The brain's reaction to COVID's inflammatory tidal wave

In a recent study published on the medRxiv* preprint server, researchers study neuroinflammation in the cerebrospinal fluid (CSF) and serum of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: The Brain Reacting to COVID-19: Analysis of the Cerebrospinal Fluid and Serum Proteome, Transcriptome and Inflammatory Proteins. Image Credit: Kateryna Kon /

Specifically, the researchers performed proteome analysis of CSF and serum using mass spectrometry (MS) to elucidate the extent of neuroimmunological pathways. Further, they examined brain proteins for a comprehensive overview of differentially expressed proteins.

A suite of other advanced techniques including enzyme-linked immunosorbent assay (ELISA), autoantibody screening, semi-quantitative cytokine arrays, and ribonucleic acid (RNA)-sequencing were also used to investigate the profile of linear and circular RNA in the CSF.

About the study

Previous studies have not evaluated neuroinflammation through routine parameters in the CSF of patients diagnosed with coronavirus disease 2019 (COVID-19). Furthermore, there has been a lack of research on the effect of concomitant bacterial superinfections (BSIs)-induced immunological responses in the central nervous system (CNS) of COVID-19 patients.

In the present study, researchers investigate whether COVID-19-associated neurological symptoms are due to passive diffusion of cytokine storm into the CNS or an intrathecal inflammatory response. Importantly, they evaluated procalcitonin levels (PCT) above one pg/ml as an indicator for BSI.

The test group consisted of 38 individuals with COVID-19 who were stratified based on the presence or absence of signs of BSI for the CSF proteome analysis. The sizes of the control and herpes simplex virus encephalitis (HSVE) cohorts were different due to different sample volume restrictions. Accordingly, 28 controls were without non-neurodegenerative neurological diseases and 10 had HSVE.

Two sets of controls for RNA measurements. While negative controls had no neurological disease, positive controls suffered from multiple sclerosis and Alzheimer’s disease. Furthermore, the researchers used CSF and serum from  11 control patients and 10 HSV patients for cytokine measurements. Likewise, 32 serum and CSF samples were used for testing anti-neuronal and anti-glial autoantibodies.

For the progranulin measurements, 22 age-matched controls from the existing cohorts were used. To this end, the test group had 21 COVID-19 patients, with 12 and nine belonging to the C19lowPCT and the C19highPCT individuals, respectively.

Taken together, the study data helped the researchers analyze the response to COVID-19 and HSVE and reveal the effect of BSI on the neuroimmunological responses.

Study findings

Proteomics revealed a similar CSF protein profile in COVID-19 patients compared to patients with HSVE in patients with and without BSI. However, the changes were much less pronounced in COVID-19 patients. Furthermore, all COVID-19 patients had similar but strongly attenuated inflammatory changes in the CSF, which included immunoglobulins and most complement components.

Routine CSF parameters of COVID-19 patients showed a slightly higher albumin CSF/serum ratio in the range of five to 43.6 (median 10.24), thereby indicating that the origin of elevated proteins in COVID-19 patients was extrathecal. This finding also indicated a pronounced systemic inflammatory reaction in COVID-19 and a high frequency of minor blood-CSF barrier disruption.

Intriguingly, some Serpin family proteins and the leucine-rich alpha-2-glycoprotein 1 (LRG1), which are not produced within the CNS, were detected in the plasma of COVID-19 patients by proteomic studies, thus indicating their diffusion from the blood into the CSF.

RNA sequencing in the CSF revealed 101 linear RNAs comprising micro and messenger RNAs. The observed transfer RNA (t-RNA) fragments were also differentially expressed in COVID-19 patients.

Additionally, COVID-19 patients with simultaneous BSI, as indicated by elevated PCT levels, had significantly higher inflammatory markers. The pathway analysis showed activation of immunological pathways in COVID-19highpct patients.

COVID-19 patients with BSI had elevated interleukin 6 (IL-6), IL-16, and C-X-C motif chemokine ligand 10 (CXCL10) levels in the serum. Likewise, the cytokine array analysis pointed to elevated serum levels of integrins, such as intercellular adhesion molecule 1 (ICAM1), and hemostasis-related proteins such as SerpinE1 in the serum of COVID-19 patients.

Significantly increased progranulin levels were observed in the CSF of COVID-19 patients, with or without BSI, regardless of COVID-19 severity. Presumably, progranulin levels change due to microglial and neuronal activation or are released during infiltration of the olfactory and temporal regions, as observed in animal models.

SARS-CoV-2 likely attacks the heme on the 1-B chain of hemoglobin, subsequently causing a reduction in the amount of hemoglobin. Disruption of this pathway leads to a reactive increase of hemoglobin subunit beta (HBB), resulting in the downregulation of genes associated with extracellular vesicles, as observed in the gene enrichment analysis. This finding indicates that COVID-19 may affect the RNA profile of extracellular vesicles derived from the brain.

Furthermore, an extensive screening for anti-neural antibodies, including in native neuronal tissue, did not show pathological-level titers of familiar antibodies or any new antibody reactivities.


The current study is the first to provide evidence of the neuroimmunological impact of a COVID-19 accounting for concomitant BSI. These findings depicted how the brain reacts to the inflammatory responses caused by COVID-19.

Interestingly, BSI did not affect the protein pattern but was associated with significantly higher levels of inflammation-related proteins in COVID-19 patients. The observed high progranulin CSF levels and low cytokine CSF/serum ratios together point to a defensive state of the brain against the inflammatory storm coming from the blood due to COVID-19.

Overall, the study results did not show direct SARS-CoV-2-mediated neural damage. Instead, they showed indirect and systemic effects of COVID-19 in the brain that included the diffusion of inflammatory mediators from the peripheral blood into the CNS, either passively or through a blood-brain barrier, hypoxia, and brain endothelial cell damage.

*Important notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


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