Increased Cerebrospinal Fluid Angiotensin-Converting Enzyme 2 Fragments as a Read-Out of Brain Infection in Patients With COVID-19 Encephalopathy

• Published in: The Journal of infectious diseases Vol. 231; no. 5; pp. e929 - e940
• Main Authors: Lennol, Matthew P, García-Ayllón, María-Salud, Avilés-Granados, Carlos, Trasciatti, Chiara, Tolassi, Chiara, Quaresima, Virginia, Arici, Davide, Cristillo, Viviana, Volonghi, Irene, Caprioli, Francesca, De Giuli, Valeria, Mariotto, Sara, Ferrari, Sergio, Zanusso, Gianluigi, Ashton, Nicholas J, Zetterberg, Henrik, Blennow, Kaj, Padovani, Alessandro, Pilotto, Andrea, Sáez-Valero, Javier
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 15.05.2025
• Subjects: ACE2; Adult; Aged; Angiotensin; Angiotensin-converting enzyme 2; Angiotensin-Converting Enzyme 2 - cerebrospinal fluid; biomarker; Biomarkers - cerebrospinal fluid; Cerebrospinal fluid; COVID-19; COVID-19 - cerebrospinal fluid; CSF; Emerging diseases; Encephalitis; Encephalitis, Viral - cerebrospinal fluid; Encephalopathy; Enzymes; Female; Human health and pathology; Humans; Infections; Infectious diseases; Infectious Medicine; Infektionsmedicin; Inflammation; Life Sciences; Major; Male; Middle Aged; Neurobiology; Neuronal-glial interactions; Neurons and Cognition; Peptidyl-dipeptidase A; SARS-CoV-2; Serine Endopeptidases - cerebrospinal fluid; Serine proteinase; Severe acute respiratory syndrome coronavirus 2; TMPRSS2; Western blotting; COVID-19; ACE2; TMPRSS2; biomarker; CSF; SARS-CoV-2
• ISSN: 0022-1899; 1537-6613; 1537-6613
• DOI: 10.1093/infdis/jiaf093

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 with non-COVID-19–related encephalitis (Enceph), and 21 neurologically healthy controls. Participants underwent a standardized assessment for encephalitis. A large subset of samples underwent analysis for 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 2 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 with 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 to inflammation, but not with SARS-CoV-2 infection. This study demonstrates an increase in a specific CSF ACE2 fragment in patients with SARS-CoV-2 infection presenting encephalitis that was not noticed in COVID-19 without encephalitis or in non-COVID–related encephalitis. This fragment may serve to monitor virus brain penetrance. Graphical Abstract Graphical Abstract