Coronavirus disease 2019 (COVID-19) primarily causes respiratory symptoms that range from mild cough and fever to severe pneumonia. Increasingly, studies indicate that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has an organotropism beyond the respiratory tract and that the brain is an extrapulmonary site of infection.
Central nervous system (CNS) involvement in SARS-CoV-2 involves a wide range of neurological manifestations such as headache, anosmia, fatigue, confusion, ageusia, and loss of consciousness. These symptoms often represent underlying morbidity that contributes considerably to COVID-19 mortality.
The human angiotensin-converting enzyme (ACE2) receptor, a component of the renin-angiotensin system, is the main entry point for SARS-CoV-2. However, there is no conclusive evidence about the localization of ACE2 in the human CNS, and the mechanism of brain pathology in SARS-CoV-2 infection in the brain is unclear.
Using multiplexed immunohistochemistry and spatial immunophenotyping to study the brain tissue of COVID-19 patients
Recently, researchers from the UK and Sweden used highly sensitive multiplexed immunohistochemistry to study the brain tissue of COVID-19 patients and controls to analyze ACE2 expression in brain pericytes of patients with neurological symptoms. They also used spatial immunophenotyping to assess inflammation in brain tissue of COVID-19 patients.
They applied advanced multiplexed immunostaining on six human brains from COVID-19 patients. The median age of the patients was 69.5 years. There were seven controls with a median age of 68 years. This study is published on the bioRxiv* preprint server,
Results show that patients with neurological symptoms exhibit moderate to high expression of ACE2 in peri-vascular cells
The work demonstrated that the expression of the ACE2 receptor is exclusive to a subset of brain pericytes. Interestingly, neurological symptoms were restricted to patients exhibiting moderate to high expression of ACE2 in peri-vascular cells.
Viral particles were found in the vascular wall accompanied by perivascular inflammation, as shown by T cell and macrophage infiltration. Moreover, leakage of fibrinogen suggested that the integrity of the blood-brain barrier is compromised. Cerebrospinal fluid from an additional eight COVID-19 patients with a median age of 67 years and eight controls with a median age of 69.5 years showed significantly lower levels of the pericyte marker PDGFRβ in SARS-CoV-2-infected individuals. This indicated disruption in pericyte homeostasis.
Based on our observations, we hypothesize that infection and subsequent damage of brain vascular pericytes by SARS-CoV-2 and peri-vascular inflammation may lead to impairment of the BBB, instigating neurological complications and possibly virus entry into the CNS.”
SARS-CoV-2 infection of pericytes leads to viral entry to the central nervous system, inflammation, and neurological symptoms
The researchers concluded that pericyte infection by SARS-CoV-2 triggers entry of the virus into the privileged space central nervous system, peri-vascular inflammation leading to neurological symptoms, and compromise of the blood-brain barrier.
Interestingly, COVID-19 patients having neurological symptoms had a reduced concentration of pericyte-derived sPDGFRβ in the cerebrospinal fluid.
A likely explanation for the diminished expression of PDGFRβ in patients with COVID-19 might be that SARS-CoV-2 infection of pericytes diverts the protein synthesis system to make viral proteins. This leads to a loss of expression of an endogenous marker, resulting in functional impairment.
Better understanding of SARS-CoV-2 neurotropism is vital for the management of acute neurological symptoms in COVID-19 patients
Based on the study's findings, the researchers propose that ACE2-expressing pericytes can be a possible site of SARS-CoV-2 entry into the CNS. According to the authors, a better understanding of SARS-CoV-2 neurotropism is needed in order to guide the management of acute neurological symptoms in COVID-19 patients. It will also help define strategies that can prevent post-COVID-19 neurological complications.
Further studies are needed to confirm if interventions aiming at supporting the integrity of the blood-brain barrier would help alleviate the neurological symptoms in patients with COVID-19.
“An improved understanding of SARS-CoV-2 neurotropism is urgently needed to guide the clinical management of acute neurological symptoms, as well as to define strategies to prevent post-infectious neurological complications.”
bioRxiv 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.
- Infection of brain pericytes underlying neuropathology of COVID-19 patients, Matteo Bocci, Clara Oudenaarden, Xavier Sàenz-Sardà, Joel Simrén, Arvid Edén, Jonas Sjölund, Christina Möller, Magnus Gisslén, Henrik Zetterberg, Elisabet Englund, Kristian Pietras, bioRxiv, 2021.05.24.445532; doi: https://doi.org/10.1101/2021.05.24.445532, https://www.biorxiv.org/content/10.1101/2021.05.24.445532v1