Department of Biological Sciences, Indian Institute of Science Education and Research Kolkata, Mohanpur 741246, India.
Department of Computational and Data Sciences, Indian Institute of Science, Bengaluru 560012, India.
Viruses. 2023 Jan 12;15(1):215. doi: 10.3390/v15010215.
The β-Coronavirus mouse hepatitis virus (MHV-A59)-RSA59 has a patent stretch of fusion peptide (FP) containing two consecutive central prolines (PP) in the S2 domain of the Spike protein. Our previous studies compared the PP-containing fusogenic-demyelinating strain RSA59(PP) to its one proline-deleted mutant strain RSA59(P) and one proline-containing non-fusogenic non-demyelinating parental strain RSMHV2(P) to its one proline inserted mutant strain RSMHV2(PP). These studies highlighted the crucial role of PP in fusogenicity, hepato-neuropathogenesis, and demyelination. Computational studies combined with biophysical data indicate that PP at the center of the FP provides local rigidity while imparting global fluctuation to the Spike protein that enhances the fusogenic properties of RSA59(PP) and RSMHV2(PP). To elaborate on the understanding of the role of PP in the FP of MHV, the differential neuroglial tropism of the PP and P mutant strains was investigated. Comparative studies demonstrated that PP significantly enhances the viral tropism for neurons, microglia, and oligodendrocytes. PP, however, is not essential for viral tropism for either astroglial or oligodendroglial precursors or the infection of meningeal fibroblasts in the blood-brain and blood-CSF barriers. PP in the fusion domain is critical for promoting gliopathy, making it a potential region for designing antivirals for neuro-COVID therapy.
β-冠状病毒鼠肝炎病毒 (MHV-A59)-RSA59 的 Spike 蛋白 S2 结构域中含有一段连续的融合肽 (FP)，其中包含两个连续的中央脯氨酸 (PP)。我们之前的研究比较了含有 PP 的融合性脱髓鞘毒株 RSA59(PP)与其一个脯氨酸缺失的突变株 RSA59(P)，以及一个含有脯氨酸的非融合性非脱髓鞘亲本株 RSMHV2(P)与其一个脯氨酸插入的突变株 RSMHV2(PP)。这些研究强调了 PP 在融合性、肝神经病理学和脱髓鞘中的关键作用。计算研究结合生物物理数据表明，FP 中心的 PP 提供了局部刚性，同时赋予 Spike 蛋白全局波动，从而增强了 RSA59(PP)和 RSMHV2(PP)的融合特性。为了详细了解 PP 在 MHV FP 中的作用，研究了 PP 和 P 突变株在神经胶质细胞中的差异嗜性。比较研究表明，PP 显著增强了病毒对神经元、小胶质细胞和少突胶质细胞的嗜性。然而，PP 对于病毒对星形胶质细胞或少突胶质细胞前体的嗜性，或者血脑屏障和血脑脊液屏障中的脑膜成纤维细胞的感染都不是必需的。融合结构域中的 PP 对于促进神经胶质病至关重要，使其成为神经 COVID 治疗中设计抗病毒药物的潜在区域。
