Ebola virus infection induces a delayed type I IFN response in bystander cells and the shutdown of key liver genes in human iPSC-derived hepatocytes

Scoon, Whitney A; Mâncio-Silva, Liliana; Suder, Ellen L.; Villacorta‐Martin, Carlos; Lindstrom-Vautrin, Jonathan; Bernbaum, John G.; Mazur, Steve; Johnson, Reed F.; Olejnik, Judith; Flores, Elizabeth; Mithal, Aditya; Wang, Feiya; Hume, Adam J.; Kaserman, Joseph E.; March-Riera, Sandra; Wilson, Andrew; Bhatia, Sangeeta N.; Mühlberger, Elke; Mostoslavsky, Gustavo

doi:10.1016/j.stemcr.2022.08.003

Cited by 7 publications

(4 citation statements)

References 57 publications

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“…ZINC000034518176, ZINC000095485942, NANPDB2933, ZINC000014089759, ZINC000085545967, ZINC000014089743, and ZINC000101564200 were also predicted to be hepatoprotectants with Pa values of 0.926, 0.377, 0.282, 0.929, 0.429, 0.932, and 0.317 and Pi values of 0.002, 0.036, 0.066, 0.002, 0.027, 0.002, and 0.054, respectively. Liver damage is one of the hallmarks of EVD infection [ 103 , 104 , 105 ]. These compounds may be beneficial with respect to managing liver failure and may support the liver during recovery from EVD.…”

Section: Resultsmentioning

confidence: 99%

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Broni

Ashley

Adams

et al. 2023

IJMS

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The Ebola virus (EBOV) is still highly infectious and causes severe hemorrhagic fevers in primates. However, there are no regulatorily approved drugs against the Ebola virus disease (EVD). The highly virulent and lethal nature of EVD highlights the need to develop therapeutic agents. Viral protein 40 kDa (VP40), the most abundantly expressed protein during infection, coordinates the assembly, budding, and release of viral particles into the host cell. It also regulates viral transcription and RNA replication. This study sought to identify small molecules that could potentially inhibit the VP40 protein by targeting the N-terminal domain using an in silico approach. The statistical quality of AutoDock Vina’s capacity to discriminate between inhibitors and decoys was determined, and an area under the curve of the receiver operating characteristic (AUC-ROC) curve of 0.791 was obtained. A total of 29,519 natural-product-derived compounds from Chinese and African sources as well as 2738 approved drugs were successfully screened against VP40. Using a threshold of −8 kcal/mol, a total of 7, 11, 163, and 30 compounds from the AfroDb, Northern African Natural Products Database (NANPDB), traditional Chinese medicine (TCM), and approved drugs libraries, respectively, were obtained after molecular docking. A biological activity prediction of the lead compounds suggested their potential antiviral properties. In addition, random-forest- and support-vector-machine-based algorithms predicted the compounds to be anti-Ebola with IC50 values in the micromolar range (less than 25 μM). A total of 42 natural-product-derived compounds were identified as potential EBOV inhibitors with desirable ADMET profiles, comprising 1, 2, and 39 compounds from NANPDB (2-hydroxyseneganolide), AfroDb (ZINC000034518176 and ZINC000095485942), and TCM, respectively. A total of 23 approved drugs, including doramectin, glecaprevir, velpatasvir, ledipasvir, avermectin B1, nafarelin acetate, danoprevir, eltrombopag, lanatoside C, and glycyrrhizin, among others, were also predicted to have potential anti-EBOV activity and can be further explored so that they may be repurposed for EVD treatment. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area calculations corroborated the stability and good binding affinities of the complexes (−46.97 to −118.9 kJ/mol). The potential lead compounds may have the potential to be developed as anti-EBOV drugs after experimental testing.

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Section: Resultsmentioning

confidence: 99%

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Broni

Ashley

Adams

et al. 2023

IJMS

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“…3c). 288,[376][377][378][379] The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the scientific community to rapidly repurpose experimental platforms, so that SARS-CoV-2 cellular tropism, molecular mechanisms of entry, life cycle, and SARS-CoV-2 targeting therapeutics could be investigated. [380][381][382] Although animal cell lines and models permissive to SARS-CoV-2 have been identified and developed, human iPSC-derived cellular models have the advantage of revealing human-specific SARS-CoV-2 tropism and vulnerabilities.…”

Section: Modeling Covid-19 With Ipsc-derived Cellsmentioning

confidence: 99%

Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications

Cerneckis,

Cai,

Shi

2024

Sig Transduct Target Ther

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The induced pluripotent stem cell (iPSC) technology has transformed in vitro research and holds great promise to advance regenerative medicine. iPSCs have the capacity for an almost unlimited expansion, are amenable to genetic engineering, and can be differentiated into most somatic cell types. iPSCs have been widely applied to model human development and diseases, perform drug screening, and develop cell therapies. In this review, we outline key developments in the iPSC field and highlight the immense versatility of the iPSC technology for in vitro modeling and therapeutic applications. We begin by discussing the pivotal discoveries that revealed the potential of a somatic cell nucleus for reprogramming and led to successful generation of iPSCs. We consider the molecular mechanisms and dynamics of somatic cell reprogramming as well as the numerous methods available to induce pluripotency. Subsequently, we discuss various iPSC-based cellular models, from mono-cultures of a single cell type to complex three-dimensional organoids, and how these models can be applied to elucidate the mechanisms of human development and diseases. We use examples of neurological disorders, coronavirus disease 2019 (COVID-19), and cancer to highlight the diversity of disease-specific phenotypes that can be modeled using iPSC-derived cells. We also consider how iPSC-derived cellular models can be used in high-throughput drug screening and drug toxicity studies. Finally, we discuss the process of developing autologous and allogeneic iPSC-based cell therapies and their potential to alleviate human diseases.

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“…However, donor-to-donor variations, limited accessibility, and short lifespan substantially limit primary cell practicability [ 126 , 129 ]. Nonetheless, induced pluripotent stem cell (iPSC)-derived human cells such as hepatocytes are physiologically more similar to human primary hepatocytes than the well-established Huh7 cell line, thereby better modeling the host cell response, for instance, in filoviral infection [ 130 ]. Moreover, primary cell culture may be further advanced by micropatterned co-culture (MPCC) [ 129 , 130 , 131 ] to model a certain niche with adequate cell–cell-interactions.…”

Section: Complex In Vitro Models In Viral Researchmentioning

confidence: 99%

“…Nonetheless, induced pluripotent stem cell (iPSC)-derived human cells such as hepatocytes are physiologically more similar to human primary hepatocytes than the well-established Huh7 cell line, thereby better modeling the host cell response, for instance, in filoviral infection [ 130 ]. Moreover, primary cell culture may be further advanced by micropatterned co-culture (MPCC) [ 129 , 130 , 131 ] to model a certain niche with adequate cell–cell-interactions. Such models can be more predictive of clinical outcomes compared to standard culture [ 129 , 131 ].…”

Section: Complex In Vitro Models In Viral Researchmentioning

confidence: 99%

Animal Model Alternatives in Filovirus and Bornavirus Research

Widerspick

Steffen

Tappe

et al. 2023

Viruses

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The order Mononegavirales contains a variety of highly pathogenic viruses that may infect humans, including the families Filoviridae, Bornaviridae, Paramyxoviridae, and Rhabodoviridae. Animal models have historically been important to study virus pathogenicity and to develop medical countermeasures. As these have inherent shortcomings, the rise of microphysiological systems and organoids able to recapitulate hallmarks of the diseases caused by these viruses may have enormous potential to add to or partially replace animal modeling in the future. Indeed, microphysiological systems and organoids are already used in the pharmaceutical R&D pipeline because they are prefigured to overcome the translational gap between model systems and clinical studies. Moreover, they may serve to alleviate ethical concerns related to animal research. In this review, we discuss the value of animal model alternatives in human pathogenic filovirus and bornavirus research. The current animal models and their limitations are presented followed by an overview of existing alternatives, such as organoids and microphysiological systems, which might help answering open research questions.

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Ebola virus infection induces a delayed type I IFN response in bystander cells and the shutdown of key liver genes in human iPSC-derived hepatocytes

Cited by 7 publications

References 57 publications

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Cheminformatics-Based Study Identifies Potential Ebola VP40 Inhibitors

Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications

Animal Model Alternatives in Filovirus and Bornavirus Research

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