Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion.
Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion.
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DOI：
10.1126/sciimmunol.abl9929
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发表时间：
2022-01-28
影响因子：
24.8
通讯作者：
Iannacone, Matteo
中科院分区：
文献类型：
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作者：
Fumagalli, Valeria;Rava, Micol;Marotta, Davide;Di Lucia, Pietro;Laura, Chiara;Sala, Eleonora;Grillo, Marta;Bono, Elisa;Giustini, Leonardo;Perucchini, Chiara;Mainetti, Marta;Sessa, Alessandro;Garcia-Manteiga, Jose M.;Donnici, Lorena;Manganaro, Lara;Delbue, Serena;Broccoli, Vania;De Francesco, Raffaele;D'Adamo, Patrizia;Kuka, Mirela;Guidotti, Luca G.;Iannacone, Matteo
开发一种易于控制的小动物模型，忠实地再现人类COVID-19的发病机制，可以说是满足生物医学研究的迫切需要。到目前为止，大多数研究人员使用的是在上皮细胞中表达人类ACE2的转基因小鼠（K18-hACE2转基因小鼠），这些小鼠在深度麻醉下经鼻注入液体SARS-CoV-2悬浮液。不幸的是，这种实验方法导致不成比例的高中枢神经系统感染导致致命的脑炎，这在人类中很少观察到，严重限制了该模型的实用性。在这里，我们描述了一种吸入塔系统的使用，该系统允许在受控条件下将未麻醉的小鼠暴露于雾化的病毒。K18-hACE2转基因小鼠气溶胶暴露于SARS-CoV-2可导致病毒在呼吸道的强劲复制、嗅觉缺失和气道阻塞，但不会导致致命的病毒神经侵袭。与鼻内接种相比，气溶胶感染导致更明显的肺部病理，包括免疫浸润增加、纤维蛋白沉积和与sars - cov -2感染患者相似的转录特征。该模型可能有助于研究病毒传播、疾病发病机制（包括SARS-CoV-2感染的长期后果）和治疗干预措施。K18-hACE2小鼠气溶胶暴露于SARS-CoV-2可导致呼吸道感染和嗅觉丧失，但不会导致致命的神经侵袭。
The development of a tractable small animal model faithfully reproducing human COVID-19 pathogenesis would arguably meet a pressing need in biomedical research. Thus far, most investigators have used transgenic mice expressing the human ACE2 in epithelial cells (K18-hACE2 transgenic mice) that are intranasally instilled with a liquid SARS-CoV-2 suspension under deep anesthesia. Unfortunately, this experimental approach results in disproportionate high CNS infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness. Here, we describe the use of an inhalation tower system that allows exposure of unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction, but did not lead to fatal viral neuroinvasion. When compared to intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition and a transcriptional signature comparable to that observed in SARS-CoV-2-infected patients. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection) and therapeutic interventions. Aerosol exposure of K18-hACE2 mice to SARS-CoV-2 leads to respiratory infection and anosmia but not to fatal neuroinvasion.
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影响因子：
64.8
作者：
Delorey TM;Ziegler CGK;Heimberg G;Normand R;Yang Y;Segerstolpe Å;Abbondanza D;Fleming SJ;Subramanian A;Montoro DT;Jagadeesh KA;Dey KK;Sen P;Slyper M;Pita-Juárez YH;Phillips D;Biermann J;Bloom-Ackermann Z;Barkas N;Ganna A;Gomez J;Melms JC;Katsyv I;Normandin E;Naderi P;Popov YV;Raju SS;Niezen S;Tsai LT;Siddle KJ;Sud M;Tran VM;Vellarikkal SK;Wang Y;Amir-Zilberstein L;Atri DS;Beechem J;Brook OR;Chen J;Divakar P;Dorceus P;Engreitz JM;Essene A;Fitzgerald DM;Fropf R;Gazal S;Gould J;Grzyb J;Harvey T;Hecht J;Hether T;Jané-Valbuena J;Leney-Greene M;Ma H;McCabe C;McLoughlin DE;Miller EM;Muus C;Niemi M;Padera R;Pan L;Pant D;Pe'er C;Pfiffner-Borges J;Pinto CJ;Plaisted J;Reeves J;Ross M;Rudy M;Rueckert EH;Siciliano M;Sturm A;Todres E;Waghray A;Warren S;Zhang S;Zollinger DR;Cosimi L;Gupta RM;Hacohen N;Hibshoosh H;Hide W;Price AL;Rajagopal J;Tata PR;Riedel S;Szabo G;Tickle TL;Ellinor PT;Hung D;Sabeti PC;Novak R;Rogers R;Ingber DE;Jiang ZG;Juric D;Babadi M;Farhi SL;Izar B;Stone JR;Vlachos IS;Solomon IH;Ashenberg O;Porter CBM;Li B;Shalek AK;Villani AC;Rozenblatt-Rosen O;Regev A
通讯作者：
Regev A
影响因子：
13.6
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影响因子：
5.8
作者：
Fodoulian L;Tuberosa J;Rossier D;Boillat M;Kan C;Pauli V;Egervari K;Lobrinus JA;Landis BN;Carleton A;Rodriguez I
通讯作者：
Rodriguez I
影响因子：
2.7
作者：
Klingenstein, Moritz;Klingenstein, Stefanie;Milazzo, Alfio
通讯作者：
Milazzo, Alfio
影响因子：
64.5
作者：
Karki R;Sharma BR;Tuladhar S;Williams EP;Zalduondo L;Samir P;Zheng M;Sundaram B;Banoth B;Malireddi RKS;Schreiner P;Neale G;Vogel P;Webby R;Jonsson CB;Kanneganti TD
通讯作者：
Kanneganti TD