Neuropathology of COVID-19 brains

Abstract

Although primarily targeting the respiratory system, coronavirus disease 2019 (COVID-19) also manifests with central nervous system (CNS)-related symptoms in up to 80% of the patients. Little is known not only about SARS-CoV-2 neuropathology, but also about the clinical course of pre-existing CNS autoimmune disease and concurrent SARS-CoV-2-infection.

Multiple sclerosis (MS) is the most frequent autoimmune disease of the CNS with inflammatory demyelination and blood-brain barrier (BBB) disruption being typical pathological hallmarks. Whether multiple sclerosis (MS) renders patients more susceptible to CNS involvement during SARS-CoV-2 infection and whether SARS-CoV-2 infection affects the MS disease course remains elusive.
Here, we assessed (I) whether the reported neuropathological abnormalities in COVID-19 patients are SARS-CoV-2 specific, (II) whether COVID-19-associated immune activation exacerbates MS, and (III) whether an impaired BBB renders MS patient more susceptible to viral entry into the CNS. We performed an in-depth histopathological assessment of six COVID-19 and one MS COVID-19 autoptic brain tissue in comparison to 13 septic and non-septic control brains. Further, we executed spatial transcriptomic analysis using multiplex in situ hybridization analysis for SARS-CoV-2 and ACE2 transcripts in autoptic brain tissue of an MS COVID-19 patient.

Besides a general non-SARS-CoV-2 specific microglia activation in COVID-19 and non-COVID 19 septic control brains compared to non-septic control brains, we did not observe further neurological abnormalities in the COVID-19 brains. Despite minor BBB leakage in an MS COVID-19 brain, we found neither evidence for active demyelination nor presence of SARS-CoV-2 transcripts in MS lesions and adjacent areas. SARS-CoV-2 and ACE2 transcripts were consistently detected in epithelial cells of the choroid plexus (CP) and ependymal cells of the cerebrospinal fluid (CSF)-brain interface in both MS and non-MS COVID-19 cases.

Our findings suggest no SARS-CoV-2 specific neuropathological abnormalities in most COVID-19 patients. Moreover, the observations provide neither evidence for clinical or neuropathological signs of MS disease exacerbation nor presence of viral transcripts in neuronal and glial cells. Notably, presence of viral transcripts in the CP suggests the CP being a key restraint of SARS-CoV-2 entry into the CNS. Future studies will need to shed light on SARS-CoV-2-associated pathologies in COVID-19 patients with a more active MS course and other autoimmune comorbidities.

Popular Abstract

Neuropathology of COVID-19 brains

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, primarily targets the respiratory system. However, mounting evidence suggests that the virus may affect various other organs, including the brain, which is further supported by the high prevalence of neurological symptoms found in COVID-19 patients. Even less is known about possible COVID-19-associated disease exacerbation of autoimmune neurological diseases such as multiple sclerosis.

Multiple sclerosis (MS) is one of the most frequent autoimmune central nervous system (CNS) disease. The pathological hallmark of MS is demyelination, which is a destruction of the isolating layer around the nerve cells, and disruption of the blood-brain barrier (BBB). It is important to understand how MS disease course is affected by concurrent SARS-CoV-2 infection as it is known that viral infections can worsen MS. Therefore, we designed a study to assess, (I) whether reported neuropathological abnormalities in COVID-19 patients are SARS-CoV-2 specific, (II) whether SARS-CoV-2 infection is worsening MS disease course, and (III) whether MS-associated BBB break-down is facilitating SARS-CoV-2 infection of the brain.

To answer these questions, we performed a neuropathological analysis of seven COVID-19 patients, one of them with concomitant MS. As controls, we analysed autoptic brain tissue from patients deceased from other viral infections (septic controls) and other non-septic causes, like cardiac failure. The brain tissue was analysed histologically and by in situ hybridization.

Besides a general innate immune cells activation in COVID-19 and non-COVID 19 septic control brains compared to non-septic control brains, we did not observe further neurological abnormalities in the COVID-19 brains. Despite minor BBB leakage in an MS COVID-19 brain, we found neither evidence for active demyelination nor presence of SARS-CoV-2 transcripts in MS lesions and adjacent areas. However, SARS-CoV-2 and ACE2 transcripts were consistently detected in epithelial cells of the choroid plexus (CP), the main structure of the blood-cerebrospinal fluid barrier (BCB), in both MS and non-MS COVID-19 cases.

Our findings suggest no SARS-CoV-2 specific neuropathological abnormalities in most COVID-19 patients. Moreover, the observations provide no evidence for neuropathological signs of MS disease exacerbation or reactivation, despite the minor BBB damage. Notably, presence of viral transcripts in the CP suggests the CP being a key restraint of SARS-CoV-2 entry into the CNS.

Master’s Degree Project in Molecular Biology 60 hp 2021
Department of Biology, Lund University

Advisor: PD Dr. Anne-Katrin Pröbstel
University Hospital and University of Basel, Switzerland

Published results:
1. Deigendesch N, Sironi L, Kutza M, et al. Correlates of critical illness-related encephalopathy predominate postmortem COVID-19 neuropathology. Acta Neuropathol 2020.
2. Fuchs V, Kutza M, Wischnewski S, et al. Presence of SARS-CoV-2 Transcripts in the Choroid Plexus of MS and Non-MS Patients With COVID-19. Neurology - Neuroimmunology Neuroinflammation 2021;8:e957.

• author: Fuchs, Vidmante
• supervisor: Anne-Katrin Pröbstel
• organization: Degree Projects in Molecular Biology
• course: MOBN03 20201
• year: 2021
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• language: English
• id: 9041731
• date added to LUP: 2021-03-11 16:10:08
• date last changed: 2021-03-11 16:10:08