Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells

Zhu, Na; Wang, Wenling; Liu, Zhidong; Liang, Chaoyang; Wang, Wen; Ye, Fei; Huang, Baoying; Zhao, Li; Wang, Huijuan; Zhou, Weimin; Deng, Yao; Mao, Longfei; Su, Chen; Qiang, Guangliang; Jiang, Taijiao; Zhao, Jincun; Wu, Guizhen; Song, Jingdong; Tan, Wenjie

doi:10.1038/s41467-020-17796-z

Cited by 311 publications

(368 citation statements)

References 32 publications

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“…It is curious that secretory goblet and club cells behave in opposite ways to SARS-CoV-2 infection, since both of these cell types are surface epithelial cells accessible on the airway lumen (38). The permissibility of goblet cells to SARS-CoV-2 infection was previously reported by immunochemistry staining of biopsy airway section specimens from COVID-19 patients (36), as well as being supported by a recent in vitro modeling of HAE (34). Club cells express the viral receptor ACE2, but at a lower level than goblet, ciliated, and basal cells (43) (see Fig.…”

Section: Discussionmentioning

confidence: 69%

“…This in vitro model of human airway epithelium (HAE) cultured at an ALI (HAE-ALI) closely recapitulates many important characteristics of respiratory virus-host cell interactions seen in the infected upper and lower airways in vivo and has been used to study many human respiratory viruses (20)(21)(22)(23)(24)(25)(26)(27)(28)(29), including SARS-CoV (30,31). Primary HAE-ALI can be infected by SARS-CoV-2 (32,33), resulting in epithelial damage (34), and they can be used for virus isolation (1,16). Notably, differentiation at an ALI results in a drastic increase in expression and the polar presentation of the viral receptor angiotensin-converting enzyme 2 (ACE2) (2,35) on the apical membrane (30,31).…”

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confidence: 99%

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Long-Term Modeling of SARS-CoV-2 Infection of In Vitro Cultured Polarized Human Airway Epithelium

Hao

Ning

Küz

et al. 2020

mBio

109

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates throughout human airways. The polarized human airway epithelium (HAE) cultured at an airway-liquid interface (HAE-ALI) is an in vitro model mimicking the in vivo human mucociliary airway epithelium and supports the replication of SARS-CoV-2. Prior studies characterized only short-period SARS-CoV-2 infection in HAE. In this study, continuously monitoring the SARS-CoV-2 infection in HAE-ALI cultures for a long period of up to 51 days revealed that SARS-CoV-2 infection was long lasting with recurrent replication peaks appearing between an interval of approximately 7 to 10 days, which was consistent in all the tested HAE-ALI cultures derived from 4 lung bronchi of independent donors. We also identified that SARS-CoV-2 does not infect HAE from the basolateral side, and the dominant SARS-CoV-2 permissive epithelial cells are ciliated cells and goblet cells, whereas virus replication in basal cells and club cells was not detected. Notably, virus infection immediately damaged the HAE, which is demonstrated by dispersed zonula occludens-1 (ZO-1) expression without clear tight junctions and partial loss of cilia. Importantly, we identified that SARS-CoV-2 productive infection of HAE requires a high viral load of >2.5 × 105 virions per cm2 of epithelium. Thus, our studies highlight the importance of a high viral load and that epithelial renewal initiates and maintains a recurrent infection of HAE with SARS-CoV-2. IMPORTANCE The pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to >35 million confirmed cases and >1 million fatalities worldwide. SARS-CoV-2 mainly replicates in human airway epithelia in COVID-19 patients. In this study, we used in vitro cultures of polarized human bronchial airway epithelium to model SARS-CoV-2 replication for a period of 21 to 51 days. We discovered that in vitro airway epithelial cultures endure a long-lasting SARS-CoV-2 propagation with recurrent peaks of progeny virus release at an interval of approximately 7 to 10 days. Our study also revealed that SARS-CoV-2 infection causes airway epithelia damage with disruption of tight junction function and loss of cilia. Importantly, SARS-CoV-2 exhibits a polarity of infection in airway epithelium only from the apical membrane; it infects ciliated and goblet cells but not basal and club cells. Furthermore, the productive infection of SARS-CoV-2 requires a high viral load of over 2.5 × 105 virions per cm2 of epithelium. Our study highlights that the proliferation of airway basal cells and regeneration of airway epithelium may contribute to the recurrent infections.

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Section: Discussionmentioning

confidence: 69%

mentioning

confidence: 99%

Long-Term Modeling of SARS-CoV-2 Infection of In Vitro Cultured Polarized Human Airway Epithelium

Hao

Ning

Küz

et al. 2020

mBio

109

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“…This model also demonstrates key aspects of host antiviral epithelial immunity [8, 9]. Recently, several studies using primary human lung cell cultures and respiratory cells isolated from SARS-CoV-2 infected patients have identified SARS-CoV-2 tropism for ciliated and secretory cells in the upper airway [10-13]. However, the heterogeneity of virus replication and induction of antiviral genes and proinflammatory cytokines within these cells is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium

Fiege

Thiede

Nanda

et al. 2020

Preprint

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The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-Sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of cell types are susceptible to infection, ciliated cells are a predominant cell target for SARS-CoV-2. Remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. We also found that heavily infected epithelial cells demonstrate impaired IFN signaling and express abundant IL-6, a potential mediator of COVID-19 pathogenesis.

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“…SARS-CoV-2 can simultaneously infect ciliated cells and secretory cells of human respiratory epithelium. Therefore, compared with common coronaviruses, it is more infectious and pathogenic [3] . As of August14, 2020 (03:37 pm CEST), the WHO website reported that there were 89,625 con rmed cases in China, of which 4,707 patients died.…”

Section: Introductionmentioning

confidence: 99%

The Prognostic Value of the SOFA Score in Patients with COVID-19: A Retrospective, Observational Study

Yang

Huang

et al. 2020

Preprint

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Background: Patients with Coronavirus disease 2019 (COVID-19) have a high mortality rate, and thus, it is particularly important to predict the severity and prognosis of COVID-19. The Sequential Organ Failure Assessment (SOFA) score has been used to predict the clinical outcomes of patients with multiple organ failure requiring intensive care. Therefore, we retrospectively analyzed the clinical characteristics, risk factors, and relationship between the SOFA score and the prognosis of COVID-19 patients.Methods: Clinical variables were compared between patients with mild and severe COVID-19. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for severe COVID-19. The Cox proportional hazards model was used to analyze risk factors for hospital-related death. Survival analysis was performed by the Kaplan-Meier method, and survival differences were assessed by the log-rank test. Receiver operating characteristic (ROC) curves of the SOFA score in different situations were drawn, and the area under the ROC curve was calculated.Results: The median SOFA score of all patients was 2 (IQR, 1-3). Patients with severe COVID-19 exhibited a significantly higher SOFA score than patients with mild COVID-19 [3 (IQR, 2-4) vs 1 (IQR, 0-1); P<0.001]. The SOFA score increased the risk of severe COVID-19, with an odds ratio of 5.851 (95% CI: 3.044-11.245; P<0.001). The area under the ROC curve (AUC) was used to evaluate the diagnostic accuracy of the SOFA score in predicting severe COVID-19 [cutoff value = 2; AUC = 0.908 (95% CI: 0.857-0.960); sensitivity: 85.20%; specificity: 80.40%] and the risk of death in COVID-19 patients [cutoff value = 5; AUC = 0.995 (95% CI: 0.985-1.000); sensitivity: 100.00%; specificity: 95.40%]. Regarding the 60-day mortality rates of patients in the two groups classified by the optimal cutoff value of the SOFA score (5), patients in the high SOFA score group (SOFA score ≥5) had a significantly greater risk of death than those in the low SOFA score group (SOFA score <5).Conclusion: The SOFA score could be used to evaluate the severity and 60-day mortality of COVID-19. The SOFA score may be an independent risk factor for in-hospital death.

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Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells

Cited by 311 publications

References 32 publications

Long-Term Modeling of SARS-CoV-2 Infection of In Vitro Cultured Polarized Human Airway Epithelium

Long-Term Modeling of SARS-CoV-2 Infection of In Vitro Cultured Polarized Human Airway Epithelium

Single cell resolution of SARS-CoV-2 tropism, antiviral responses, and susceptibility to therapies in primary human airway epithelium

The Prognostic Value of the SOFA Score in Patients with COVID-19: A Retrospective, Observational Study

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