SARS-CoV-2 Invades the Central Nervous System <i>via</i> the Olfactory Route in Rhesus Monkeys

Abstract

Neurological manifestations are frequently reported in the COVID-19 patients. Neuromechanism of SARS-CoV-2 remains to be elucidated. In this study, we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19. In rhesus monkey, SARS-CoV-2 invades the CNS primarily via the olfactory bulb. Thereafter, viruses rapidly spread to functional areas of the central nervous system such as hippocampus, thalamus and medulla oblongata. The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons, microglia and astrocytes in the CNS. Consistently, SARS-CoV-2 infects neuro-derived SK-N-SH, glial-derived U251 and brain microvascular endothelial cells in vitro. To our knowledge, this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model, which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.Funding Statement: This study was supported by the National Research and Development Project of 5 China (2020YFC0841100, 2020YFC0846400, 2020YFA0707600), CAMS Innovation Fund for Medical Sciences (2016-I2M-2-006, 2020-I2M-CoV19-012) and Major special Projects in Yunnan Province (Establishment of animal model of novel coronavirus infection and development of emergency vaccine).Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: All animal procedures were approved by the Institutional Animal Care and Use Committee of Institute of Medical Biology, Chinese Academy of Medical Science (ethics number: DWSP202002001).