4.6 Article

Expression of the ACE2 Virus Entry Protein in the Nervus Terminalis Reveals the Potential for an Alternative Route to Brain Infection in COVID-19

Journal

FRONTIERS IN CELLULAR NEUROSCIENCE
Volume 15, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2021.674123

Keywords

nervus terminalis; ACE2; SARS-CoV-2; COVID-19; brain infection; olfactory system; cathepsin

Categories

Funding

  1. Excellence Initiative-Research University program at the Nicolaus Copernicus University
  2. National Institutes of Health [GM103554]

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There is a possibility that SARS-CoV-2 virus may enter the brain through nervus terminalis neurons as an alternative route from the nose.
Previous studies suggested that the SARS-CoV-2 virus may gain access to the brain by using a route along the olfactory nerve. However, there is a general consensus that the obligatory virus entry receptor, angiotensin converting enzyme 2 (ACE2), is not expressed in olfactory receptor neurons, and the timing of arrival of the virus in brain targets is inconsistent with a neuronal transfer along olfactory projections. We determined whether nervus terminalis neurons and their peripheral and central projections should be considered as a potential alternative route from the nose to the brain. Nervus terminalis neurons in postnatal mice were double-labeled with antibodies against ACE2 and two nervus terminalis markers, gonadotropin-releasing hormone (GnRH) and choline acetyltransferase (CHAT). We show that a small fraction of CHAT-labeled nervus terminalis neurons, and the large majority of GnRH-labeled nervus terminalis neurons with cell bodies in the region between the olfactory epithelium and the olfactory bulb express ACE2 and cathepsins B and L. Nervus terminalis neurons therefore may provide a direct route for the virus from the nasal epithelium, possibly via innervation of Bowman's glands, to brain targets, including the telencephalon and diencephalon. This possibility needs to be examined in suitable animal models and in human tissues.

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