Spike protein mediated membrane fusion during SARS-CoV-2 infection

Abstract

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed a serious threat to public health and has quickly become a global concern. The infection of SARS-CoV-2 begins with the binding of its spike protein to the receptor-angiotensin-converting enzyme 2 (ACE2), which, after a series of conformation changes, results in the fusion of viral-cell membranes and the release of the viral RNA genome into the cytoplasm. In addition, infected host cells can express spike protein on their cell surface, which will interact with ACE2 on neighboring cells, leading to cell membrane fusion and the formation of multinucleated cells or syncytia. Both viral entry and syncytia formation are mediated by spike-ACE2 interaction and share some common mechanisms of membrane fusion. Here in this review, we will summarize our current understanding of spike-mediated membrane fusion, which may shed light on future broad-spectrum antiviral development.

Keywords: antiviral agents; cell fusion; cellular effect; coronavirus; entry inhibitors; virus classification.

Figure 1

SARS‐CoV‐2 enters cells via endocytosis or cell surface membrane fusion. (A). Diagram of SARS‐CoV‐2 and spike trimer. S, spike; M, membrane; E, envelope; N, nucleocapsid protein; RBD, receptor‐binding domain. (B). The full‐length SARS‐CoV‐2 S protein. S could be cleaved by furin at S1/S2 and be processed by protease at S2′. FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; TM, transmembrane domain. (C). Virus entry by endocytosis or membrane fusion. In the endocytic pathway, the entire viral particle enters the cell and fuses its membrane with the luminal side of the endosomal membrane. In the nonendocytosis pathway, a fusion pore is generated by the direct fusion of the viral membrane and cell membrane. Both pathways share similar mechanisms of membrane fusion. SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2

Figure 2

Diagrams showing different methods for syncytia detection. Syncytia could be observed with a light microscope for fused multinucleated cells (A); to detect the expression of fluorescence protein (B–D) or luciferase (E) in fused cells

Figure 3

Spike mediated cell‐cell fusion. Syncytia are formed by S on infected cells interacting with ACE2 on neighboring cells. IFITMs could inhibit S‐mediated syncytia that can be reversed by TMPRSS2. In addition, TMEM16F, PS and cholesterol are host factors to enhance syncytia. PS, phosphatidylserine. ACE2, angiotensin‐converting enzyme 2