SARS-CoV‑2\nand HSV‑1 Induce Amyloid\nAggregation in Human CSF Resulting in Drastic Soluble Protein Depletion

The corona virus (SARS-CoV-2) pandemic and the resulting\nlong-term\nneurological complications in patients, known as long COVID, have\nrenewed interest in the correlation between viral infections and\nneurodegenerative brain disorders. While many viruses can reach the\ncentral nervous system (CNS) causing acute or chronic infections (such\nas herpes simplex virus 1, HSV-1), the lack of a clear mechanistic\nlink between viruses and protein aggregation into amyloids, a characteristic\nof several neurodegenerative diseases, has rendered such a connection\nelusive. Recently, we showed that viruses can induce aggregation of\npurified amyloidogenic proteins via the direct physicochemical mechanism\nof heterogeneous nucleation (HEN). In the current study, we show that\nthe incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid\n(CSF) leads to the amyloid aggregation of several proteins known to\nbe involved in neurodegenerative diseases, such as APLP1 (amyloid\nβ precursor like protein 1), ApoE, clusterin, α2-macroglobulin,\nPGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3,\ntransthyretin, and vitronectin. Importantly, UV-inactivation of SARS-CoV-2\ndoes not affect its ability to induce amyloid aggregation, as amyloid\nformation is dependent on viral surface catalysis via HEN and not\nits ability to replicate. Additionally, viral amyloid induction led\nto a dramatic drop in the soluble protein concentration in the CSF.\nOur results show that viruses can physically induce amyloid aggregation\nof proteins in human CSF and result in soluble protein depletion,\n thus providing a potential mechanism that may account for the association\nbetween persistent and latent/reactivating brain infections and neurodegenerative\ndiseases.