Increased cerebrospinal fluid ACE2 fragments as a read-out of brain infection in COVID-19 encephalopathy patients

Abstract

Background This study assesses the cerebrospinal fluid (CSF) levels of the viral receptor angiotensin-converting enzyme 2 (ACE2) and of the serine protease TMPRSS2 fragments in patients with SARS-CoV-2 infection presenting encephalitis (CoV-Enceph). Methods The study included biobanked CSF from 18 CoV-Enceph, 4 subjects with COVID-19 without encephalitis (CoV), 21 non-COVID-related encephalitis (Enceph), and 21 neurologically healthy controls. Participants underwent a standardized assessment for encephalitis. A large subset of samples underwent an extended panel of CSF neuronal, glial and inflammatory biomarkers. ACE2 and TMPRSS2 species were determined in the CSF by western blotting. Results ACE2 was present in CSF as several species, full-length forms, and two cleaved fragments of 80 and 85 kDa. CoV-Enceph patients displayed increased CSF levels of full-length species, as well as the 80 kDa fragment, but not the alternative 85 kDa fragment, compared with controls and Enceph patients, characterized by increases of both fragments. Furthermore, TMPRSS2 was increased in the CSF of Enceph patients compared with controls, but not in CoV-Enceph patients. The CoV patients without encephalitis displayed unaltered CSF levels of ACE2 and TMPRSS2 species. Conclusions Patients suffering from encephalitis displayed an overall increase in CSF ACE2 probably as a consequence of brain inflammation. The increase of the shortest ACE2 fragment only in CoV-Enceph patients may reflect the enhanced cleavage of the receptor triggered by SARS-CoV-2, thus serving to monitor brain penetrance of the virus associated with the rare encephalitis complication. TMPRSS2 changes in the CSF appeared related with inflammation, but not with SARS-CoV-2 infection.