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Severe acute respiratory syndrome virus 2 (SARS-CoV-2) invades host cells by interacting with receptors/coreceptors, as well as with other cofactors, via its spike (S) protein that further mediates fusion between viral and cellular membranes. The host membrane protein, angiotensin-converting enzyme 2 (ACE2), is the major receptor for SARS-CoV-2 and is a crucial determinant for cross-species transmission. In addition, some auxiliary receptors and cofactors are also involved that expand the host/tissue tropism of SARS-CoV-2. After receptor engagement, specific proteases are required that cleave the S protein and trigger its fusogenic activity. Here we discuss the recent advances in understanding the molecular events during SARS-CoV-2 entry which will contribute to developing vaccines and therapeutics. Both severe acute respiratory syndrome virus 2 (SARS-CoV-2) and SARS-CoV mainly invade human lungs, although increasing evidence shows that SARS-CoV-2 can also infect many other tissues to develop systematic infection and multiple organ damage, and can also hijack T cells to directly paralyze host immunity. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 infection and is a crucial determinant for cross-species transmission of the virus; SARS-CoV-2 can establish infections in a panel of domestic or wild animals via their ACE2 orthologs. Several proteins and non-protein molecules have been found to interact with SARS-CoV-2 S protein and serve as potential alternative/auxiliary attachment receptors/coreceptors to facilitate SARS-CoV-2 entry into specific types of host cells. Membrane fusion of SARS-CoV-2 requires two proteolytic events of S protein by host proteases, and the S1/S2 boundary of SARS-CoV-2 S protein harbors a polybasic insertion that expands the spectrum of available proteases and thus the tropism for different tissues. [ABSTRACT FROM AUTHOR]

Thogotoviruses are important zoonotic viruses infecting a variety of domestic animals, as well as humans. Among these viruses, Bourbon virus (BRBV) is one of the several human-infecting members, which emerged in the US in recent years and caused human deaths. Here, we report the crystal structure of the BRBV envelope glycoprotein in the postfusion conformation. The structure adopts the typical fold of a class III viral fusion protein and displays an extensive positively charged electrostatic potential pattern, which resembles the glycoprotein of Dhori virus and is consistent with our previous predictions. In addition, compared to other previously defined class III viral fusion proteins, the structures of all thogotovirus glycoproteins and homologs are more similar to herpes virus glycoprotein Bs than to the rhabdovirus G proteins. Thus, class III viral fusion proteins are quite diverse in structure, and sub-classes may have developed during evolution. [ABSTRACT FROM AUTHOR]

Pseudorabies virus (PRV) belongs to the Herpesviridae family, and is an important veterinary pathogen. Highly pathogenic PRV variants have caused severe epidemics in China since 2011, causing huge economic losses. To tackle the epidemics, we identified a panel of mouse monoclonal antibodies (mAbs) against PRV glycoprotein B (gB) that effectively block PRV infection. Among these 15 mAbs, fourteen of them block PRV entry in a complement-dependent manner. The remaining one, 1H1 mAb, however can directly neutralize the virus independent of complement and displays broad-spectrum neutralizing activities. We further determined the crystal structure of PRV gB and mapped the epitopes of these antibodies on the structure. Interestingly, all the complement-dependent neutralizing antibodies bind gB at the crown region (domain IV). In contrast, the epitope of 1H1 mAb is located at the bottom of domain I, which includes the fusion loops, indicating 1H1 mAb might neutralize the virus by interfering with the membrane fusion process. Our studies demonstrate that gB contains multiple B-cell epitopes in its crown and base regions and that antibodies targeting different epitopes block virus infection through different mechanisms. These findings would provide important clues for antiviral drug design and vaccine development. [ABSTRACT FROM AUTHOR]

Enterovirus B (EV-B), a major proportion of the genus Enterovirus in the family Picornaviridae , is the causative agent of severe human infectious diseases. Although cellular receptors for coxsackievirus B in EV-B have been identified, receptors mediating virus entry, especially the uncoating process of echovirus and other EV-B remain obscure. Here, we found that human neonatal Fc receptor (FcRn) is the uncoating receptor for major EV-B. FcRn binds to the virus particles in the "canyon" through its FCGRT subunit. By obtaining multiple cryo-electron microscopy structures at different stages of virus entry at atomic or near-atomic resolution, we deciphered the underlying mechanisms of enterovirus attachment and uncoating. These structures revealed that different from the attachment receptor CD55, binding of FcRn to the virions induces efficient release of "pocket factor" under acidic conditions and initiates the conformational changes in viral particle, providing a structural basis for understanding the mechanisms of enterovirus entry. • CRISPR screening identified FcRn as an essential and universal EV-B receptor • FcRn facilitates EV-B uncoating and CD55 for attachment • High-resolution Cryo-EM structures described the mechanism of virus entry • The molecular mechanism of dual (attachment versus uncoating) receptor-usage was illustrated The human neonatal Fc receptor is the uncoating receptor that facilitates cellular viral entry for Enteroviruses, such as echovirus. [ABSTRACT FROM AUTHOR]