The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice

Bao, Linlin; Deng, Wei; Huang, Baoying; Gao, Hong; Liu, Jiangning; Ren, Lili; Wang, Qiang; Yü, Ping; Xu, Yanfeng; Qi, Feifei; Qu, Yajin; Li, Fengdi; Lv, Qi; Wang, Wenling; Xue, Jing; Gong, Shuran; Liu, Mingya; Wang, Guanpeng; Wang, Shunyi; Song, Zhiqi; Zhao, Linna; Li, Peipei; Zhao, Li; Ye, Fei; Wang, Huijuan; Zhou, Weimin; Zhu, Na; Wei, Zhen; Yu, Haisheng; Zhang, Xiaojuan; Guo, Li; Chen, Lan; Wang, Conghui; Wang, Ying; Wang, Xinming; Xiao, Yan; Sun, Qiangming; Liu, Hongqi; Zhu, Fanli; Ma, Chang–Jin; Liu, Yan; Yang, Mengli; Han, Jun; Xu, Wenbo; Tan, Wenjie; Jin, Qi; Wu, Guizhen; Qin, Chuan

doi:10.1038/s41586-020-2312-y

Cited by 1,035 publications

(777 citation statements)

References 9 publications

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“…19 In addition, viral antigens were also detected in macrophages infiltrated into the alveolar interstitium and cavities of SARS-CoV-2-infected hACE2-expressing mice. 20 Moreover, immunofluorescent double staining showed that IL-6 is primarily produced by infected macrophages. 17 These observations suggest that SARS-CoV-2 can also enter into monocytes/macrophages, 21 possibly through the Fc receptor.…”

Section: Ade Can Explain Characteristics Of Severe Covid-19mentioning

confidence: 99%

Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines

Zheng¹,

Liu

2020

Journal of Medical Virology

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Coronavirus disease 2019 (COVID-19) has become a major global public health concern. The mortality rate for critically ill patients is up to 60%, and, thus, reducing the disease severity and case mortality is a top priority. Currently, cytokine storms are considered as the major cause of critical illness and death due to COVID-19.After a systematical review of the literature, we propose that cross-reactive antibodies associated with antibody-dependent enhancement (ADE) may actually be the cause of cytokine storms. It would be more difficult to develop vaccines for highly pathogenic human coronaviruses (CoVs) if ADE characteristics are taken into consideration. Therefore, it is urgent to find an effective way to prevent the occurrence of severe illness as severe acute respiratory syndrome CoV-2 specific drugs or vaccines are still in development. If the activation of memory B cells can be selectively inhibited in high-risk patients at an early stage of COVID-19 to reduce the production of cross-reactive antibodies against the virus, we speculate that ADE can be circumvented and severe symptoms can be prevented. The mammalian target of rapamycin (mTOR) inhibitors satisfy such needs and it is recommended to conduct clinical trials for mTOR inhibitors in preventing the severity of COVID-19. K E Y W O R D S ADE, antibody-dependent enhancement, coronavirus, cross-reactive antibody, cytokine storm, immunity, mTOR inhibitors, rapamycin How to cite this article: Zheng Y, Li R, Liu S. Immunoregulation with mTOR inhibitors to prevent COVID-19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines.

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Section: Ade Can Explain Characteristics Of Severe Covid-19mentioning

confidence: 99%

Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines

Zheng¹,

Liu

2020

Journal of Medical Virology

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“…Four other hACE2-expressing mouse lines have been created to date and tested for the ability to support SARS-CoV-2 infection (Lutz, 2020). Two lines express the hACE2 gene under the control of the mouse ACE2 promotor (Bao et al, 2020); one was made using CRISPR/Cas9 technology (Sun et al, 2020). The third strain uses the lung ciliated epithelial cell HFH4 promoter (Menachery et al, 2016) (Dinnon et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of K18-hACE2mice as a model of SARS-CoV-2 infection

Moreau

Burgess

Sturek

et al. 2020

Preprint

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Abstract/SummaryMurine models of SARS-CoV-2 infection are critical for elucidating the biological pathways underlying COVID-19 disease. Because human ACE2 is the receptor for SARS-CoV-2, mice expressing the human ACE2 gene have shown promise as a potential model for COVID-19. Five mice from the transgenic mouse strain K18-hACE2 were intranasally inoculated with SARS-CoV-2 Hong Kong/VM20001061/2020. Mice were followed twice daily for five days and scored for weight loss and clinical symptoms. Infected mice did not exhibit any signs of infection until day four, when weight loss, but no other obvious clinical symptoms were observed. By day five all infected mice had lost around 10% of their original body weight, but exhibited variable clinical symptoms. All infected mice showed high viral titers in the lungs as well as altered lung histology associated with proteinaceous debris in the alveolar space, interstitial inflammatory cell infiltration and alveolar septal thickening. Overall, these results show that symptomatic SARS-CoV-2 infection can be established in the K18-hACE2 transgenic background and should be a useful mouse model for COVID-19 disease.

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“…However, no monkey developed severe symptoms during the study [58]. In a study using a mouse model, transgenic mice with human ACE2 expression, but not wild-type mice, were found to be susceptible to SARS-CoV-2 infection [59]. Mice inoculated with SARS-CoV-2 through the intranasal route had a 5-10% loss of body weight and histopathology in the lung, such as interstitial pneumonia and infiltration of immune cells.…”

Section: In Vivo Models For Testing Sars-cov-2 Neutralizing Antibodiesmentioning

confidence: 98%

“…Monkey and mouse models have been reported for testing SARS-CoV-2-neutralizing antibodies [58][59][60]. In the monkey study, researchers found that rhesus macaques infected with SARS-CoV-2 through the intratracheal route had mild illness, and their lungs showed signs of pneumonia similar to those in humans with COVID-19 [58].…”

Section: In Vivo Models For Testing Sars-cov-2 Neutralizing Antibodiesmentioning

confidence: 99%

“…Mice inoculated with SARS-CoV-2 through the intranasal route had a 5-10% loss of body weight and histopathology in the lung, such as interstitial pneumonia and infiltration of immune cells. No mice died during the study [59]. To establish a model that can mimic more severe human infections, different animal models and other experimental factors must be considered and tested.…”

Section: In Vivo Models For Testing Sars-cov-2 Neutralizing Antibodiesmentioning

confidence: 99%

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Antibody therapies for the treatment of COVID-19

Salazar

et al. 2020

Antibody Therapeutics

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The outbreak of COVID-19, the disease caused by infection of the coronavirus SARS-CoV-2 that began in December 2019 in Wuhan, China, has caused more than 2 990 559 confirmed human infections and 207 446 deaths as of 27 April 2020 (Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University). Scientists are working quickly on multiple aspects of the pandemic. Genetic analyses are conducted to reveal the source and evolution of SARS-CoV-2, providing knowledge that can be used to contain it and to avoid future outbreaks. Epidemiological studies that incorporate lessons learned from outbreaks of previous related viral diseases can guide the development of public health measures effective to contain the current and future outbreaks. Basic virology studies reveal viral structure and function. Pathology studies inform the development of strategies to interfere with infection. COVID-19 prevention and treatment strategies are being developed in preclinical and clinical studies. Antibody-based therapy is one viable treatment option. Here, we discuss some of the most active areas of developing strategies to treat COVID-19, focusing on the approaches to generate neutralizing antibodies against SARS-CoV-2 for prophylactic and therapeutic treatment of COVID-19. Statement of Significance:The development of SARS-CoV-2 neutralizing antibodies with the desired efficacy and safety profile is a critical part of the toolbox of therapies for the treatment of COVID-19. We discuss in this review the current state of discovery and development of such antibodies.

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The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice

Abstract: Cite this article as: Bao, L. et al. The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice. Nature https://doi.

Cited by 1,035 publications

References 9 publications

Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines

Immunoregulation with mTOR inhibitors to prevent COVID‐19 severity: A novel intervention strategy beyond vaccines and specific antiviral medicines

Evaluation of K18-hACE2mice as a model of SARS-CoV-2 infection

Antibody therapies for the treatment of COVID-19

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