Cerebrospinal Fluid Protein Markers Indicate Neuro-Damage in SARS-CoV-2-Infected Nonhuman Primates

Neurologic manifestations are among the most frequently reported complications of COVID-19. However, given the paucity of tissue samples and the highly infectious nature of the etiologic agent of COVID-19, we have limited information to understand the neuropathogenesis of COVID-19. Therefore, to better understand the impact of COVID-19 on the brain, we used mass-spectrometry- based proteomics with a data-independent acquisition mode to investigate cerebrospinal fluid (CSF) proteins collected from two different nonhuman primates, Rhesus Macaque and African Green Monkeys, for the neurologic effects of the infection. These monkeys exhibited minimal to mild pulmonary pathology but moderate to severe central nervous system (CNS) pathology. Our results indicated that CSF proteome changes after infection res-olution corresponded with bronchial virus abundance during early infection and revealed substantial differences between the infected nonhuman primates and their age -matched uninfected controls, suggesting these differ-ences could reflect altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. We also observed the infected animals exhibited highly scat-tered data distributions compared to their corresponding controls indicating the heterogeneity of the CSF proteome change and the host response to the viral infection. Dys-regulated CSF proteins were preferentially enriched in functional pathways associated with progressive neuro-degenerative disorders, hemostasis, and innate immune responses that could influence neuroinflammatory re-sponses following COVID-19. Mapping these dysregulated proteins to the Human Brain Protein Atlas found that they tended to be enriched in brain regions that exhibit more frequent injury following COVID-19. It, therefore, appears reasonable to speculate that such CSF protein changes could serve as signatures for neurologic injury, identify important regulatory pathways in this process, and potentially reveal therapeutic targets to prevent or atten-uate the development of neurologic injuries following COVID-19.

Automated summary

Neurologic manifestations are common complications of COVID-19, but little is known about the neuropathogenesis of the disease. To understand its impact on the brain, researchers used mass-spectrometry-based proteomics to study cerebrospinal fluid (CSF) proteins from Rhesus Macaque and African Green Monkeys. The results showed significant differences between infected and uninfected monkeys, suggesting altered secretion of CNS factors in response to SARS-CoV-2-induced neuropathology. Dysregulated CSF proteins were found to be associated with neurodegenerative disorders, hemostasis, and innate immune responses, indicating their potential role in neuroinflammatory responses following COVID-19.