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肥胖和代谢功能障碍在感染SARS-CoV-2的hACE2小鼠中导致与性别相关的疾病差异特征。

Obesity and metabolic dysfunction drive sex-associated differential disease profiles in hACE2-mice challenged with SARS-CoV-2.

作者信息

Lee Katherine S, Russ Brynnan P, Wong Ting Y, Horspool Alexander M, Winters Michael T, Barbier Mariette, Bevere Justin R, Martinez Ivan, Damron F Heath, Cyphert Holly A

机构信息

Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV, USA.

Vaccine Development Center at West Virginia University Health Sciences Center, Morgantown, WV, USA.

出版信息

iScience. 2022 Oct 21;25(10):105038. doi: 10.1016/j.isci.2022.105038. Epub 2022 Sep 2.

DOI:10.1016/j.isci.2022.105038
PMID:36068847
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9436780/
Abstract

Severe outcomes from SARS-CoV-2 infection are highly associated with preexisting comorbid conditions like hypertension, diabetes, and obesity. We utilized the diet-induced obesity (DIO) model of metabolic dysfunction in K18-hACE2 transgenic mice to model obesity as a COVID-19 comorbidity. Female DIO, but not male DIO mice challenged with SARS-CoV-2 were observed to have shortened time to morbidity compared to controls. Increased susceptibility to SARS-CoV-2 in female DIO was associated with increased viral RNA burden and interferon production compared to males. Transcriptomic analysis of the lungs from all mouse cohorts revealed sex- and DIO-associated differential gene expression profiles. Male DIO mice after challenge had decreased expression of antibody-related genes compared to controls, suggesting antibody producing cell localization in the lung. Collectively, this study establishes a preclinical comorbidity model of COVID-19 in mice where we observed sex- and diet-specific responses that begin explaining the effects of obesity and metabolic disease on COVID-19 pathology.

摘要

严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染导致的严重后果与高血压、糖尿病和肥胖等既往存在的合并症高度相关。我们利用K18-hACE2转基因小鼠的饮食诱导肥胖（DIO）代谢功能障碍模型，将肥胖作为2019冠状病毒病（COVID-19）的一种合并症进行建模。与对照组相比，感染SARS-CoV-2的雌性DIO小鼠发病时间缩短，而雄性DIO小鼠则未观察到这一现象。与雄性相比，雌性DIO小鼠对SARS-CoV-2易感性增加与病毒RNA载量增加和干扰素产生增加有关。对所有小鼠队列的肺组织进行转录组分析，揭示了与性别和DIO相关的差异基因表达谱。与对照组相比，受攻击后的雄性DIO小鼠抗体相关基因的表达降低，提示抗体产生细胞定位于肺组织。总体而言，本研究在小鼠中建立了一种COVID-19临床前合并症模型，我们在该模型中观察到了性别和饮食特异性反应，这些反应开始解释肥胖和代谢疾病对COVID-19病理的影响。

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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb90/9485072/7b92615de157/fx1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb90/9485072/3dab176a8a61/gr1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb90/9485072/e4a6c3071dc2/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb90/9485072/c21da9c58cad/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/cb90/9485072/eaf74aa001f8/gr7.jpg
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