Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model

Rockx, Barry; Kuiken, Thijs; Herfst, Sander; Bestebroer, Theo M.; Lamers, Mart M.; Munnink, Bas B. Oude; Meulder, Dennis de; Amerongen, Geert van; Brand, Judith M. A. van den; Okba, Nisreen M.A.; Schipper, Debby; Run, Peter van; Leijten, Lonneke; Sikkema, Reina S.; Verschoor, Ernst J.; Verstrepen, Babs E.; Bogers, Willy; Langermans, Jan A. M.; Drosten, Christian; Vlissingen, Martje Fentener van; Fouchier, Ron A. M.; Swart, Rik L. de; Koopmans, Marion; Haagmans, Bart L.

doi:10.1126/science.abb7314

Cited by 844 publications

(1,011 citation statements)

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“…If these findings are reproducible with greater sample sizes, the greater proportion of ACE2 and TMPRSS2 co-expression in male type II pneumocytes may contribute to the associated disparities in COVID-19 pathogenesis. SARS-CoV-2-related alveolar damage has been implicated to primarily take effect via infiltration of type I and II pneumocytes and ciliated epithelial cells [13]. Type II pneumocytes perform essential functions for alveolar integrity via stem-cell properties and surfactant secretion [14], and their demise can contribute to alveolar collapse and respiratory failure.…”

Section: Discussionmentioning

confidence: 99%

Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells

Song

Seddighzadeh

Cooperberg

et al. 2020

Preprint

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The COVID-19 pandemic has spread across more than 200 countries and resulted in over 170,000 deaths. For unclear reasons, higher mortality rates from COVID-19 have been reported in men compared to women. While the SARS-CoV-2 receptor ACE2 and co-receptor TMPRSS2 have been detected in lung and other tissues, it is not clear what sex differences may exist. We analyzed a publicly-available normal human prostate single-cell RNA sequencing dataset and found TMPRSS2 and ACE2 co-expressing cells in epithelial cells, with a higher proportion in club and hillock cells. Then we investigated datasets of lung epithelial cells and also found club cells co-expressing TMPRSS2 and ACE2. A comparison of ACE2 expression in lung tissue between males and females showed higher expression in males and a larger proportion of ACE2+ cells in male type II pneumocytes, with preliminary evidence that type II pneumocytes of all lung epithelial cell types showed the highest expression of ACE2. These results raise the possibility that sex differences in ACE2 expression and the presence of doublepositive cells in the prostate may contribute to the observed disparities of COVID-19.

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Section: Discussionmentioning

confidence: 99%

Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells

Song

Seddighzadeh

Cooperberg

et al. 2020

Preprint

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“…SARS-CoV-2 showed good binding for human ACE2 but limited binding to murine ACE2 1 , which has limited the use of inbred mice for research. Macaques and transgenic ICR mice expressing human ACE2 receptor were shown to be susceptible for SARS-CoV-2 infection [16][17][18] ; however, there is limited availability of these animal models. Cynomolgus macaques and rhesus macaques challenged with SARS-CoV-2 showed pneumonia with limited 17 and moderate 18 clinical signs, respectively.…”

Section: Pathogenesis and Transmission Of Sars-cov-2 In Golden Hamstersmentioning

confidence: 99%

Pathogenesis and transmission of SARS-CoV-2 in golden hamsters

Sia

Yan

Chin

et al. 2020

Nature

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SARS-CoV-2, a novel coronavirus with high nucleotide identity to SARS-CoV and SARS-related coronaviruses detected in horseshoe bats, has spread across the world and impacted global healthcare systems and economy 1,2 . A suitable small animal model is needed to support vaccine and therapy development. We report the pathogenesis and transmissibility of the SARS-CoV-2 in golden Syrian hamsters. Immunohistochemistry demonstrated viral antigens in nasal mucosa, bronchial epithelial cells, and in areas of lung consolidation on days 2 and 5 post-inoculation (dpi), followed by rapid viral clearance and pneumocyte hyperplasia on 7 dpi. Viral antigen was also found in the duodenum epithelial cells with viral RNA detected in feces. Notably, SARS-CoV-2 transmitted efficiently from inoculated hamsters to naïve hamsters by direct contact and via aerosols. Transmission via fomites in soiled cages was less efficient. Although viral RNA was continuously detected in the nasal washes of inoculated hamsters for 14 days, the communicable period was short and correlated with the detection of infectious virus but not viral RNA. Inoculated and naturally-infected hamsters showed apparent weight loss, and all animals recovered with the detection of neutralizing antibodies. Our results suggest that SARS-CoV-2 infection in golden Syrian hamsters resemble features found in humans with mild infections.SARS-CoV-2 was first detected from a cluster of pneumonia patients in Wuhan, Hubei Province, China in December 2019. Although 55% of the initial cases were linked to one seafood wholesale market where wild animals were also sold 3 , multiple viral (sustained human-to-human transmissibility by symptomatic and pre-symptomatic patients 4 ) and ecological factors (extensive domestic and international travel during Chinese Lunar New Year) have contributed to the rapid global spread of the virus. The clinical spectrum of patients with the novel coronavirus disease (COVID-19) is wide, 19% of 72,314 symptomatic patients in China progressed to severe and critical illness 5 with an estimated 1.4% symptomatic case fatality risk 6 . There is no approved vaccine or treatment against SARS-CoV-2, and the available interventions including country lock-down and social distancing have severely disrupted the global supply chain and economy.A suitable animal model is essential for understanding the pathogenesis of this disease and for evaluating vaccine and therapeutic candidates. Previous animal studies on SARS-CoV suggested the importance of the interaction between the viral spike protein and the host angiotensin converting enzyme 2 (ACE2) receptors 7-10 as well as age and innate immune status of the animals 11-14 in pathogenesis. As with SARS-CoV, the spike protein of SARS-CoV-2 also utilizes ACE2 receptors that are distributed predominantly in the epithelial cells of the lungs and small intestine to gain entry into epithelial cells for viral replication 1,15 . SARS-CoV-2 showed good binding for human ACE2 but limited binding to murine ACE2 1 , which has limited...

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“…ACE2 is expressed in a diverse range of species throughout the subphylum Vertebrata . Several recent studies demonstrated that ferrets, cats, dogs and some non-human primates are susceptible to SARS-CoV-2 (Kim et al, 2020; Lu et al, 2020; Rockx et al, 2020; Shi et al, 2020; Zhang et al, 2020a). However, the exact host tropism of SARS-CoV-2 remains unknown and is an urgent area to explore for identifying other putative zoonotic reservoirs.…”

Section: Introductionmentioning

confidence: 99%

Functional and Genetic Analysis of Viral Receptor ACE2 Orthologs Reveals a Broad Potential Host Range of SARS-CoV-2

Liu

Wang

et al. 2020

Preprint

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The pandemic of a newly emerging coronavirus (SARS-CoV-2), the causative agent of severe pneumonia disease , is a major global health threat. Epidemiological studies suggest that bats are the natural zoonotic reservoir for SARS-CoV-2, however, the host range of SARS-CoV-2 and the identity of intermediate hosts that may facilitate the transmission to humans remains unknown. Coronavirus-receptor interaction is a key genetic determinant of the host range, cross-species transmission, and tissue tropism. SARS-CoV-2 uses Angiotensin-converting enzyme II (ACE2) as the receptor to enter its host cells in a species-dependent manner. It has been shown that human, palm civet, pig and bat ACE2 can support virus entry, while the murine ortholog cannot. In this study, we aimed to characterize ACE2 from diverse species for its ability to support viral entry. We found that ACE2 is expressed in a wide range of host species, with high conservation especially in mammals. By analyzing critical amino acid residues in ACE2 for virus entry, based on the well-characterized SARS-CoV spike protein interaction with ACE2 (human, bat, palm civet, pig and ferret ACE2), we identified approximately eighty ACE2 proteins from mammals could potentially function as the receptor to mediate SARS-CoV-2 entry. Functional assays showed that 44 of these mammalian ACE2 orthologs, including domestic animals, pet animals, livestock animals and even animals in the zoos or aquaria, could bind viral spike protein and support SARS-CoV-2 entry. In summary, our study demonstrates that ACE2 from a remarkably broad range of species support SARS-CoV-2 entry. These findings highlight a potentially broad host tropism and suggest that SARS-CoV-2 might be distributed much more widely than previously recognized, emphasizing the necessity to monitor the susceptible hosts, especially their potential of cross-species, which could prevent the future outbreaks.

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Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model

Cited by 844 publications

References 31 publications

Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells

Expression of ACE2, the SARS-CoV-2 receptor, and TMPRSS2 in prostate epithelial cells

Pathogenesis and transmission of SARS-CoV-2 in golden hamsters

Functional and Genetic Analysis of Viral Receptor ACE2 Orthologs Reveals a Broad Potential Host Range of SARS-CoV-2

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