知错误折叠的蛋白质“标签”，并激活细胞途径，帮助在进入过程中分解病毒外壳。在这项研究中，我们将研究HDAC6和泛素修饰酶之间的相互作用，并针对多种宿主因子阻止病毒脱壳，从而阻断感染。我们的发现可能有助于理解一般的病毒脱膜途径，并导致广谱抗病毒药物的概念化，这种抗病毒药物可以对抗具有医学重要性的新出现和再出现的病毒。

Influenza A virus (IAV) causes annual epidemics and occasional pandemics with continuous threat of emerging and potentially lethal strains derived from reassortment with avian or swine IAV. In addition to development of a universal influenza vaccine, a deeper understanding of cell biology of IAV infections is needed to discover antiviral strategies that target cellular proteins and pathways. Viral uncoating is an early step in infection that is poorly understood, but we think that the host cell factors involved can be targeted effectively as an antiviral strategy.IAV entry and uncoating is well-studied compared to many enveloped RNA viruses. Uncoating requires a ubiquitin-mediated, misfolded protein degradation pathway known as aggresome processing. Here, the key host player, the cytosolic histone deacetylase 6 (HDAC6), senses misfolded protein 'tags' and activates a cellular pathway that helps to break apart the viral shell during entry. In this study we will address the interplay between HDAC6 and ubiquitin-modifying enzymes, and target multiple host factors to block viral uncoating and thus block infectivity. Our findings may contribute to the understanding of general viral uncoating pathways and lead to conceptualisation of a broad spectrum antiviral that can combat emerging and re-emerging viruses of medical importance.