Virus-Receptor Interactions: The Key to Cellular Invasion

Abstract

Virus-receptor interactions play a key regulatory role in viral host range, tissue tropism, and viral pathogenesis. Viruses utilize elegant strategies to attach to one or multiple receptors, overcome the plasma membrane barrier, enter, and access the necessary host cell machinery. The viral attachment protein can be viewed as the "key" that unlocks host cells by interacting with the "lock"-the receptor-on the cell surface, and these lock-and-key interactions are critical for viruses to successfully invade host cells. Many common themes have emerged in virus-receptor utilization within and across virus families demonstrating that viruses often target particular classes of molecules in order to mediate these events. Common viral receptors include sialylated glycans, cell adhesion molecules such as immunoglobulin superfamily members and integrins, and phosphatidylserine receptors. The redundancy in receptor usage suggests that viruses target particular receptors or "common locks" to take advantage of their cellular function and also suggests evolutionary conservation. Due to the importance of initial virus interactions with host cells in viral pathogenesis and the redundancy in viral receptor usage, exploitation of these strategies would be an attractive target for new antiviral therapeutics.

Keywords: IgSF receptors; PtdSer receptors; cellular adhesion molecules; integrins; sialic acid; viral attachment; viral entry; viral signaling.

Graphical abstract

Fig. 1

Classes of common viral receptors. Common viral receptors include sialylated glycans such as SAs and SA-containing gangliosides, CAMs such as igSF members including CD4, JAM-A, CAR and integrins such as αvβ3, and PtdSer receptors, cell immunoglobulin and mucin domain (TIM), and the Tyro3, Axl, and Mer (TAM) receptors. Virus binding to IgSF members is mediated through the D1 domain.

Fig. 2

Viral receptors function to unlock host cells. (a) JCPyV attaches to host cell α2,6 SA-containing LSTc and requires 5-HT₂ receptors for internalization, presumably through clathrin-mediated endocytosis (CME). (b) Adenovirus binds to CAR then binds to integrins including αvβ3 and αvβ5 to mediate CME, activation of signaling events through PI3K, and activation of Rho GTPases to induce actin remodeling. (c) Zika virus utilizes the AXL receptor tyrosine kinase (AXL) through AXL ligand Gas6, which bridges AXL and PtdSer on the viral envelope to mediate viral entry and activation of the Type 1 IFN pathway and IFN-stimulated genes (ISGs).