Age‐related rhesus macaque models of COVID‐19

Yü, Ping; Qi, Feifei; Xu, Yanfeng; Li, Fengdi; Li, Peipei; Liu, Jiayi; Bao, Linlin; Deng, Wei; Gao, Hong; Xiang, Zhiguang; Xiao, Cheng; Lv, Qi; Gong, Shuran; Liu, Jiangning; Song, Zhiqi; Qu, Yajin; Xue, Jing; Wang, Qiang; Liu, Mingya; Wang, Guanpeng; Wang, Shunyi; Yu, Haisheng; Liu, Xing; Huang, Baoying; Wang, Wenling; Zhao, Li; Wang, Huijuan; Ye, Fei; Zhou, Weimin; Wei, Zhen; Han, Jun; Wu, Guizhen; Jin, Qi; Wang, Jianwei; Tan, Wenjie; Qin, Chuan

doi:10.1002/ame2.12108

Cited by 247 publications

(284 citation statements)

References 10 publications

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“…More specifically, the interaction of the viral spike (S) glycoprotein receptor binding domain with its hACE2 counterpart was examined 8,9 , and in some cases examined in vivo 10 . Productive SARS-CoV-2 infection was shown in non-human primates, which developed respiratory disease recapitulating moderate disease as observed in humans 11-14 . Mice are not naturally susceptible to SARS-CoV-2, but mouse-adapted virus strains have been developed and used in BALB/c mice 15,16 .…”

Section: Main Textmentioning

confidence: 83%

Age-dependent progression of SARS-CoV-2 infection in Syrian hamsters

Osterrieder

Bertzbach

Dietert

et al. 2020

Preprint

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22In late 2019, an outbreak of a severe respiratory disease caused by an emerging 23 coronavirus, SARS-CoV-2, resulted in high morbidity and mortality in infected humans 1 . 24Complete understanding of COVID-19, the multi-faceted disease caused by SARS-CoV-25 2, requires suitable small animal models, as does the development and evaluation of 26 vaccines and antivirals 2 . Because age-dependent differences of COVID-19 were identified 27 in humans 3 , we compared the course of SARS-CoV-2 infection in young and aged Syrian 28 hamsters. We show that virus replication in the upper and lower respiratory tract was 29 independent of the age of the animals. However, older hamsters exhibited more 30 pronounced and consistent weight loss. In situ hybridization in the lungs identified viral 31 RNA in bronchial epithelium, alveolar epithelial cells type I and II, and macrophages. 32Histopathology revealed clear age-dependent differences, with young hamsters launching 33 earlier and stronger immune cell influx than aged hamsters. The latter developed 34 conspicuous alveolar and perivascular edema, indicating vascular leakage. In contrast, 35we observed rapid lung recovery at day 14 after infection only in young hamsters. We 36propose that comparative assessment in young versus aged hamsters of SARS-CoV-2 37 vaccines and treatments may yield valuable information as this small-animal model 38 appears to mirror age-dependent differences in human patients.

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Section: Main Textmentioning

confidence: 83%

Age-dependent progression of SARS-CoV-2 infection in Syrian hamsters

Osterrieder

Bertzbach

Dietert

et al. 2020

Preprint

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“…Ferrets are also a preferred model of respiratory viral infections and have been shown to be infected by SARS-CoV 2, but develop only mild symptoms [96]. So far, the most promising disease models amongst primates are rhesus macaques (Macaca mulatta) that develop pneumonia [97], although results of infection in capuchins (Sapaju appella) are yet to be published. In non-primates, cats present the most symptoms with massive lung lesions [89].…”

Section: Comparison Between Species Can Predict Animal Model Accuracymentioning

confidence: 99%

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

Moustaqil

Ollivier

Chiu

et al. 2020

Preprint

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The genome of SARS-CoV-2 (SARS2) encodes for two viral proteases (NSP3/ papain-like protease and NSP5/ 3C-like protease or major protease) that are responsible for cleaving viral polyproteins for successful replication. NSP3 and NSP5 of SARS-CoV (SARS1) are known interferon antagonists. Here, we examined whether the protease function of SARS2 NSP3 and NSP5 target proteins involved in the host innate immune response. We designed a fluorescent based cleavage assay to rapidly screen the protease activity of NSP3 and NSP5 on a library of 71 human innate immune proteins (HIIPs), covering most pathways involved in human innate immunity. By expressing each of these HIIPs with a genetically encoded fluorophore in a cell-free system and titrating in the recombinant protease domain of NSP3 or NSP5, we could readily detect cleavage of cognate HIIPs on SDS-page gels. We identified 3 proteins that were specifically and selectively cleaved by NSP3 or NSP5: IRF-3, and NLRP12 and TAB1, respectively. Direct cleavage of IRF3 by NSP3 could explain the blunted Type-I IFN response seen during SARS-CoV-2 infections while NSP5 mediated cleavage of NLRP12 and TAB1 point to a molecular mechanism for enhanced production of IL-6 and inflammatory response observed in COVID-19 patients. Surprisingly, both NLRP12 and TAB1 have each two distinct cleavage sites. We demonstrate that in mice, the second cleavage site of NLRP12 is absent. We pushed this comparative alignment of IRF-3 and NLRP12 homologs and show that the lack or presence of cognate cleavage motifs in IRF-3 and NLRP12 could contribute to the presentation of disease in cats and tigers, for example. Our findings provide an explanatory framework for in-depth studies into the pathophysiology of COVID-19 and should facilitate the search or development of more effective animal models for severe COVID-19. Finally, we discovered that one particular species of bats, David's Myotis, possesses the five cleavage sites found in humans for NLRP12, TAB1 and IRF3. These bats are endemic from the Hubei province in China and we discuss its potential role as reservoir for the evolution of SARS1 and SASR2.

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“…Therefore, animal models are urgently expected to be established for this severe COVID-19. Although several models of COVID-19 have recently been reported [5][6][7] , including the non-human primate model, none of model should be considered to be the best one, depending on what questions we are going to answer with the animal models. About 16 years ago, the nonhuman primate models recapitulated several important aspects of SARS [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

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

Zhao

et al. 2020

Preprint

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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Age‐related rhesus macaque models of COVID‐19

Cited by 247 publications

References 10 publications

Age-dependent progression of SARS-CoV-2 infection in Syrian hamsters

Age-dependent progression of SARS-CoV-2 infection in Syrian hamsters

SARS-CoV-2 proteases cleave IRF3 and critical modulators of inflammatory pathways (NLRP12 and TAB1): implications for disease presentation across species and the search for reservoir hosts

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

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