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; Peng, Xiaozhong; Jin, Qi; Wu, Guizhen; Qin, Chuan

doi:10.1101/2020.02.07.939389

Cited by 441 publications

(632 citation statements)

References 10 publications

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“…However, while plasma from mice infected with SARS-CoV virus could react with its autologous S ectodomain (p-value < 8e-6, two-tailed t-test, Figure 2C) and RBD (p-value < 2e-5, two-tailed t-test, Figure 2D), the reactivity of plasma from mice infected with SARS-CoV-2 virus to its autologous S ectodomain and RBD could not be observed in this assay (p-value > 0.28, two-tailed t-test, Figure 2A-B). Unlike SARS-CoV virus, which can replicate in wild-type mice (Yang et al, 2004), it has been recently shown that SARS-CoV-2 is only able to replicate in human ACE2-expression transgenic mice but not wild-type mice (Bao et al, 2020), which then can explain the weak immune response from SARS-CoV-2-infected wild-type mice in this study.…”

Section: Resultsmentioning

confidence: 69%

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

Tsang

et al. 2020

Preprint

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26The World Health Organization has recently declared the ongoing outbreak of COVID-27 19, which is caused by a novel coronavirus SARS-CoV-2, as pandemic. There is 28 currently a lack of knowledge in the antibody response elicited from SARS-CoV-2 29 infection. One major immunological question is concerning the antigenic differences 30 between SARS-CoV-2 and SARS-CoV. We address this question by using plasma from 31 patients infected by SARS-CoV-2 or SARS-CoV, and plasma obtained from infected or 32 immunized mice. Our results show that while cross-reactivity in antibody binding to the 33 spike protein is common, cross-neutralization of the live viruses is rare, indicating the 34 presence of non-neutralizing antibody response to conserved epitopes in the spike. 35Whether these non-neutralizing antibody responses will lead to antibody-dependent 36 disease enhancement needs to be addressed in the future. Overall, this study not only 37 addresses a fundamental question regarding the antigenicity differences between 38 SARS-CoV-2 and SARS-CoV, but also has important implications in vaccine 39 development. : bioRxiv preprint 4 polyclonal human sera from patients to evaluate the antibody response elicited by 67 SARS-CoV-2 infection and to determine whether cross-reactive antibody responses 68 between SARS-CoV-2 and SARS-CoV can be generated. In this study, we examined the 69 antibody responses in 15 patients from Hong Kong who were infected by SARS-CoV-2, 70 and seven by SARS-CoV. Mice infected or immunized with SARS-CoV-2 or SARS-CoV 71 were also used to investigate cross-reactivity of antibody responses between SARS-72 CoV-2 and SARS-CoV. 73 74 Results 75 Patient samples show cross-reactivity in binding 76 Fifteen heparin anticoagulated plasma samples (from day 2 to 22 post-symptom onset) 77 from SARS-CoV-2 infected patients were analyzed (Table S1). Binding of plasma to the 78 S ectodomain and RBD of both SARS-CoV-2 and SARS-CoV (see Methods) was 79 measured by ELISA ( Figure 1B, Figure S1). Plasma samples from healthy donors 80 collected from the Hong Kong Red Cross served as controls. As compared to the 81 plasma from healthy donors, plasma from patients from day 10 post-symptom onward 82 reacted strongly in ELISA binding assays to the S ectodomain (p-value < 2e-16, two-83 tailed t-test) and RBD (p-value = 2e-13, two-tailed t-test) of SARS-CoV-2. Interestingly, 84 the plasma from SARS-CoV-2-infected patients could also cross-react, although less 85 strongly, with the SARS-CoV S ectodomain (p-value = 8e-06, two-tailed t-test) and the 86 SARS-CoV RBD (p-value = 0.048, two-tailed t-test) ( Figure 1B). Nevertheless, only five 87 of the samples from the SARS-CoV-2-infected patients had convincing antibody binding 88 responses to the SARS-CoV RBD. The other plasma reacted more weakly or not at all 89 with the SARS-CoV RBD ( Figure 1B). This result indicates that the cross-reactive 90 antibody response to the S protein after SARS-CoV-2 infection mostly targets non-RBD 91 regions. Consistent with that observation, reactivi...

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Section: Resultsmentioning

confidence: 69%

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

Tsang

et al. 2020

Preprint

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“…The nasal/throat/anal swab samples and mainly tissue compartments collected from infected monkeys were tested for SARS-CoV-2 RNA by quantitative real-time reverse transcription-PCR (qRT-PCR). Total RNA was extracted and reverse transcription was performed as previously described 7 . qRT-PCR reactions were carried out on an ABI 9700 Real-time PCR system (Applied Biosystems Instrument), the cycling protocol and the primers as follows: 50°C for 2 min, 95°C for 2 min, followed by 40 cycles at 95°C for 15 s and 60°C for 30 s, and then 95°C for 15 s, 60°C for 1 min, 95°C for 45 s. Forward primer: 5’-TCGTTTCGGAAGAGACAGGT-3’, Reverse primer: 5’-GCGCAGTAAGGATGGCTAGT-3’.…”

Section: Methodsmentioning

confidence: 99%

“…For immunohistochemistry (IHC) staining to identify the antigen of SARS-CoV-2, paraffin dehydrated sections (3-4 µm in thickness) were treated with an antigen retrieval kit (Boster, AR0022) for 1 min at 37°C and quenched for endogenous peroxidases in 3% H 2 O 2 in methanol for 10 min. After blocking in 1% normal goat serum for 1 hour at roomtemperature, the slices were stained with 7D2 monoclonal antibody (laboratory preparation 7 ) at 4°C overnight, following with the incubation of HRP-labeled goat anti-mouse IgG (Beijing ZSGB Biotechnology, ZDR-5307) for 1 hour. Then, the slices were visualized by incubation with 3,30-diaminobenzidine tetrahydrochloride (DAB) and the image was viewed under an Olympus microscope.…”

Section: Methodsmentioning

confidence: 99%

Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2

Bao

Deng

Gao

et al. 2020

Preprint

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288

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19An outbreak of the Corona Virus Disease 2019 , caused by the severe acute 20 respiratory syndrome CoV-2 (SARS-CoV-2), began in Wuhan and spread globally. 21Recently, it has been reported that discharged patients in China and elsewhere were 22 testing positive after recovering. However, it remains unclear whether the convalescing 23 patients have a risk of "relapse" or "reinfection". The longitudinal tracking of re-24 exposure after the disappeared symptoms of the SARS-CoV-2-infected monkeys was 25 performed in this study. We found that weight loss in some monkeys, viral replication 26 mainly in nose, pharynx, lung and gut, as well as moderate interstitial pneumonia at 7 27 days post-infection (dpi) were clearly observed in rhesus monkeys after the primary 28 infection. After the symptoms were alleviated and the specific antibody tested positively, 29 the half of infected monkeys were rechallenged with the same dose of SARS-CoV-2 30 strain. Notably, neither viral loads in nasopharyngeal and anal swabs along timeline nor 31 viral replication in all primary tissue compartments at 5 days post-reinfection (dpr) was 32 found in re-exposed monkeys. Combined with the follow-up virologic, radiological and 33 pathological findings, the monkeys with re-exposure showed no recurrence of COVID-34 19, similarly to the infected monkey without rechallenge. Taken together, our results 35 indicated that the primary SARS-CoV-2 infection could protect from subsequent 36 exposures, which have the reference of prognosis of the disease and vital implications 37 for vaccine design.

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“…Since December of 2019, scientists all over the world have been working to establish animal model of COVID-19. So far there are several models reported in preprinted journals or peer-reviewed published journals, including two small murine models (hACE2 transgenic mouse 14 and Gold Syrian hamster 15 ), one ferret model 16 Retrospective studies of clinical features of COVID-19 show that older patients have more severe diseases, which may be associated with comorbidities, including tumor, diabetes, obesity, hypertension, heart diseases and so on [18][19][20] . These underlying diseases may make senior patients more susceptible to SARS-CoV-2 infection and worsen COVID-19.…”

Section: Sars-cov-2 Recently Reported As Another Novel Coronavirus Ementioning

confidence: 99%

Comparison of SARS-CoV-2 infections among 3 species of non-human primates

Zhao

et al. 2020

Preprint

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149

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COVID-19, caused by SARS-CoV-2 infection, has recently been announced as a pandemic all over the world. Plenty of diagnostic, preventive and therapeutic knowledges have been enriched from clinical studies since December 2019. However, animal models, particularly non-human primate models, are urgently needed for critical questions that could not be answered in clinical patients, evaluations of anti-viral drugs and vaccines. In this study, two families of non-human primates, old world monkeys (12 Macaca mulatta, 6 Macaca fascicularis) and new world monkeys (6 Callithrix jacchus), were experimentally inoculated with SARS-CoV-2. Clinical signs were recorded. Samples were collected for analysis of viral shedding, viremia and histopathological examination. Increased body temperature was observed in 100% (12/12) M. mulatta, 33.3% (2/6) M. fascicularis and none (0/6) of C. jacchus post inoculation of SARS-CoV-2. All of M. mulatta and M. fascicularis showed chest radiographic abnormality. Viral genomes were detected in nasal swabs, throat swabs, anal swabs and blood from all 3 species of monkeys. Viral shedding from upper respiratory reached the peak between day 6 and day 8 post inoculation. From necropsied M. mulatta and M. fascicularis, tissues showing virus positive were mainly lung, weasand, bronchus and spleen. No viral genome was seen in any of tissues from 2 necropsied C.jacchus. Severe gross lesions and histopathological changes were observed in lung, heart and stomach of SARS-CoV-2 infected animals. In summary, we have established a NHP model for COVID-19, which could be used to evaluate drugs and vaccines, and investigate viral pathogenesis. M. mulatta is the most susceptible to SARS-CoV2 infection, followed by M. fascicularis and C. jacchus. One Sentence Summary:M. mulatta is the most susceptible to SARS-CoV-2 infection as compared to M. fascicularis and C. jacchus.

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The Pathogenicity of SARS-CoV-2 in hACE2 Transgenic Mice

Cited by 441 publications

References 10 publications

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

Cross-reactive antibody response between SARS-CoV-2 and SARS-CoV infections

Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2

Comparison of SARS-CoV-2 infections among 3 species of non-human primates

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