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Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2

ABSTRACT: Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for hAT2 cells, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of defined 3D hAT2 cultures as models for respiratory diseases.

ORGANISM(S): Chlorocebus aethiops

PROVIDER: GSE159316 | GEO | 2020/10/10

REPOSITORIES: GEO

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Three-dimensional human alveolar stem cell culture models reveal infection response to SARS-CoV-2

Project description:Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of defined 3D hAT2 cultures as models for respiratory diseases.

| EGAS00001004508 | EGA

bulk RNAseq of SARS-COV2 infected human lung organoid

Project description:Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic resulting from zoonotic transmission of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Severe symptoms include viral pneumonia secondary to infection and inflammation of the lower respiratory tract, in some cases causing death. We developed primary human lung epithelial 5 infection models to understand responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface cultures of proximal airway epithelium and 3D organoid cultures of alveolar epithelium were readily infected by SARS-CoV-2 leading to an epithelial cell-autonomous proinflammatory response. We validated the efficacy of selected candidate COVID-19 drugs confirming that Remdesivir strongly suppressed viral 10 infection/replication. We provide a relevant platform for studying COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and future emergent respiratory pathogens.

2020-11-06 | GSE160435 | GEO

SARS-CoV-2 infection of primary human lung epithelium for COVID-19 modeling and drug discovery

Project description:Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic resulting from zoonotic transmission of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Severe symptoms include viral pneumonia secondary to infection and inflammation of the lower respiratory tract, in some cases causing death. We developed primary human lung epithelial infection models to understand responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface cultures of proximal airway epithelium and 3D organoid cultures of alveolar epithelium were readily infected by SARS-CoV-2 leading to an epithelial cell-autonomous proinflammatory response. We validated the efficacy of selected candidate COVID-19 drugs confirming that Remdesivir strongly suppressed viral infection/replication. We provide a relevant platform for studying COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and future emergent respiratory pathogens.

2020-11-06 | GSE155518 | GEO

Absence of host innate immune responses in SARS-CoV-infected ferrets upon subsequent challenge

Project description:To further investigate the underlying mechanisms of severe acute respiratory syndrome (SARS) pathogenesis and evaluate the therapeutic efficacy of potential drugs and vaccines it is necessary to use an animal model that is highly representative of the human condition in terms of respiratory anatomy, physiology and clinical sequelae. The ferret, Mustela putorius furo, supports SARS-CoV replication and displays many of the symptoms and pathological features seen in SARS-CoV-infected humans. We have recently established a SARS-CoV infection-challenge ferret platform for use in evaluating potential therapeutics to treat SARS. The main objective of the current study was to extend our previous results and identify early host immune responses upon infection and determine immune correlates of protection upon challenge with SARS-CoV in ferrets. Keywords: time course This study is a simple time course (58 day) examination of host responses in 35 SARS-CoV (TOR2) infected ferrets with the addition of a challenge inoculation of SARS CoV (TOR2) at day 29 post infection. Three mock-infected ferrets are included as negative controls. Due to the unavailability of ferret microarrays, Affymetrix Canine 2.0 oligonucleotide arrays were chosen following sequence analysis of our ferret cDNA library (~5000 clones) and demonstration of high levels of homology (>80%) between dog and ferret.

2013-05-28 | E-GEOD-11704 | biostudies-arrayexpress

LY6E blocks coronavirus fusion and confers immune control of viral disease

Project description:Zoonotic coronaviruses (CoVs) are significant threats to global health, as exemplified by the recent emergence of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Host immune responses to CoV are complex and regulated in part through antiviral interferons. However, the interferon-stimulated gene products that inhibit CoV are not well characterized. Here, we show that interferon-inducible lymphocyte antigen 6 complex, locus E (LY6E) potently restricts cellular infection by multiple CoVs, including SARS-CoV, SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV). Mechanistic studies revealed that LY6E inhibits CoV entry into cells by interfering with spike protein-mediated membrane fusion. Importantly, mice lacking Ly6e in hematopoietic cells were highly susceptible to murine CoV infection. Exacerbated viral pathogenesis in Ly6e knockout mice was accompanied by loss of hepatic and splenic immune cells and reduction in global antiviral gene pathways. Accordingly, we found that Ly6e directly protects primary B cells and dendritic cells from murine CoV infection. Our results demonstrate that LY6E is a critical antiviral immune effector that controls CoV infection and pathogenesis. These findings advance our understanding of immune-mediated control of CoV in vitro and in vivo, knowledge that could help inform strategies to combat infection by emerging CoV.

2020-02-28 | GSE146074 | GEO

SARS-CoV-2 utilizes a multipronged strategy to suppress host protein synthesis

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 19 (COVID-19) pandemic. Despite the urgent need, we still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses. Here, we use RNA-sequencing and ribosome profiling along SARS-CoV-2 infection and comprehensively define the mechanisms that are utilized by SARS-CoV-2 to shutoff cellular protein synthesis. We show SARS-CoV-2 infection leads to a global reduction in translation but that viral transcripts are not preferentially translated. Instead, we reveal that infection leads to accelerated degradation of cytosolic cellular mRNAs which facilitates viral takeover of the mRNA pool in infected cells. Moreover, we show that the translation of transcripts whose expression is induced in response to infection, including innate immune genes, is impaired, implying infection prevents newly transcribed cellular mRNAs from accessing the ribosomes. Overall, our results uncover the multipronged strategy employed by SARS-CoV-2 to commandeer the translation machinery and to suppress host defenses.

2021-04-01 | GSE162323 | GEO

Comparative Pathogenesis of Three Human and Zoonotic SARS-CoV Strains in Cynomolgus Macaques

Project description:The severe acute respiratory syndrome (SARS) epidemic was characterized by increased pathogenicity in the elderly due to an early exacerbated innate host response. SARS-CoV is a zoonotic pathogen that entered the human population through an intermediate host like the palm civet. To prevent future introductions of zoonotic SARS-CoV strains and subsequent transmission into the human population, heterologous disease models are needed to test the efficacy of vaccines and therapeutics against both late human and zoonotic isolates. Here we show that both human and zoonotic SARS-CoV strains can infect cynomolgus macaques and resulted in radiological as well as histopathological changes similar to those seen in mild human cases. Viral replication was higher in animals infected with a late human phase isolate compared to a zoonotic isolate. Host responses to the three SARS-CoV strains were similar and only apparent early during infection with the majority of genes associated with interferon signalling pathways.This study characterizes critical disease models in the evaluation and licensure of therapeutic strategies against SARS-CoV for human use 4 strains, time course, lungs

2011-08-31 | E-GEOD-23955 | biostudies-arrayexpress

Genes and transposons expression profiling of wild-type Bone Marrow Derived Macrophages (BMDMs) after VSV and HSV infection.

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging and highly pathogenic coronavirus that causes coronavirus disease (COVID-19), and might even lead to death. The long terminal repeat of the endogenous retrovirus (LTR ERVs), a type of mammalian genome elements derived from ancient viruses which infected the host and now accounts for 8% of human genome, are implicated in multi viral pathogenesis and host immune responses. However, their expression patterns and functions during SARS-CoV-2 infection still remain to be uncover. We first identified that SARS-CoV-2 infection could upregualted the expression of TEs and ERVs from the published RNA-seq data. Then in this study, we also conducted the genome-wide analysis of ERVs from wild-type mice Bone Marrow Derived Macrophages (BMDMs) after VSV and HSV infection. Collectively, these results provides the first glimpse into the expression patterns and potentail roles of ERVs after viral infection, and would serve as a valuable resource for future studies on SARS-CoV-2 infection and pathogenesis.

2023-11-30 | GSE244322 | GEO

Administration of aerosolized SARS-CoV-2 to K18-hACE2 mice uncouples respiratory infection from fatal neuroinvasion

Project description:The development of tractable animal models that faithfully reproduce COVID-19 pathogenesis would arguably be a major benefit. Infection of transgenic mice expressing the human version of the SARS-CoV-2 receptor (hACE2) by intranasal instillation of a liquid SARS-CoV-2 suspension under deep anesthesia results in disproportionate high CNS infection leading to fatal encephalitis, which is rarely observed in humans and severely limits this model’s usefulness. Here, we describe the characterization of a novel COVID-19 mouse model based on an inhalation tower system that allows to expose unanesthetized mice to aerosolized virus under controlled conditions. Aerosol exposure of K18-hACE2 transgenic mice to SARS-CoV-2 resulted in robust viral replication in the respiratory tract, anosmia, and airway obstruction, but did not lead to fatal viral neuroinvasion. When compared to intranasal inoculation, aerosol infection resulted in a more pronounced lung pathology including increased immune infiltration, fibrin deposition and a transcriptional signature comparable to that observed in humans. This model may prove useful for studies of viral transmission, disease pathogenesis (including long-term consequences of SARS-CoV-2 infection) and therapeutic interventions.

2021-11-23 | GSE184657 | GEO

Cytokine stimulation systems approach demonstrates differences in innate and pro-inflammatory host responses between genetically distinct MERS-CoV isolates.

Project description:Background: The recent emergence of a novel coronavirus in the Middle East (designated MERS-CoV) is a reminder of the zoonotic potential of coronaviruses and the severe disease these etiologic agents can cause in humans. Clinical features of Middle East respiratory syndrome (MERS) include severe acute pneumonia and renal failure that is highly reminiscent of severe acute respiratory syndrome (SARS) caused by SARS-CoV. The host response is a key component of highly pathogenic respiratory virus infection. Here, we computationally analyzed gene expression changes in a human airway epithelial cell line infected with two genetically distinct MERS-CoV strains obtained from human patients, MERS-CoV-EMC (designated EMC) and MERS-CoV-London (designated LoCoV). Results: Using topological techniques, such as persistence homology and filtered clustering, we characterized the host response system to the different MERS-CoVs, with LoCoV inducing early kinetic changes, between 3 and 12 hours post infection, compared to EMC. Robust transcriptional changes distinguished the two MERS-CoV strains predominantly at the late time points. Combining statistical analysis of infection and cytokine-stimulated treatment transcriptomics, we identified differential innate and pro-inflammatory responses between the two virus strains, including up-regulation of extracellular remodeling genes following LoCoV infection and differential pro-inflammatory responses between the two strains. Conclusions: These transcriptional differences may be the result of amino acid differences in viral proteins known to modulate innate immunity against MERS infection. Triplicate wells of Calu-3 2B4 cells were infected with Human Coronavirus EMC 2012 (HCoV-EMC) or time-matched mock infected. Cells were harvested at 0, 3, 7, 12, 18 and 24 hours post-infection (hpi), RNA extracted and transcriptomics analyzed by microarray.

2014-08-31 | E-GEOD-56677 | biostudies-arrayexpress

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