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 neuroinvasiveness, 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. Although fulminant brain infection is not a feature of COVID-19, evidence for brain infection and brain damage in some COVID-19 patients with severe disease is becoming compelling, with the results herein suggesting that evolving omicron variants may have increasing intrinsic neuropathogenic potential.

中文翻译：

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与 BA.1 相比，omicron BA.5 和 XBB 变体在 K18-hACE2 小鼠和人脑类器官中的神经毒力增强

与早期变体相比，omicron BA.1 亚谱系的致病性降低已得到充分描述，尽管后来的变体（如 BA.5 和 XBB）是否保留这种减弱作用仍存在争议。我们发现，BA.5 和 XBB 分离株对 K18-hACE2 小鼠的致病性明显高于 BA.1 分离株，显示出神经侵袭性增加，导致暴发性脑部感染和死亡，与原始祖先分离株相似。BA.5 还比 BA.1 和原始祖先分离株更大程度地感染人皮质脑类器官。在小鼠大脑中，神经元是感染的主要目标，而在人类类器官中，神经元祖细胞和未成熟神经元被感染。尽管暴发性脑部感染不是 COVID-19 的特征，