Disparate temperature-dependent virus – host dynamics for SARS-CoV-2 and SARS-CoV in the human respiratory epithelium

V’kovski, Philip; Gultom, Mitra; Steiner, Silvio; Kelly, Jenna N.; Russeil, Julie; Mangeat, Bastien; Cora, Elisa; Pezoldt, Joern; Holwerda, Melle; Kratzel, Annika; Laloli, Laura; Wider, Manon; Portmann, Jasmine; Thao, Tran Thi Nhu; Ebert, Nadine; Stalder, Hanspeter; Hartmann, Rune; Gardeux, Vincent; Alpern, Daniel; Deplancke, Bart; Thiel, Volker; Dijkman, Ronald

doi:10.1101/2020.04.27.062315

Cited by 47 publications

(84 citation statements)

References 63 publications

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“…This delay in the induction of the antiviral response suggests a "too little too late" scenario, where antiviral mechanisms are overwhelmed and subverted by active viral replication. Our findings are compatible with studies showing a limited and/or delayed IFN induction by SARS-CoV-2 as compared to other respiratory viruses, in primary epithelial cells from the airways and the intestine (Blanco-Melo et al, 2020;Lamers et al, 2020;V'kovski et al, 2020;Vanderheiden et al, 2020).…”

Section: Discussionsupporting

confidence: 92%

“…We observed that pretreatment with IFN-b or IFN-l markedly decreased SARS-CoV-2 replication in our reconstituted bronchial epithelium model. These findings are in agreement with studies in various culture systems documenting the inhibitory effect of both type I and type III IFN on SARS-CoV-2 replication, when treatment occurs prior to the stage of massive viral replication (Felgenhauer et al, 2020;Mantlo et al, 2020;Stanifer et al, 2020;V'kovski et al, 2020;Vanderheiden et al, 2020). However, studies in animal models suggest that, at an advanced stage of infection, IFN may contribute to the decline of respiratory function, possibly by worsening inflammation (Boudewijns et al, 2020) and impairing epithelial cell regeneration (Broggi et al, 2020;Major et al, 2020).…”

Section: Discussionsupporting

confidence: 87%

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SARS-CoV-2 infection damages airway motile cilia and impairs mucociliary clearance

Robinot

Hubert

Melo

et al. 2020

Preprint

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Understanding how SARS-CoV-2 spreads within the respiratory tract is important to define the parameters controlling the severity of COVID-19. We examined the functional and structural consequences of SARS-CoV-2 infection in a reconstituted human bronchial epithelium model. SARS-CoV-2 replication caused a transient decrease in epithelial barrier function and disruption of tight junctions, though viral particle crossing remained limited. Rather, SARS-CoV-2 replication led to a rapid loss of the ciliary layer, characterized at the ultrastructural level by axoneme loss and misorientation of remaining basal bodies. The motile cilia function was compromised, as measured in a mucociliary clearance assay. Epithelial defense mechanisms, including basal cell mobilization and interferon-lambda induction, ramped up only after the initiation of cilia damage. Analysis of SARS-CoV-2 infection in Syrian hamsters further demonstrated the loss of motile cilia in vivo. This study identifies cilia damage as a pathogenic mechanism that could facilitate SARS-CoV-2 spread to the deeper lung parenchyma.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 87%

SARS-CoV-2 infection damages airway motile cilia and impairs mucociliary clearance

Robinot

Hubert

Melo

et al. 2020

Preprint

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“…Several recent studies have revealed the induction of innate immunity during SARS-CoV-2 infection is dependent on viral growth kinetics and multiplicity of infection. [37,38]. Here, we show that the innate response to SARS-CoV-2 is intact and rapid, as characterized by interferon, chemokine, and IL-6 induction.…”

Section: Discussionmentioning

confidence: 70%

Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium

Ravindra

Alfajaro

Gasque

et al. 2020

Preprint

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SARS-CoV-2, the causative agent of COVID-19, has resulted in more than 3,000,000 infections and 200,000 deaths. There are currently no approved drugs or vaccines for the treatment or prevention of COVID-19. Enhanced understanding of SARS-CoV-2 infection and pathogenesis is critical for the development of therapeutics. To reveal insight into viral replication, cell tropism, and host-viral interactions of SARS-CoV-2 we performed single-cell RNA sequencing of experimentally infected human bronchial epithelial cells (HBECs) in air-liquid interface cultures over a time-course. This revealed novel polyadenylated viral transcripts and highlighted ciliated cells as the major target of infection, which we confirmed by electron microscopy. Over the course of infection, cell tropism of SARS-CoV-2 expands to other epithelial cell types including basal and club cells. Infection induces cell intrinsic expression of type I and type III IFNs and IL6 but not IL1. This results in expression of interferon stimulated genes in both infected and bystander cells. Here, we have conducted an in-depth analysis of SARS-CoV-2 infection in HBECs and provide a detailed characterization of genes, cell types, and cell state changes associated with the infection.CoVs are enveloped viruses with positive-sense, single-stranded RNA genomes ranging from 26-30 kb [3]. Six human CoVs have been previously identified: HCoV-NL63 and HCoV-229E, which belong to the Alphacoronavirus genus; and HCoV-OC43, HCoV-HKU1, SARS-CoV, and Middle East Respiratory Syndrome CoV (MERS-CoV), which belong to the Betacoronavirus genus [4]. In the past two decades, CoVs have become a major public health concern due to potential zoonotic transmission, as revealed by the emergence of SARS-CoV in 2002, which infected 8, 000 people worldwide with a mortality rate of 10-15%, and MERS-CoV in 2012 and 2019, which infected 2, 500 people with a mortality rate of 35%, and now SARS-CoV-2 (WHO).Tissue and cell tropism are key determinants of viral pathogenesis. SARS-CoV-2 entry into cells depends on the binding of the viral spike (S) protein to its cognate receptor angiotensin-converting enzyme II (ACE2) on the cell surface [2]. ACE2 is also the receptor for SARS-CoV and HCoV-NL63, yet these viruses induce profoundly different morbidity and mortality suggesting unknown determinants of coronavirus pathogenesis [5,6]. Additionally, proteolytic priming of the S protein by host proteases is also critical for viral entry [7]. The cellular serine protease Type II transmembrane (TMPRSS2) is used by SARS-CoV-2 for S protein priming [8,7,9,10]. This is also used by SARS-CoV alongside the endosomal cysteine proteases cathepsin B and L [11,12]. Another host protease, furin, has been suggested to mediate SARS-CoV-2 pathogenesis; however, the precise role of host proteases in SARS-CoV-2 entry remains to be determined [13,10].SARS-CoV and MERS-CoV caused fatal pneumonia associated with rapid virus replication, elevation of proinflammatory cytokines, and immune cell infiltration [14]. These characteri...

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“…Consistently, host responses, such as cytokine expression, that are known to drive inflammation and immunopathologies have been assessed in studies that revealed that SARS-CoV-2 considerably affects the transcriptional landscape of infected cells by inducing inflammatory cytokine and chemokine signatures 38 , 146 , 147 . Although interferon responses have been shown to potently impair SARS-CoV-2 replication, only moderate induction of type I interferon, type II interferon and interferon-stimulated genes was reported 38 , 147 .…”

Section: Coronavirus Biology and Covid-19mentioning

confidence: 99%

Coronavirus biology and replication: implications for SARS-CoV-2

et al. 2020

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The SARS-CoV-2 pandemic and its unprecedented global societal and economic disruptive impact has marked the third zoonotic introduction of a highly pathogenic coronavirus into the human population. Although the previous coronavirus SARS-CoV and MERS-CoV epidemics raised awareness of the need for clinically available therapeutic or preventive interventions, to date, no treatments with proven efficacy are available. The development of effective intervention strategies relies on the knowledge of molecular and cellular mechanisms of coronavirus infections, which highlights the significance of studying virus–host interactions at the molecular level to identify targets for antiviral intervention and to elucidate critical viral and host determinants that are decisive for the development of severe disease. In this Review, we summarize the first discoveries that shape our current understanding of SARS-CoV-2 infection throughout the intracellular viral life cycle and relate that to our knowledge of coronavirus biology. The elucidation of similarities and differences between SARS-CoV-2 and other coronaviruses will support future preparedness and strategies to combat coronavirus infections.

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Disparate temperature-dependent virus – host dynamics for SARS-CoV-2 and SARS-CoV in the human respiratory epithelium

Cited by 47 publications

References 63 publications

SARS-CoV-2 infection damages airway motile cilia and impairs mucociliary clearance

SARS-CoV-2 infection damages airway motile cilia and impairs mucociliary clearance

Single-cell longitudinal analysis of SARS-CoV-2 infection in human airway epithelium

Coronavirus biology and replication: implications for SARS-CoV-2

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