The Neuro-modulatory Function of the Proline-Proline Pair at the Core of the Fusion Peptide within the Spike Protein of Murine β-Coronavirus

Alao, Safiriyu Abass (2024) The Neuro-modulatory Function of the Proline-Proline Pair at the Core of the Fusion Peptide within the Spike Protein of Murine β-Coronavirus. PhD thesis, Indian Institute of Science Education and Research Kolkata.

Text (PhD thesis of Safiriyu Abass Alao (19RS001)) 19RS001.pdf - Submitted Version Restricted to Repository staff only Download (19MB)

Abstract

Murine β coronavirus mouse hepatitis virus (MHV) recombinant strains RSA59 and RSMHV2 have a patent stretch of fusion peptide (FP) containing two consecutive central prolines (PP) and one central proline (P) in their S2 domain of the spike protein. Previous studies have highlighted the crucial role of the proline-proline dyad on fusogenicity, hepato-neuropathogenesis, and demyelination. PP at the center of the FP provides local rigidity and enhances the fusogenic properties. I have studied differential neuroglial tropism by the PP and P containing RSA59 and RSMHV2 in vivo mouse brain and spinal cord and in vitro isolated primary neuroglial cultures. Colocalization studies were performed on viral antigens with specific neuroglial cells in brain and spinal cord sections of tissues harvested on day 5 post-infection. An in vitro study of differential infectivity and tropism was performed on primary neuroglial cultures. Comparative studies revealed the presence of PP in the FP of the spike protein of MHV-enhancing neuronal, microglial, and white matter oligodendroglial tropism and the subsequent spread of viral antigen from gray matter to white matter. PP is not essential for viral tropism of astrocytes, oligodendrocytes precursors, and fibroblast-like cells in the meninges and choroid plexus of blood-brain and blood–CSF barriers. Two prolines-containing strains are more potent to induce demyelination during the chronic phase of inflammation. Custom mimetic peptides analogous to the FP domain of MHV with proline deletion/insertion mutations were designed to investigate their antiviral activity using biophysical, in vitro, and in vivo studies. One liposomal encapsulated MFP-treated mice demonstrated restriction of viral antigen spread throughout the brain parenchyma. MFPs might act on the host cell membrane by competing with the viral FP during the early stage of host-viral membrane fusion events. Mimetic peptides make it a promising peptide for developing antiviral drugs for pan-coronavirus.

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