Weir Daniel, Bentley-Abbot Calum, McCowan Jack, Loney Colin, Roberts Edward, Hutchinson Edward
MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
Cancer Research UK Scotland Institute, Glasgow, United Kingdom.
PLoS Pathog. 2025 Jun 5;21(6):e1013191. doi: 10.1371/journal.ppat.1013191. eCollection 2025 Jun.
As well as spreading through virions, influenza A viruses (IAVs) can evade antiviral drugs and neutralising antibodies by spreading directly from cell to cell. In cell culture this can occur by the induction of intercellular membrane connections known as tunnelling nanotube-like structures (TLSs), which are capable of trafficking the viral genome between cells. Here, we showed that TLSs are formed by IAV infected cells in vivo, and then used in vitro models to ask how IAVs induce their formation. We found that TLS formation is not induced by cytokine signalling from infected to uninfected cells, but induction does require intracellular IAV replication. IAV replication can form filamentous virions which have structural similarities to TLSs, but we found that TLS induction is independent of virion morphology. We therefore looked at the intracellular responses to infection and found that the induction of TLSs correlated with the induction of apoptosis. Furthermore, the ability of IAVs to drive TLS formation can be modulated by chemically inhibiting, or inducing apoptosis. Finally, we found that inhibiting apoptosis, which prevents IAVs from inducing TLSs, lead to a significant reduction in the ability of IAVs to directly spread between cells. Our results, which suggest that IAVs can control their ability to spread directly from cell to cell by driving infected cells into apoptosis, identifies a new way in which a virus can manipulate its host to evade antiviral immune responses.
甲型流感病毒(IAV)除了通过病毒粒子传播外,还能通过细胞间直接传播来逃避抗病毒药物和中和抗体。在细胞培养中,这可能是通过诱导形成称为隧道纳米管样结构(TLSs)的细胞间膜连接来实现的,这种结构能够在细胞间运输病毒基因组。在这里,我们表明TLSs是由IAV感染的细胞在体内形成的,然后利用体外模型来研究IAV如何诱导其形成。我们发现,TLS的形成不是由感染细胞向未感染细胞的细胞因子信号传导诱导的,但诱导确实需要细胞内IAV复制。IAV复制可以形成与TLSs具有结构相似性的丝状病毒粒子,但我们发现TLS的诱导与病毒粒子形态无关。因此,我们研究了细胞内对感染的反应,发现TLSs的诱导与细胞凋亡的诱导相关。此外,IAV驱动TLS形成的能力可以通过化学抑制或诱导细胞凋亡来调节。最后,我们发现抑制细胞凋亡(这会阻止IAV诱导TLSs)会导致IAV在细胞间直接传播的能力显著降低。我们的结果表明,IAV可以通过驱动感染细胞凋亡来控制其在细胞间直接传播的能力,这确定了病毒操纵其宿主以逃避抗病毒免疫反应的一种新方式。
Cochrane Database Syst Rev. 2025-5-7
J Virol. 2025-4-15
Eur J Pharm Sci. 2024-12-1
Nat Rev Mol Cell Biol. 2024-5
Life Sci Alliance. 2023-7