EV-A71 Mechanism of Entry: Receptors/Co-Receptors, Related Pathways and Inhibitors

Abstract

Enterovirus A71, a non-enveloped single-stranded (+) RNA virus, enters host cells through three stages: attachment, endocytosis and uncoating. In recent years, receptors/co-receptors anchored on the host cell membrane and involved in this process have been continuously identified. Among these, hSCARB-2 was the first receptor revealed to specifically bind to a definite site of the EV-A71 viral capsid and plays an indispensable role during viral entry. It actually acts as the main receptor due to its ability to recognize all EV-A71 strains. In addition, PSGL-1 is the second EV-A71 receptor discovered. Unlike hSCARB-2, PSGL-1 binding is strain-specific; only 20% of EV-A71 strains isolated to date are able to recognize and bind it. Some other receptors, such as sialylated glycan, Anx 2, HS, HSP90, vimentin, nucleolin and fibronectin, were discovered successively and considered as “co-receptors” because, without hSCARB-2 or PSGL-1, they are not able to mediate entry. For cypA, prohibitin and hWARS, whether they belong to the category of receptors or of co-receptors still needs further investigation. In fact, they have shown to exhibit an hSCARB-2-independent entry. All this information has gradually enriched our knowledge of EV-A71’s early stages of infection. In addition to the availability of receptors/co-receptors for EV-A71 on host cells, the complex interaction between the virus and host proteins and various intracellular signaling pathways that are intricately connected to each other is critical for a successful EV-A71 invasion and for escaping the attack of the immune system. However, a lot remains unknown about the EV-A71 entry process. Nevertheless, researchers have been continuously interested in developing EV-A71 entry inhibitors, as this study area offers a large number of targets. To date, important progress has been made toward the development of several inhibitors targeting: receptors/co-receptors, including their soluble forms and chemically designed compounds; virus capsids, such as capsid inhibitors designed on the VP1 capsid; compounds potentially interfering with related signaling pathways, such as MAPK-, IFN- and ATR-inhibitors; and other strategies, such as siRNA and monoclonal antibodies targeting entry. The present review summarizes these latest studies, which are undoubtedly of great significance in developing a novel therapeutic approach against EV-A71.

Cordycepin Inhibits Enterovirus A71 Replication and Protects Host Cell from Virus-Induced Cytotoxicity through Adenosine Action Pathway

“…The life cycle of EV-A71 is composed of a series of consecutive events, including virus–receptor binding, receptor-mediated endocytosis, uncoating, viral protein synthesis, RNA genome synthesis, assembly, virus maturation, and release from the host cell. Candidate drugs that inhibit any step in the EV-A71 life cycle may reduce virus production [ 2 ]. The results of Figure 2 , Figure 3 , Figure 4 and Figure 5 demonstrate the impact of the long-term presence of cordycepin on the entire process of the EV-A71 life cycle, thereby inhibiting virus production.…”

“…Enterovirus A71 (EV-A71) infection is an emerging infectious disease that has become a serious threat to public health around the world in recent years, especially in the Asia-Pacific region [ 1 ]. EV-A71 belongs taxonomically to the genus Enterovirus in the family Picornaviridae [ 2 , 3 ]. The common infectious age groups are infants and young children, and it is transmitted through the fecal–oral route [ 4 , 5 ].…”

“…After EV-A71 infects the host, it first invades gastrointestinal cells and utilizes them as the primary replication site [ 7 ]. Infection is initiated when the virus binds to a specific receptor on the cell surface, such as scavenger receptor class B, member 2, and then enters the cytoplasm of the target cell using receptor-mediated endocytosis [ 2 , 8 ]. When the virus enters the cell, the capsid will disintegrate due to the acidic environment of the vesicle, and then release the genome into the cytoplasm.…”

“…Eventually, the viruses are released from the infected host cells and infect neighboring cells [ 6 ]. Potential drug candidates may form blockades to various stages of the EV-A71 life cycle [ 2 ]. Once infection is established at the primary replication site, the virus may spread to other tissues and organs, causing different types of complications, such as hand-food-and-mouth disease (HFMD) and herpangina [ 9 ].…”

Cathelicidin peptide analogues inhibit EV71 infection through blocking viral entry and uncoating

“…Crystal structure showed that a depression (the “canyon”) encircles the icosahedral fivefold axes of the virions, which was predicted to be the binding site of receptors that have an immunoglobulin-like fold [ 5 ]. Several molecules have been found to act as receptors for EV71 infection, including Scavenger receptor class B member 2 (SCARB2), P-selectin glycoprotein ligand-1(PSGL-1), annexin II, heparan sulfate (HS), etc [ 6 , 7 ]. Among them, SCARB2 is the major function receptor that supports both attachment and uncoating of virions, while others are classified as “attachment receptors” [ 6 , 7 ].…”