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

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.

Tracking inflammation resolution signatures in lungs after SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice

“…As described previously [52, 67, 68], most mice in the BA.1/K18-hACE2 model do not develop a brain infection. Brain infection is associated with >20% weight loss and an ensuing ethical requirement for euthanasia (S1a Fig).…”

“…Brain infection is associated with >20% weight loss and an ensuing ethical requirement for euthanasia (S1a Fig). After infection of K18-hACE2 mice with original strain isolates, mice succumb to brain infections between 4 and 7 dpi [52, 60]. This BA.1 model thus provides a significant lung infection, and permits analysis of long term responses to SARS-CoV-2.…”

“…Heterozygous K18-hACE2 mice (strain B6.Cg-Tg(K18-ACE2)2Prlmn/J, JAX Stock No: 034860) were purchased from The Jackson Laboratory, USA, and were maintained in-house as heterozygotes by backcrossing to C57BL/6J mice (Animal Resources Center, Canning Vale WA, Australia). Heterozygotes were inter-crossed to generate homozygous K18-hACE2 mice (on a C57BL/6J background [53, 59]) as described [52, 53]. Mice were held under standard animal house conditions (for details see [55]) and homozygous female mice received intrapulmonary infections delivered via the intranasal route with 5×10 4 CCID 50 of virus in 50 μl RPMI 1640 whilst under light anesthesia as described [60].…”

“…Herein we provide the transcriptional profile of lung infection over time in a model of SARS-CoV-2 omicron BA.1 infection of K18-hACE2 mice, wherein the majority of mice showed no significant overt signs or symptoms of disease [52]. The acute phase was characterised by a significant lung infection and a pattern of proinflammatory cytokine signatures differing only slightly from those reported previously [53].…”

TMEM106B-mediated SARS-CoV-2 infection allows for robust ACE2-independent infectionin vitrobut notin vivo

“…K18-hACE2 mice express the human ACE2 receptor from the K18 promoter, which was an important mouse model for original SARS-CoV-2 as the spike of this virus does not engage mouse ACE2 32 . K18-hACE2 mice allow for SARS-CoV-2 to enter the brain via infection of the olfactory epithelium 33,34 , often leading to fulminant brain infection 30 .…”