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小鼠新冠后急性后遗症中的持续性神经功能缺损揭示了抗病毒药物的局限性

Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations.

作者信息

Verma Abhishek Kumar, Lowery Shea, Lin Li-Chin, Duraisami Eazhisaivallabi, Lloréns Juan E Abrahante, Qiu Qiang, Hefti Marco, Yu C Ron, Albers Mark W, Perlman Stanley

机构信息

Department of Microbiology and Immunology, University of Iowa, Iowa City, IA 52242.

Iowa Neuroscience Institute, University of Iowa, IA, USA 52242.

出版信息

bioRxiv. 2024 Jun 3:2024.06.02.596989. doi: 10.1101/2024.06.02.596989.

DOI:10.1101/2024.06.02.596989
PMID:38895239
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11185538/
Abstract

Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation.

摘要

新冠后遗症（PASC）包括持续的神经症状，如嗅觉和自主神经功能障碍。在此，我们报告感染了一种适应小鼠的高致病性SARS-CoV-2（该病毒不感染大脑）的小鼠出现慢性神经功能障碍。在从鼻腔感染中恢复很久之后，我们观察到嗅球肾小球中酪氨酸羟化酶（TH）表达缺失，且黑质（SN）中的神经递质水平持续存在。这些脑区中多巴胺能神经元的易损性伴随着促炎细胞因子水平的升高和神经行为变化。RNA测序分析揭示了持续的小胶质细胞激活，这在人类神经退行性疾病中也有发现。抗病毒药物（奈玛特韦和莫努匹韦）的早期治疗降低了病毒滴度和肺部炎症，但未能预防如患者中所观察到的神经异常。这些结果共同表明，SARS-CoV-2感染小鼠的神经元功能慢性缺陷与持续的嗅觉上皮功能障碍没有直接联系。相反，它们与神经退行性疾病相似，慢性炎症炎症会加剧了其易损性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/da2d6a0a824b/nihpp-2024.06.02.596989v1-f0007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/36ef49b310b8/nihpp-2024.06.02.596989v1-f0004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/27045872b205/nihpp-2024.06.02.596989v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/da2d6a0a824b/nihpp-2024.06.02.596989v1-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/958480c98efa/nihpp-2024.06.02.596989v1-f0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/c306a8c07473/nihpp-2024.06.02.596989v1-f0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/4333b8eac1f0/nihpp-2024.06.02.596989v1-f0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/7568d3750512/nihpp-2024.06.02.596989v1-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/1dab98314299/nihpp-2024.06.02.596989v1-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/0c8fc34d35c9/nihpp-2024.06.02.596989v1-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/36ef49b310b8/nihpp-2024.06.02.596989v1-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/330350efd1fb/nihpp-2024.06.02.596989v1-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/27045872b205/nihpp-2024.06.02.596989v1-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/405f/11185538/da2d6a0a824b/nihpp-2024.06.02.596989v1-f0007.jpg

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