Increased neurovirulence of omicron BA.5 over BA.1 in human brain organoids and K18-hACE2 mice

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 remains controversial. We show that a BA.5 isolate was significantly more pathogenic in K18-hACE2 mice than a BA.1 isolate, with BA.5 infections showing increased neuroinvasiveness, resulting in 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. Evidence for brain infection and brain damage in certain COVID-19 patients is becoming compelling, with the results herein illustrating the increasing intrinsic neuropathogenic potential of evolving omicron variants.

Neurovirulence of the Australian outbreak Japanese Encephalitis virus genotype 4 is lower compared to genotypes 2 and 3 in mice and human cortical brain organoids

“…Human cortical brain organoids (hBOs) have been used to investigate the pathogenesis of flaviviruses, including JEV and ZIKV (21, 62, 63). We generated ∼30 day old hBOs from adult human dermal fibroblast (HDFa) cells, growing the hBOs in a CelVivo Clinostar incubator as described (32) (Figure 7A). hBOs were infected with 10 5 CCID 50 of the indicated JEV and MVEV isolates, as well as (i) the Imojev chimeric virus vaccine (previously called ChimeriVax-JE) comprising the prME genes of the attenuated JEV SA14-14-2 strain on the YFV 17D backbone (33, 64) and (ii) the Yellow Fever live attenuated vaccine strain (YFV 17D) (30), with wild-type YFV infection (65), and occasionally YFV 17D vaccination (66), able to cause neuropathology.…”

“…hBOs were reprogrammed from adult dermal fibroblasts (HDFa, Gibco, C0135C) using the CytoTune-iPS 2.0 Sendai Reprogramming Kit (Invitrogen, A16518) (31), and were grown using the CelVivo Clinostar incubator (Invitro Technologies) as described (32). On the day of infection, ∼30-day-old hBOs were transferred from each Clinoreactor into an ultra-low-binding 24 well plate (one hBO per well), and each hBO was infected with 10 5 CCID 50 of either JEV Nakayama , JEV FU , JEV NSW/22 , MVEV TC123130 , Imojev (33), or YFV 17D (30) for ∼4 hrs.…”