Nature Microbiology Zhou Zhenghong's group reveals the molecular mechanism of BTV virus invasion

Responsible Editor | The virus invades the host cell and then replicates and assembles in the cell is a highly regulated process.
In this process, the virus needs to pass through the cell membrane without destroying the integrity of the host cell
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This process has been studied more clearly for enveloped viruses, such as influenza virus, HIV virus, and the new coronavirus (SARS-CoV-2) that is pandemic worldwide
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The invasion of these viruses is achieved through the fusion of the viral envelope and the host cell membrane mediated by surface glycoproteins
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However, it is not clear how non-enveloped viruses penetrate the cell membrane barrier and enter the host cytoplasm to start replication
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On October 26, 2021, Zhou Zhenghong's team from UCLA and Polly Roy's team from London School of Hygiene and Tropical Medicine (the first author is Xia Xian) published a titled Bluetongue virus capsid protein VP5 perforates membranes at Nature Microbiology.
The article on low endosomal pH during viral entry uses the double-stranded RNA virus bluetongue virus (BTV) as the research object to analyze the conformational changes and the mechanism of invasion of non-encapsulated diseases induced by late endosome low pH
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A typical representative of non-enveloped viruses is bluetongue virus (BTV)
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Bluetongue disease is a serious infectious disease caused by the bluetongue virus, which is mainly spread among ruminants, such as cattle, sheep, and deer.
There is currently no effective treatment
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BTV virus particles are composed of capsid proteins VP3 and VP7, which wrap 10 double-stranded RNA genomes and transcription replication complexes to form a core particle.
The outer layer of the core particle is attached to receptor binding protein VP2 and membrane perforin VP5
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During the invasion process, the virus binds to cell surface receptors and enters the cell by means of endocytosis
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Under the induction of the late endosome's low pH environment, the virus will undergo conformational changes, and VP5 will penetrate the late endosome's capsule and enter the cytoplasm [1]
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However, the mechanism of how VP5 undergoes conformational changes induced by low pH and how it interacts with the capsule is not clear
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In this article, the author spreads the purified BTV virus on the electron microscope grid, changes the pH on the grid to induce the conformational change of the virus, and immediately prepares a frozen sample
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After single particle reconstruction and three-dimensional classification, the BTV virus 3.
4Å low pH state structure and three low pH-induced intermediate state structures were obtained
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The results show that low pH first induces conformational changes of VP5 to form a long stem-like structure, then the receptor binding protein VP2 in the outer layer will gradually fall off, and finally the virus becomes a low pH state
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The author then analyzed the interaction between the virus and the liposomes using cryo-electron microscopy tomographic reconstruction, and found that the length of the VP5 stem-like structure was inserted into the phospholipid bilayer, and the length decreased from 19.
5 nm to 15.
5 nm
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Then, under the combined action of other membrane-bound elements, the BTV virus can punch holes in the envelope
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Subsequently, this hole gradually expanded to allow the virus core particles to escape and enter the host cytoplasm to start virus replication.

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At the same time, the author verified these experimental results through mutation and biochemical experiments, and proposed a mechanism model of BTV virus invasion induced by low pH
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The conformational change of BTV in late endosome reported in this paper is similar to that of another non-encapsulated virus rotaviruses [2], indicating that the mechanism model of virus invasion proposed in this study may also be applicable to other non-encapsulated viruses.
Membrane viruses have important guiding significance for the research of other non-enveloped viruses and the design of drugs for virus invasion
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Original link: https:// Platemaker: 11 References 1.
X.
Zhang et al.
, Atomic model of a nonenveloped virus reveals pH sensors for a coordinated process of cell entry.
Nat Struct Mol Biol 23, 74-80 (2016).
2.
T.
Herrmann et al.
, Functional refolding of the penetration protein on a non-enveloped virus.
Nature 590, 666-670 (2021).
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