Neuroinvasion and neurotropism by SARS-CoV-2 variants in the K18-hACE2 mouse



Seehusen, Frauke, Clark, Jordan ORCID: 0000-0003-1790-7883, Sharma, Parul, Bentley, Eleanor, Kirby, Adam, Subramaniam, Krishanthi ORCID: 0000-0002-7567-7185, Subramaniam, Krishanthi ORCID: 0000-0002-1734-9351, Giuliani, Sabina Wunderlin, Hughes, Grant, Patterson, Edward
et al (show 5 more authors) (2021) Neuroinvasion and neurotropism by SARS-CoV-2 variants in the K18-hACE2 mouse. [Preprint]

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Abstract

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) not only affects the respiratory tract but also causes neurological symptoms such as loss of smell and taste, headache, fatigue or severe cerebrovascular complications. Using transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) we investigated the spatiotemporal distribution and pathomorphological features in the CNS following intranasal infection with SARS-CoV-2 variants, also after prior influenza A virus infection. Apart from Omicron, we found all variants to frequently spread to and within the CNS. Infection was restricted to neurons and appeared to spread from the olfactory bulb mainly in basally orientated regions in the brain and into the spinal cord, independent of ACE2 expression and without evidence of neuronal cell death, axonal damage or demyelination. However, microglial activation, microgliosis and a mild macrophage and T cell dominated inflammatory response was consistently observed, accompanied by apoptotic death of endothelial, microglial and immune cells, without their apparent infection. Microgliosis and immune cell apoptosis indicate a potential role of microglia for pathogenesis and viral effect in COVID-19 and possible impairment of neurological functions, especially in long COVID. These data may also be informative for the selection of therapeutic candidates, and broadly support investigation of agents with adequate penetration into relevant regions of the CNS.

Item Type: Preprint
Uncontrolled Keywords: Infectious Diseases, Neurodegenerative, Pneumonia & Influenza, Pneumonia, Neurosciences, Emerging Infectious Diseases, Lung, Brain Disorders, 2 Aetiology, 2.1 Biological and endogenous factors, Neurological, Infection
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User: Symplectic Admin
Date Deposited: 26 Apr 2021 09:20
Last Modified: 14 Mar 2024 19:09
DOI: 10.1101/2021.04.16.440173
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3120297