The brain reacting to COVID-19: analysis of the cerebrospinal fluid proteome, RNA and inflammation

• Published in: Journal of neuroinflammation 2023-02, Vol.20 (1), p.30-16, Article 30
• Main Authors: Reinhold, Dirk, Farztdinov, Vadim, Yan, Yan, Meisel, Christian, Sadlowski, Henrik, Kühn, Joachim, Perschel, Frank H, Endres, Matthias, Düzel, Emrah, Vielhaber, Stefan, Guttek, Karina, Goihl, Alexander, Venø, Morten, Teegen, Bianca, Stöcker, Winfried, Stubbemann, Paula, Kurth, Florian, Sander, Leif E, Ralser, Markus, Otto, Carolin, Streit, Simon, Jarius, Sven, Ruprecht, Klemens, Radbruch, Helena, Kjems, Jørgen, Mülleder, Michael, Heppner, Frank, Körtvelyessy, Peter
• Format: Article
• Language: English
• Subjects: Analysis; Antibodies; Apolipoproteins; Autoantibodies; Blood; Brain - metabolism; Care and treatment; Central nervous system; Cerebrospinal fluid; Circular RNA; Complement system; Coronaviruses; COVID-19; CXCL10 protein; Cytokines; Diagnosis; Diagnostic tests; Encephalitis; Encephalitis, Herpes Simplex - cerebrospinal fluid; Ethics; Extracellular matrix; Glycoproteins; Herpes simplex; Humans; Immunology; Infections; Inflammation; Inflammation - metabolism; Inflammation Mediators - metabolism; Interleukin 16; Interleukin 6; Laboratories; Meningitis; Neuroinflammation; Neurologic manifestations of general diseases; Neurological diseases; Non-coding RNA; Patients; Prevention; Procalcitonin; Progranulin; Proteome - metabolism; Proteomes; Proteomics; Risk factors; RNA; RNA sequencing; RNA, Viral - metabolism; SARS-CoV-2; Severe acute respiratory syndrome coronavirus 2; Superinfection; Superinfection - metabolism; Testing; Transcriptomes
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-023-02711-2

Patients with COVID-19 can have a variety of neurological symptoms, but the active involvement of central nervous system (CNS) in COVID-19 remains unclear. While routine cerebrospinal fluid (CSF) analyses in patients with neurological manifestations of COVID-19 generally show no or only mild inflammation, more detailed data on inflammatory mediators in the CSF of patients with COVID-19 are scarce. We studied the inflammatory response in paired CSF and serum samples of patients with COVID-19 (n = 38). Patients with herpes simplex virus encephalitis (HSVE, n = 10) and patients with non-inflammatory, non-neurodegenerative neurological diseases (n = 28) served as controls. We used proteomics, enzyme-linked immunoassays, and semiquantitative cytokine arrays to characterize inflammatory proteins. Autoantibody screening was performed with cell-based assays and native tissue staining. RNA sequencing of long-non-coding RNA and circular RNA was done to study the transcriptome. Proteomics on single protein level and subsequent pathway analysis showed similar yet strongly attenuated inflammatory changes in the CSF of COVID-19 patients compared to HSVE patients with, e.g., downregulation of the apolipoproteins and extracellular matrix proteins. Protein upregulation of the complement system, the serpin proteins pathways, and other proteins including glycoproteins alpha-2 and alpha-1 acid. Importantly, calculation of interleukin-6, interleukin-16, and CXCL10 CSF/serum indices suggest that these inflammatory mediators reach the CSF from the systemic circulation, rather than being produced within the CNS. Antibody screening revealed no pathological levels of known neuronal autoantibodies. When stratifying COVID-19 patients into those with and without bacterial superinfection as indicated by elevated procalcitonin levels, inflammatory markers were significantly (p