Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms

Song, Eric; Bartley, Christopher M.; Chow, Ryan D.; Ngo, Thomas T.; Jiang, Ruoyi; Zamecnik, Colin R.; Dandekar, Ravi; Loudermilk, Rita P.; Dai, Yile; Liu, Feimei; Sunshine, Sara; Liu, Jamin; Wu, Wesley; Hawes, Isobel A.; Alvarenga, Bonny D.; Huynh, Trung; McAlpine, Lindsay; Rahman, Nur-Taz; Geng, Bertie; Chiarella, Jennifer; Goldman-Israelow, Benjamin; Vogels, Chantal B.F.; Grubaugh, Nathan D.; Casanovas-Massana, Arnau; Phinney, Brett S.; Salemi, Michelle; Alexander, Jessa R.; Gallego, Juan A.; Lencz, Todd; Walsh, Hannah; Wapniarski, Anne E.; Mohanty, Subhasis; Lucas, Carolina; Klein, Jon; Mao, Tianyang; Oh, Jieun; Ring, Aaron; Spudich, Serena; Ko, Albert I.; Kleinstein, Steven H.; Pak, John; DeRisi, Joseph L.; Iwasaki, Akiko; Pleasure, Samuel J.; Wilson, Michael R.; Farhadian, Shelli F.

COVID-19 patients frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single cell RNA-seq and cytokine analyses of CSF and blood from COVID-19 patients with neurological symptoms, we find compartmentalized, CNS specific T cell activation and B cell responses. All COVID-19 cases had CSF anti-SARS-CoV-2 antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are found only during brain infection, and are not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from a COVID-19 patient, and find that these mAbs target both anti-viral and anti-neural antigens—including one mAb that reacted to both spike protein and neural tissue. Overall, CSF IgG from 5/7 patients contains anti-neural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of COVID-19 patients and suggests a role for autoimmunity in neurologic sequelae of COVID-19.