The S2 Subunit of QX-type Infectious Bronchitis Coronavirus Spike Protein Is an Essential Determinant of Neurotropism

Abstract

Some coronaviruses (CoVs) have an extra furin cleavage site (RRKR/S, furin-S2′ site) upstream of the fusion peptide in the spike protein, which plays roles in virion adsorption and fusion. Mutation of the S2′ site of QX genotype (QX-type) infectious bronchitis virus (IBV) spike protein (S) in a recombinant virus background results in higher pathogenicity, pronounced neural symptoms and neurotropism when compared with conditions in wild-type IBV (WT-IBV) infected chickens. In this study, we present evidence suggesting that recombinant IBV with a mutant S2′ site (furin-S2′ site) leads to higher mortality. Infection with mutant IBV induces severe encephalitis and breaks the blood–brain barrier. The results of a neutralization test and immunoprotection experiment show that an original serum and vaccine can still provide effective protection in vivo and in vitro. This is the first demonstration of IBV-induced neural symptoms in chickens with encephalitis and the furin-S2′ site as a determinant of neurotropism.

TMPRSS2 and furin are both essential for proteolytic activation and spread of SARS-CoV-2 in human airway epithelial cells and provide promising drug targets

“…IBV belongs to the genus Gammacoronavirus and causes a highly contagious, acute respiratory disease of chickens. Cleavage of IBV S protein by furin at the S2’ site has been associated with neurotropism in chicken (Cheng et al, 2019). Congruently, here, FRET substrates of the S1/S2 and S2’ site of the IBV Beaudette S protein were efficiently cleaved by furin (Fig.…”

The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

“…For instance, the pathogenesis of some CoV https://doi.org/10.1016/j.antiviral.2020.104742 Received 3 February 2020; Received in revised form 7 February 2020; Accepted 8 February 2020 has been previously related to the presence of a furin-like cleavage site in the S-protein sequence. For example, the insertion of a similar cleavage site in the infectious bronchitis virus (IBV) S-protein results in higher pathogenicity, pronounced neural symptoms and neurotropism in infected chickens (Cheng et al, 2019).…”

Recombination and purifying selection preserves covariant movements of mosaic SARS-CoV-2 protein S

“…On the contrary S glycoprotein of previously circulating SARS-CoV strains do not have a favorable furin-like cleavage site 1 and remain un-cleaved after biosynthesis 37 . Furin has the potential to cleave specifically viral envelope glycoproteins, to enhance viral fusion with host cell membranes 38 , thereby any variation/mutational changes in amino acid composition at cleavage sites may impact tissue and cell tropism, host range, and pathogenesis 39 , as reported for other respiratory viruses 40-42 . Moreover, our MD simulations correlated furin-like cleavage site correlated with pre-fusion conformation.…”