SARS-CoV-2 integral membrane proteins shape the serological responses of patients with COVID-19

Abstract

SARS-CoV-2 pandemic has elicited a unique mobilization of the scientific community to develop efficient tools to understand and combat infection. Like other coronavirae , SARS-CoV-2 hijacks host cell secretory machinery to produce viral proteins that compose the nascent virions; including Spike (S), Envelope (E) and Membrane (M) proteins, the most exposed transmembrane proteins to the host immune system. As antibody response is part of the anti-viral immune arsenal, we investigate the immunogenic potential of S, E and M using a human cell-based system to mimic membrane insertion and N-glycosylation. Both S and M elicit specific Ig production in SARS-CoV-2 patients. Patients with moderate and severe diseases exhibit elevated Ig responses. Finally, reduced Ig binding was observed with Spike G614 compared to D614 variant. Altogether, our assay points towards an unexpected immune response against M and represents a powerful tool to test humoral responses against actively evolving SARS-CoV-2 variants and vaccine effectiveness.

A comprehensive analysis of the mutational landscape of the newly emerging Omicron (B.1.1.529) variant and comparison of mutations with VOCs and VOIs

“…We observed that the mutation in D614 has a high risk related to antibody-binding and can reduce the recognition capability by targeting antibodies to the S-glycoprotein. The outcome of our in silico risk analysis study of D614G corroborates the previous experimental study’s result by Martin et al [ 72 ]. Their study has found that the D614G mutation decreased antibody binding of the S-glycoprotein.…”

Structural epitope profiling identifies antibodies associated with critical COVID-19 and long COVID

“…One study has investigated clinical outcome associations of IgM responses to whole proteins in a mammalian cell-based assay, where the membrane is presumed to be presented in a similar fashion as on virions: exposing only the M1 epitope. Consistent with our findings, membrane protein specific IgM was associated with severe disease, although that method is unable to resolve the spike binding to the epitope level and so the unusual isotype pattern and strength of the IgM responses of the membrane epitope relative to other single epitopes is less apparent (71).…”

Structure of SARS-CoV-2 M protein in lipid nanodiscs

“…1, S2). The N-terminus (amino acids [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and C-terminus (amino acids [205][206][207][208][209][210][211][212][213][214][215][216][217][218][219][220][221][222] are not resolved in the map and were not modeled. Loops connecting transmembrane helices (amino acids 36-42 and 71-78) are the least well resolved regions of the structure.…”

“…Despite this, the M protein sequence has remained virtually unchanged-a testament to the critical role that M plays in viral replication and assembly 35 . Furthermore, while only 20 amino acids in length, the N-terminus of M has been found to be highly immunogenic in COVID-19 patients [8][9][10][11] . M has also been shown to modulate innate immune response and could contribute to lung injury often seen in severe cases 25,26 .…”

“…M organizes the assembly and structure of new virions and is essential for virus formation [2][3][4][5] . M is the most abundant membrane protein in the viral envelope and anti-M antibodies are found in plasma of patients infected with SARS-CoV-2 and other coronaviruses [6][7][8][9][10][11] . Based on its functional importance and immunogenicity, M has been proposed as a target for coronavirus vaccines or therapeutics.…”