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

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

doi:10.1371/journal.pbio.3001158

Cited by 97 publications

(121 citation statements)

References 69 publications

(100 reference statements)

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“…The anatomical distance and ambient temperature between upper and lower human respiratory tracts have a profound influence on the replication kinetics of respiratory viruses ( Corman et al, 2016 ; Tyrrell and Bynoe, 1965 ; Holwerda et al, 2019 ; Kendall et al, 1962 ). In agreement with other studies, we observed SARS-CoV-2 growth in favour of lower temperature (35 °C) which can be attributed to the temperature preference of SARS-CoV-2 S protein for its folding and transport ( V'kovski et al, 2020 ; Laporte et al, 2020 ). Both primary HtAEC and HsAEC cultures are shown to be a robust model for SARS-CoV-2 replication that can be used for antiviral drug profiling.…”

Section: Discussionsupporting

confidence: 92%

“…We demonstrate that ex vivo models reconstituted from human tracheal or small airway epithelium are permissive for SARS-CoV-2 infection and robustly produces viral progenies from the apical side in long-term experiments (up to 14 days p.i.). Recent studies have also reported on the effect of different SARS-CoV-2 isolates and incubation temperatures on virus replication kinetics ( Corman et al, 2016 ; Pohl et al, 2021 ; V'kovski et al, 2020 ; Zhu et al, 2020 ). We tested two isolates, BavPat1 and GHB-03021, and found that BavPat1 proved to be more infectious.…”

Section: Discussionmentioning

confidence: 99%

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A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

et al. 2021

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There are, besides remdesivir, no approved antivirals for the treatment of SARS-CoV-2 infections. To aid in the search for antivirals against this virus, we explored the use of human tracheal airway epithelial cells (HtAEC) and human small airway epithelial cells (HsAEC) grown at the air/liquid interface (ALI). These cultures were infected at the apical side with one of two different SARS-CoV-2 isolates. Each virus was shown to replicate to high titers for extended periods of time (at least 8 days) and, in particular an isolate with the D614G in the spike (S) protein did so more efficiently at 35 °C than 37 °C. The effect of a selected panel of reference drugs that were added to the culture medium at the basolateral side of the system was explored. Remdesivir, GS-441524 (the parent nucleoside of remdesivir), EIDD-1931 (the parent nucleoside of molnupiravir) and IFN (β1 and λ1) all resulted in dose-dependent inhibition of viral RNA and infectious virus titers collected at the apical side. However, AT-511 (the free base form of AT-527 currently in clinical testing) failed to inhibit viral replication in these in vitro primary cell models. Together, these results provide a reference for further studies aimed at selecting SARS-CoV-2 inhibitors for further preclinical and clinical development.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

et al. 2021

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“…Although we did not evaluate viral load by plaque assay, other studies that measured SARS-CoV-2 titer during replication in similar culture systems also observed a period of exponential replication at the start of infection, consistent with our results. However, not unexpectedly, the reported kinetics vary with experimental conditions, such as viral load in the inoculum and incubation temperature ( Hou et al, 2020 ; Zhu et al, 2020 ; V’kovski et al, 2021 ). Thus, we sought to estimate the replication kinetics in vivo using serial patient samples.…”

Section: Resultsmentioning

confidence: 99%

Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics

Cheemarla

Watkins

Mihaylova

et al. 2021

Journal of Experimental Medicine

172

134

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Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication. Conversely, blocking ISG induction during SARS-CoV-2 infection enhanced viral replication from a low infectious dose. These results show that the activity of ISG-mediated defenses at the time of SARS-CoV-2 exposure impacts infection progression and that the heterologous antiviral response induced by a different virus can protect against SARS-CoV-2.

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“…Human bronchial epithelial cells differentiate into functional ciliated and secretory cells in ALI cultures to form a pseudostratified epithelium capable of mucus production and cilia movement (241). They are efficiently infected by SARS-CoV-2 and produce high viral titers enabling functional studies and drug screening [ (14,82,242); Figure 2]. In addition, a LOC model of the human bronchial epithelium under constant flow in the blood vessel chamber has recently been developed to study influenza A virus and SARS-CoV-2 infection and has led to the identification of candidate antiviral compounds (243).…”

Section: Modeling Sars-cov-2 Infection and Pathogenesis In The Respiratory Tractmentioning

confidence: 99%

Human-Based Advanced in vitro Approaches to Investigate Lung Fibrosis and Pulmonary Effects of COVID-19

et al. 2021

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The coronavirus disease 2019 (COVID-19) pandemic has caused considerable socio-economic burden, which fueled the development of treatment strategies and vaccines at an unprecedented speed. However, our knowledge on disease recovery is sparse and concerns about long-term pulmonary impairments are increasing. Causing a broad spectrum of symptoms, COVID-19 can manifest as acute respiratory distress syndrome (ARDS) in the most severely affected patients. Notably, pulmonary infection with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the causing agent of COVID-19, induces diffuse alveolar damage (DAD) followed by fibrotic remodeling and persistent reduced oxygenation in some patients. It is currently not known whether tissue scaring fully resolves or progresses to interstitial pulmonary fibrosis. The most aggressive form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). IPF is a fatal disease that progressively destroys alveolar architecture by uncontrolled fibroblast proliferation and the deposition of collagen and extracellular matrix (ECM) proteins. It is assumed that micro-injuries to the alveolar epithelium may be induced by inhalation of micro-particles, pathophysiological mechanical stress or viral infections, which can result in abnormal wound healing response. However, the exact underlying causes and molecular mechanisms of lung fibrosis are poorly understood due to the limited availability of clinically relevant models. Recently, the emergence of SARS-CoV-2 with the urgent need to investigate its pathogenesis and address drug options, has led to the broad application of in vivo and in vitro models to study lung diseases. In particular, advanced in vitro models including precision-cut lung slices (PCLS), lung organoids, 3D in vitro tissues and lung-on-chip (LOC) models have been successfully employed for drug screens. In order to gain a deeper understanding of SARS-CoV-2 infection and ultimately alveolar tissue regeneration, it will be crucial to optimize the available models for SARS-CoV-2 infection in multicellular systems that recapitulate tissue regeneration and fibrotic remodeling. Current evidence for SARS-CoV-2 mediated pulmonary fibrosis and a selection of classical and novel lung models will be discussed in this review.

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

Cited by 97 publications

References 69 publications

A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

A robust SARS-CoV-2 replication model in primary human epithelial cells at the air liquid interface to assess antiviral agents

Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics

Human-Based Advanced in vitro Approaches to Investigate Lung Fibrosis and Pulmonary Effects of COVID-19

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