SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids

Romal Stewart; Kexin Yan; Sevannah A Ellis; Cameron R Bishop; Troy Dumenil; Bing Tang; Wilson Nguyen; Thibaut Larcher; Rhys Parry; Julian De Jun Sng; Alexander A Khromykh; Robert K P Sullivan; Mary Lor; Frédéric A Meunier; Daniel J Rawle; Andreas Suhrbier

doi:10.3389/fmicb.2023.1320856

SARS-CoV-2 omicron BA.5 and XBB variants have increased neurotropic potential over BA.1 in K18-hACE2 mice and human brain organoids

Front Microbiol. 2023 Nov 23:14:1320856. doi: 10.3389/fmicb.2023.1320856. eCollection 2023.

Authors

Romal Stewart^#¹, Kexin Yan^#¹, Sevannah A Ellis^#², Cameron R Bishop^#¹, Troy Dumenil^#¹, Bing Tang¹, Wilson Nguyen¹, Thibaut Larcher³, Rhys Parry⁴, Julian De Jun Sng⁴, Alexander A Khromykh^{4

5}, Robert K P Sullivan², Mary Lor¹, Frédéric A Meunier^{2

5}, Daniel J Rawle¹, Andreas Suhrbier^{1

5}

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
² Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia.
³ INRAE, Oniris, PAnTher, APEX, Nantes, France.
⁴ School of Chemistry and Molecular Biosciences, University of Queensland, St Lucia, QLD, Australia.
⁵ GVN Centre of Excellence, Australian Infectious Disease Research Centre, Brisbane, QLD, Australia.

^# Contributed equally.

Abstract

The reduced pathogenicity of the omicron BA.1 sub-lineage compared to earlier variants is well described, although whether such attenuation is retained for later variants like BA.5 and XBB remains controversial. We show that BA.5 and XBB isolates were significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, showing increased neurotropic potential, resulting in fulminant brain infection and mortality, similar to that seen for original ancestral isolates. BA.5 also infected human cortical brain organoids to a greater extent than the BA.1 and original ancestral isolates. In the brains of mice, neurons were the main target of infection, and in human organoids neuronal progenitor cells and immature neurons were infected. The results herein suggest that evolving omicron variants may have increasing neurotropic potential.

Keywords: BA.5; K18-hACE2; SARS-CoV-2; XBB; brain; omicron; organoid.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The authors thank the Brazil Family Foundation (and others) for their generous philanthropic donations that helped set up the PC3 (BSL3) SARS-CoV-2 research facility at QIMR Berghofer MRI, as well as ongoing research into SARS-CoV-2, COVID-19 and long-COVID. We acknowledge the intramural grant awarded to RS and DR from QIMR Berghofer MRI to allow purchase of the CelVivo Clinostar incubator. AS is supported by the National Health and Medical Research Council (NHMRC) of Australia (Investigator grant APP1173880). FM was supported by NHMRC Project grant APP2010917, a Senior Research Fellowship APP1155794, and the Queensland Research Stimulus Package. AK was supported by an NHMRC Ideas Grant APP2012883. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.