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Natural mutations in the receptor binding domain of spike glycoprotein determine the reactivity of cross-neutralization between palm civet coronavirus and severe acute respiratory syndrome coronavirus.

ABSTRACT: The severe acute respiratory syndrome (SARS) outbreak of 2002 and 2003 occurred as a result of zoonotic transmission. Coronavirus (CoV) found in naturally infected palm civet (civet-CoV) represents the closest genetic relative to SARS-CoV, but the degree and the determinants of cross-neutralization among these viruses remain to be investigated. Studies indicate that the receptor binding domain (RBD) of the SARS-CoV spike (S) glycoprotein contains major determinants for viral entry and neutralization. We aim to characterize the impact of natural mutations within the RBDs of civet-CoVs on viral entry and cross-neutralization. In this study, the S glycoprotein genes were recovered from naturally infected civets in central China (Hubei province), extending the geographic distribution of civet-CoV beyond the southeastern province of Guangdong. Moreover, pseudoviruses generated in our laboratory with four civet S genes, each with a distinct RBD, infected cells expressing human receptor angiotensin-converting enzyme 2, but with 90 to 95% less efficiency compared to that of SARS-CoV. These four civet S genes were also constructed as DNA vaccines to immunize mice. Immunized sera elicited against most civet S glycoproteins displayed potent neutralizing activities against autologous viruses but were much less efficient (50% inhibitory concentration, 20- to 40-fold) at neutralizing SARS-CoV and vice versa. Convalescence-phase sera from humans were similarly ineffective against the dominant civet pseudovirus. Our findings suggest that the design of SARS vaccine should consider not only preventing the reemergence of SARS-CoV but also providing cross-protection, thus interrupting zoonotic transmission of a group of genetically divergent civet CoVs of broad geographic origin.

SUBMITTER: Liu L

PROVIDER: S-EPMC1900161 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The novel coronavirus originated in December 2019 in Hubei, China. This contagious disease named as COVID-19 resulted in a massive expansion within 6 months by spreading to more than 213 countries. Despite the availability of antiviral drugs for the treatment of various viral infections, it was concluded by the WHO that there is no medicine to treat novel CoV, SARS-CoV-2. It has been confirmed that SARS-COV-2 is the most highly virulent human coronavirus and occupies the third position following SARS and MERS with the highest mortality rate. The genetic assembly of SARS-CoV-2 is segmented into structural and non-structural proteins, of which two-thirds of the viral genome encodes non-structural proteins and the remaining genome encodes structural proteins. The most predominant structural proteins that make up SARS-CoV-2 include spike surface glycoproteins (S), membrane proteins (M), envelope proteins (E), and nucleocapsid proteins (N). This review will focus on one of the four major structural proteins in the CoV assembly, the spike, which is involved in host cell recognition and the fusion process. The monomer disintegrates into S1 and S2 subunits with the S1 domain necessitating binding of the virus to its host cell receptor and the S2 domain mediating the viral fusion. On viral infection by the host, the S protein is further cleaved by the protease enzyme to two major subdomains S1/S2. Spike is proven to be an interesting target for developing vaccines and in particular, the RBD-single chain dimer has shown initial success. The availability of small molecules and peptidic inhibitors for host cell receptors is briefly discussed. The development of new molecules and therapeutic druggable targets for SARS-CoV-2 is of global importance. Attacking the virus employing multiple targets and strategies is the best way to inhibit the virus. This article will appeal to researchers in understanding the structural and biological aspects of the S protein in the field of drug design and discovery.

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Natural mutations in the receptor binding domain of spike glycoprotein determine the reactivity of cross-neutralization between palm civet coronavirus and severe acute respiratory syndrome coronavirus.

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