Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment

Sun, Jing; Zhuang, Zhen; Zheng, Jian; Li, Kun; Wong, Lok-Yin Roy; Liu, Donglan; Huang, Jicheng; He, Jiangping; Zhu, Airu; Zhao, Jingxian; Li, Xiaobo; Xi, Yin; Chen, Rongchang; Alshukairi, Abeer N.; Zhao, Chen; Zhang, Zhaoyong; Chen, Chunke; Huang, Xiaofang; Li, Fang; Lai, Xiaomin; Chen, Dingbin; Wen, Liyan; Zhuo, Jianfen; Zhang, Yanjun; Wang, Yanqun; Huang, Shuxiang; Dai, Jun; Shi, Yongxia; Zheng, Kui; Leidinger, Mariah; Chen, Jiekai; Li, Yimin; Zhong, Nanshan; Meyerholz, David K.; McCray, Paul B.; Perlman, Stanley

doi:10.1016/j.cell.2020.06.010

Cited by 438 publications

(595 citation statements)

References 43 publications

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“…Other caveats of the Ad-hACE2 animal model include the non-uniform transduction of the lung epithelium (and consequently, non-uniform expression of hACE2 in the mouse lung), the possibility of triggering nonspecific inflammatory responses if used at doses higher than 2.5x10 8 PFU -or with poorly prepared Ad stocks which have large quantities of empty capsids, and the potential lack of suitability for use of the Ad-hACE2 model in immunization studies using non-replicating Ad vaccines for SARS-CoV-2. However, with this in mind, we describe the successful use of a dose of Ad-hACE2 (7.5x10 7 PFU) which supports equivalent replication of SARS-CoV-2 in the lung to the previously reported higher dose (33,61). Most importantly, the flexibility of the Ad-hACE2 model allows studies of multiple mouse strains immediately, without time-consuming breeding to a hACE2 transgenic or knock-in background.…”

Section: Discussionmentioning

confidence: 74%

Comparison of Transgenic and Adenovirus hACE2 Mouse Models for SARS-CoV-2 Infection

Rathnasinghe

Strohmeier

Amanat

et al. 2020

Preprint

134

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AbstractSevere acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide pandemic with high morbidity and mortality. Development of animal models that recapitulate important aspects of coronavirus disease 2019 (COVID-19) is critical for the evaluation of vaccines and antivirals, and understanding disease pathogenesis. SARS-CoV-2 has been shown to use the same entry receptor as SARS-CoV-1, human angiotensin-converting enzyme 2 (hACE2)(1-3). Due to amino acid differences between murine and hACE2, inbred mouse strains fail to support high titer viral replication of SARS-CoV-2 virus. Therefore, a number of transgenic and knock-in mouse models, as well as viral vector-mediated hACE2 delivery systems have been developed. Here we compared the K18-hACE2 transgenic model to adenovirus-mediated delivery of hACE2 to the mouse lung. We show that K18-hACE2 mice replicate virus to high titers in both the lung and brain leading to lethality. In contrast, adenovirus-mediated delivery results in viral replication to lower titers limited to the lung, and no clinical signs of infection with a challenge dose of 104 plaque forming units. The K18-hACE2 model provides a stringent model for testing the ability of vaccines and antivirals to protect against disease, whereas the adenovirus delivery system has the flexibility to be used across multiple genetic backgrounds and modified mouse strains.

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Section: Discussionmentioning

confidence: 74%

Comparison of Transgenic and Adenovirus hACE2 Mouse Models for SARS-CoV-2 Infection

Rathnasinghe

Strohmeier

Amanat

et al. 2020

Preprint

134

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“…T cell immunity has been shown to be an important mediator of protection against betacoronaviruses, and recent studies have specifically identified a role in protection against COVID-19 disease (Channappanavar et al, 2014a;Channappanavar et al, 2014b;Sekine et al, 2020;Sun et al, 2020). Sekine et al reported SARS-CoV-2-reactive T cells in asymptomatic and mild COVID-19 convalescent patients who were antibody seronegative (Sekine et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Intradermal-delivered DNA vaccine provides anamnestic protection in a rhesus macaque SARS-CoV-2 challenge model

Patel

Walters

Reuschel

et al. 2020

Preprint

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SummaryCoronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a dramatic global impact on public health, social, and economic infrastructures. Here, we assess immunogenicity and anamnestic protective efficacy in rhesus macaques of the intradermal (ID)-delivered SARS-CoV-2 spike DNA vaccine, INO-4800. INO-4800 is an ID-delivered DNA vaccine currently being evaluated in clinical trials. Vaccination with INO-4800 induced T cell responses and neutralizing antibody responses against both the D614 and G614 SARS-CoV-2 spike proteins. Several months after vaccination, animals were challenged with SARS-CoV-2 resulting in rapid recall of anti-SARS-CoV-2 spike protein T and B cell responses. These responses were associated with lower viral loads in the lung and with faster nasal clearance of virus. These studies support the immune impact of INO-4800 for inducing both humoral and cellular arms of the adaptive immune system which are likely important for providing durable protection against COVID-19 disease.

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“…Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in Hubai province in mainland China in December 2019, and is the etiological agent of coronavirus disease (COVID)- 19 (1). SARS-CoV-2 can cause asymptomatic to severe lower respiratory tract infections in humans, with early clinical signs including fever, cough and dyspnea (2,3).…”

Section: Introductionmentioning

confidence: 99%

K18-hACE2 mice develop respiratory disease resembling severe COVID-19

Yinda

Port

Bushmaker

et al. 2020

Preprint

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SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 104 TCID50 or 105 TCID50, the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 105 TCID50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Taken together, this suggests that this mouse model can be useful for studies of pathogenesis and medical countermeasure development.

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Generation of a Broadly Useful Model for COVID-19 Pathogenesis, Vaccination, and Treatment

Cited by 438 publications

References 43 publications

Comparison of Transgenic and Adenovirus hACE2 Mouse Models for SARS-CoV-2 Infection

Comparison of Transgenic and Adenovirus hACE2 Mouse Models for SARS-CoV-2 Infection

Intradermal-delivered DNA vaccine provides anamnestic protection in a rhesus macaque SARS-CoV-2 challenge model

K18-hACE2 mice develop respiratory disease resembling severe COVID-19

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