A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids

Yang, Liuliu; Han, Yanxiao; Nilsson-Payant, Benjamin E.; Gupta, Vikas; Wang, Pengfei; Duan, Xiaohua; Tang, Xiaoxue; Zhu, Jiajun; Zhao, Zhongyan; Jaffré, Fabrice; Zhang, Tuo; Kim, Tae Wan; Harschnitz, Oliver; Redmond, David; Houghton, Sean; Liu, Chengyang; Naji, Ali; Ciceri, Gabriele; Guttikonda, Sudha R; Bram, Yaron; Nguyen, Duc-Huy T.; Cioffi, Michèle; Chandar, Vasuretha; Hoagland, Daisy A.; Huang, Yaoxing; Xiang, Jenny; Wang, Hui; Lyden, David; Borczuk, Alain C.; Chen, Huanhuan Joyce; Studer, Lorenz; Pan, Fong Cheng; Ho, David D.; tenOever, Benjamin R.; Evans, Todd; Schwartz, Robert E.; Chen, Shuibing

doi:10.1016/j.stem.2020.06.015

Cited by 580 publications

(785 citation statements)

References 53 publications

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“…In addition, the range of different cell types detected as infected by SARS-CoV-2 keep expanding (e.g. 173,174,175,176 ) . We thus do think that this apparent limitation could be also seen as an asset of our study; (ii) In our opinion, the main limitation This first proximal interaction mapping of SARS-CoV-2 proteins provides a plethora of novel research tracks to better understand this virus pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

Laurent

Sofianatos

Komarova

et al. 2020

Preprint

128

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The worldwide SARS-CoV-2 outbreak poses a serious challenge to human societies and economies. SARS-CoV-2 proteins orchestrate complex pathogenic mechanisms that underlie COVID-19 disease. Thus, understanding how viral polypeptides rewire host protein networks enables better-founded therapeutic research. In complement to existing proteomic studies, in this study we define the first proximal interaction network of SARS-CoV-2 proteins, at the whole proteome level in human cells. Applying a proximity-dependent biotinylation (BioID)-based approach greatly expanded the current knowledge by detecting interactions within poorly soluble compartments, transient, and/or of weak affinity in living cells. Our BioID study was complemented by a stringent filtering and uncovered 2,128 unique cellular targets (1,717 not previously associated with SARS-CoV-1 or 2 proteins) connected to the N- and C-ter BioID-tagged 28 SARS-CoV-2 proteins by a total of 5,415 (5,236 new) proximal interactions. In order to facilitate data exploitation, an innovative interactive 3D web interface was developed to allow customized analysis and exploration of the landscape of interactions (accessible at http://www.sars-cov-2-interactome.org/). Interestingly, 342 membrane proteins including interferon and interleukin pathways factors, were associated with specific viral proteins. We uncovered ORF7a and ORF7b protein proximal partners that could be related to anosmia and ageusia symptoms. Moreover, comparing proximal interactomes in basal and infection-mimicking conditions (poly(I:C) treatment) allowed us to detect novel links with major antiviral response pathway components, such as ORF9b with MAVS and ISG20; N with PKR and TARB2; NSP2 with RIG-I and STAT1; NSP16 with PARP9-DTX3L. Altogether, our study provides an unprecedented comprehensive resource for understanding how SARS-CoV-2 proteins orchestrate host proteome remodeling and innate immune response evasion, which can inform development of targeted therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

Laurent

Sofianatos

Komarova

et al. 2020

Preprint

128

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“…To investigate whether organoids from different tissues exhibit similar transcriptional responses upon SARS-CoV-2 infection, we compared SARS-CoV-2 induced transcriptional changes among CPOs and published datasets from hepatocyte organoids (Yang et al, 2020a) and intestinal organoids (Lamers et al, 2020). Surprisingly, we found little overlap among upregulated or downregulated genes in the three different organoid types, suggesting a predominantly cell typespecific response to SARS-CoV-2 infection ( Figure 4E).…”

Section: Transcriptional Dysregulation Of Choroid Plexus Organoids Upmentioning

confidence: 98%

“…Additionally, these cultures were useful in screening for drugs to treat ZIKV infection (Xu et al, 2016). Recently, hiPSC-derived organoids have been used to model SARS-CoV-2 infection in many organs, including the intestine, lung, kidney, liver, pancreas, and vasculature (Lamers et al, 2020;Monteil et al, 2020;Yang et al, 2020a;Zhou et al, 2020). These studies have shown that SARS-CoV-2 can infect and replicate within cells of multiple organs, leading to transcriptional changes indicative of inflammatory responses and altered cellular functions.…”

Section: Introductionmentioning

confidence: 99%

Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism

Jacob

Pather

Huang

et al. 2020

Preprint

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SUMMARYNeurological complications are common in patients with COVID-19. While SARS-CoV-2, the causal pathogen of COVID-19, has been detected in some patient brains, its ability to infect brain cells and impact their function are not well understood, and experimental models using human brain cells are urgently needed. Here we investigated the susceptibility of human induced pluripotent stem cell (hiPSC)-derived monolayer brain cells and region-specific brain organoids to SARS-CoV-2 infection. We found modest numbers of infected neurons and astrocytes, but greater infection of choroid plexus epithelial cells. We optimized a protocol to generate choroid plexus organoids from hiPSCs, which revealed productive SARS-CoV-2 infection that leads to increased cell death and transcriptional dysregulation indicative of an inflammatory response and cellular function deficits. Together, our results provide evidence for SARS-CoV-2 neurotropism and support use of hiPSC-derived brain organoids as a platform to investigate the cellular susceptibility, disease mechanisms, and treatment strategies for SARS-CoV-2 infection.

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“…Given the fact that ACE2 is expressed on pancreatic β-cells and ACE2 is the main receptor for COVID-19 (Sars-CoV-2) internalization we would like to propose a direct cytolytic β-cell damage due to COVID-19 (Sars-CoV-2) resulting in an insulin-depended diabetes without a classical autoimmune pathology in our patient. This assumption is supported by a recent mechanistic study demonstrating that adult human pancreatic alpha and beta cells are permissive to Sars-CoV-2 pseudo-entry virus and Sars-CoV-2 virus infection [14] . Furthermore, Sars-CoV-2 infection of pancreatic endocrine cells resulted in robust chemokine induction as seen in Covid-19 patients and upregulation of markers of cell death [14] .…”

Section: Discussionmentioning

confidence: 73%

“…This assumption is supported by a recent mechanistic study demonstrating that adult human pancreatic alpha and beta cells are permissive to Sars-CoV-2 pseudo-entry virus and Sars-CoV-2 virus infection [14] . Furthermore, Sars-CoV-2 infection of pancreatic endocrine cells resulted in robust chemokine induction as seen in Covid-19 patients and upregulation of markers of cell death [14] .…”

Section: Discussionmentioning

confidence: 73%

Autoantibody-negative insulin-dependent Diabetes after COVID-19

Hollstein

Schulz

Glück

et al. 2020

Preprint

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Abstract Here we report the manifestation of insulin dependent diabetes after a COVID-19 infection in the absence of typical autoantibodies for type 1 diabetes. A 19-year-old Caucasian male subject presented to our emergency department with diabetic ketoacidosis (DKA). C-peptide levels accounted to 0.62µg/L in the presence of blood glucose concentrations of 30.6 mmol/L (552 mg/dL). The patient´s case history revealed a COVID-19 disease 6-8 weeks prior to admission. This is of interest, since COVID-19 internalization into host cells is mediated via Angiotensin-converting enzyme 2 (ACE2) [1], a transmembrane glycoprotein which amongst others is crucial for β-cell homeostasis and function [2,3,4]. Detailed laboratory testing was performed, revealing no serum-antibodies against islet-cells (ICA), glutamic acid decarboxylase (GAD65-AA), tyrosine phosphatase (IA-2-AA), insulin (IAA) and zinc-transport-8 (ZnT8-AA), but against COVID-19. Hence, this is a presentation of an insulin-dependent diabetes mellitus in the absence of markers of autoimmunity, which might suggest direct cytolytic effects of COVID-19 on pancreatic β-cells presumably mediated via ACE2.

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A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids

Cited by 580 publications

References 53 publications

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms

Human Pluripotent Stem Cell-Derived Neural Cells and Brain Organoids Reveal SARS-CoV-2 Neurotropism

Autoantibody-negative insulin-dependent Diabetes after COVID-19

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