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1.
Int J Mol Sci ; 22(19)2021 Oct 05.
Article in English | MEDLINE | ID: covidwho-1457746

ABSTRACT

Various pathogens, such as Ebola virus, Marburg virus, Nipah virus, Hendra virus, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), Middle East Respiratory Syndrome Coronavirus (MERS-CoV), and SARS-CoV-2, are threatening human health worldwide. The natural hosts of these pathogens are thought to be bats. The rousette bat, a megabat, is thought to be a natural reservoir of filoviruses, including Ebola and Marburg viruses. Additionally, the rousette bat showed a transient infection in the experimental inoculation of SARS-CoV-2. In the current study, we established and characterized intestinal organoids from Leschenault's rousette, Rousettus leschenaultii. The established organoids successfully recapitulated the characteristics of intestinal epithelial structure and morphology, and the appropriate supplements necessary for long-term stable culture were identified. The organoid showed susceptibility to Pteropine orthoreovirus (PRV) but not to SARS-CoV-2 in experimental inoculation. This is the first report of the establishment of an expandable organoid culture system of the rousette bat intestinal organoid and its sensitivity to bat-associated viruses, PRV and SARS-CoV-2. This organoid is a useful tool for the elucidation of tolerance mechanisms of the emerging rousette bat-associated viruses such as Ebola and Marburg virus.


Subject(s)
COVID-19/virology , Chiroptera/virology , Organoids/virology , Orthoreovirus/physiology , Reoviridae Infections/virology , SARS-CoV-2/physiology , Animals , COVID-19/veterinary , Cell Culture Techniques , Cells, Cultured , Chiroptera/physiology , Humans , Intestines/cytology , Intestines/virology , Organoids/cytology , Reoviridae Infections/veterinary
2.
Int J Mol Sci ; 22(3)2021 Jan 26.
Article in English | MEDLINE | ID: covidwho-1389389

ABSTRACT

A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients' CNS and serve as a platform for therapeutic development and personalized precision medicine.


Subject(s)
Central Nervous System Diseases/drug therapy , Drug Discovery/methods , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/drug effects , Tissue Engineering/methods , Animals , COVID-19/drug therapy , COVID-19/pathology , Central Nervous System Diseases/pathology , Drug Discovery/instrumentation , Drug Evaluation, Preclinical/instrumentation , Drug Evaluation, Preclinical/methods , Humans , Induced Pluripotent Stem Cells/pathology , Lab-On-A-Chip Devices , Organoids/cytology , Organoids/drug effects , Organoids/pathology , Tissue Engineering/instrumentation , Zika Virus Infection/drug therapy , Zika Virus Infection/pathology
3.
Stem Cell Res Ther ; 11(1): 448, 2020 10 23.
Article in English | MEDLINE | ID: covidwho-1388825

ABSTRACT

Gene therapy is being investigated for a range of serious lung diseases, such as cystic fibrosis and emphysema. Recombinant adeno-associated virus (rAAV) is a well-established, safe, viral vector for gene delivery with multiple naturally occurring and artificial serotypes available displaying alternate cell, tissue, and species-specific tropisms. Efficient AAV serotypes for the transduction of the conducting airways have been identified for several species; however, efficient serotypes for human lung parenchyma have not yet been identified. Here, we screened the ability of multiple AAV serotypes to transduce lung bud organoids (LBOs)-a model of human lung parenchyma generated from human embryonic stem cells. Microinjection of LBOs allowed us to model transduction from the luminal surface, similar to dosing via vector inhalation. We identified the naturally occurring rAAV2 and rAAV6 serotypes, along with synthetic rAAV6 variants, as having tropism for the human lung parenchyma. Positive staining of LBOs for surfactant proteins B and C confirmed distal lung identity and suggested the suitability of these vectors for the transduction of alveolar type II cells. Our findings establish LBOs as a new model for pulmonary gene therapy and stress the relevance of LBOs as a viral infection model of the lung parenchyma as relevant in SARS-CoV-2 research.


Subject(s)
Dependovirus/genetics , Genetic Therapy/methods , Human Embryonic Stem Cells/cytology , Lung Diseases/therapy , Organoids/cytology , Cell Line , Dependovirus/immunology , Gene Transfer Techniques , Genetic Vectors/genetics , Humans , Lung/metabolism , Models, Biological , Parenchymal Tissue/cytology
4.
Stem Cells Transl Med ; 10(11): 1491-1499, 2021 11.
Article in English | MEDLINE | ID: covidwho-1321718

ABSTRACT

Experimental cell models are indispensable for clarifying the pathophysiology of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and for developing therapeutic agents. To recapitulate the symptoms and drug response of COVID-19 patients in vitro, SARS-CoV-2 studies using physiologically relevant human embryonic stem (ES)/induced pluripotent stem (iPS) cell-derived somatic cells and organoids are ongoing. These cells and organoids have been used to show that SARS-CoV-2 can infect and damage various organs including the lung, heart, brain, intestinal tract, kidney, and pancreas. They are also being used to develop COVID-19 therapeutic agents, including evaluation of their antiviral efficacy and safety. The relationship between COVID-19 aggravation and human genetic backgrounds has been investigated using genetically modified ES/iPS cells and patient-derived iPS cells. This review summarizes the latest results and issues of SARS-CoV-2 research using human ES/iPS cell-derived somatic cells and organoids.


Subject(s)
COVID-19 , Human Embryonic Stem Cells/physiology , Organoids/physiology , SARS-CoV-2/physiology , Biomedical Research/methods , Biomedical Research/trends , COVID-19/etiology , COVID-19/pathology , COVID-19/therapy , Genetic Therapy/methods , Genetic Therapy/trends , Human Embryonic Stem Cells/transplantation , Humans , Induced Pluripotent Stem Cells/physiology , Induced Pluripotent Stem Cells/transplantation , Organoids/cytology , Organoids/transplantation
5.
Int J Mol Sci ; 22(14)2021 Jul 17.
Article in English | MEDLINE | ID: covidwho-1323268

ABSTRACT

Organoids represent one of the most important advancements in the field of stem cells during the past decade. They are three-dimensional in vitro culturing models that originate from self-organizing stem cells and can mimic the in vivo structural and functional specificities of body organs. Organoids have been established from multiple adult tissues as well as pluripotent stem cells and have recently become a powerful tool for studying development and diseases in vitro, drug screening, and host-microbe interaction. The use of stem cells-that have self-renewal capacity to proliferate and differentiate into specialized cell types-for organoids culturing represents a major advancement in biomedical research. Indeed, this new technology has a great potential to be used in a multitude of fields, including cancer research, hereditary and infectious diseases. Nevertheless, organoid culturing is still rife with many challenges, not limited to being costly and time consuming, having variable rates of efficiency in generation and maintenance, genetic stability, and clinical applications. In this review, we aim to provide a synopsis of pluripotent stem cell-derived organoids and their use for disease modeling and other clinical applications.


Subject(s)
Drug Evaluation, Preclinical/methods , Organ Culture Techniques/methods , Organoids/cytology , Pluripotent Stem Cells/cytology , Animals , Humans , Models, Biological , Organoids/drug effects , Organoids/metabolism , Pluripotent Stem Cells/drug effects , Pluripotent Stem Cells/metabolism
6.
Stem Cell Reports ; 16(5): 1156-1164, 2021 05 11.
Article in English | MEDLINE | ID: covidwho-1225409

ABSTRACT

Coronavirus disease 2019 (COVID-19) patients have manifested a variety of neurological complications, and there is still much to reveal regarding the neurotropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human stem cell-derived brain organoids offer a valuable in vitro approach to study the cellular effects of SARS-CoV-2 on the brain. Here we used human embryonic stem cell-derived cortical organoids to investigate whether SARS-CoV-2 could infect brain tissue in vitro and found that cortical organoids could be infected at low viral titers and within 6 h. Importantly, we show that glial cells and cells of the choroid plexus were preferentially targeted in our model, but not neurons. Interestingly, we also found expression of angiotensin-converting enzyme 2 in SARS-CoV-2 infected cells; however, viral replication and cell death involving DNA fragmentation does not occur. We believe that our model is a tractable platform to study the cellular effects of SARS-CoV-2 infection in brain tissue.


Subject(s)
COVID-19/pathology , Choroid Plexus/pathology , Human Embryonic Stem Cells/cytology , Neuroglia/virology , Organoids/innervation , Organoids/pathology , Cells, Cultured , Choroid Plexus/cytology , Choroid Plexus/virology , Humans , Neuroglia/pathology , Neurons/virology , Organoids/cytology , SARS-CoV-2/pathogenicity
7.
Stem Cell Reports ; 16(4): 940-953, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1180038

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to coronavirus disease 2019 (COVID-19) usually results in respiratory disease, but extrapulmonary manifestations are of major clinical interest. Intestinal symptoms of COVID-19 are present in a significant number of patients, and include nausea, diarrhea, and viral RNA shedding in feces. Human induced pluripotent stem cell-derived intestinal organoids (HIOs) represent an inexhaustible cellular resource that could serve as a valuable tool to study SARS-CoV-2 as well as other enteric viruses that infect the intestinal epithelium. Here, we report that SARS-CoV-2 productively infects both proximally and distally patterned HIOs, leading to the release of infectious viral particles while stimulating a robust transcriptomic response, including a significant upregulation of interferon-related genes that appeared to be conserved across multiple epithelial cell types. These findings illuminate a potential inflammatory epithelial-specific signature that may contribute to both the multisystemic nature of COVID-19 as well as its highly variable clinical presentation.


Subject(s)
COVID-19/pathology , Colon/pathology , Intestinal Mucosa/pathology , Organoids/pathology , Cell Line , Colon/virology , Epithelial Cells/virology , Humans , Induced Pluripotent Stem Cells/cytology , Inflammation/virology , Intestinal Mucosa/virology , Models, Biological , Organoids/cytology , Organoids/virology , SARS-CoV-2 , Virus Replication/physiology
9.
Nature ; 589(7841): 270-275, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065893

ABSTRACT

There is an urgent need to create novel models using human disease-relevant cells to study severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) biology and to facilitate drug screening. Here, as SARS-CoV-2 primarily infects the respiratory tract, we developed a lung organoid model using human pluripotent stem cells (hPSC-LOs). The hPSC-LOs (particularly alveolar type-II-like cells) are permissive to SARS-CoV-2 infection, and showed robust induction of chemokines following SARS-CoV-2 infection, similar to what is seen in patients with COVID-19. Nearly 25% of these patients also have gastrointestinal manifestations, which are associated with worse COVID-19 outcomes1. We therefore also generated complementary hPSC-derived colonic organoids (hPSC-COs) to explore the response of colonic cells to SARS-CoV-2 infection. We found that multiple colonic cell types, especially enterocytes, express ACE2 and are permissive to SARS-CoV-2 infection. Using hPSC-LOs, we performed a high-throughput screen of drugs approved by the FDA (US Food and Drug Administration) and identified entry inhibitors of SARS-CoV-2, including imatinib, mycophenolic acid and quinacrine dihydrochloride. Treatment at physiologically relevant levels of these drugs significantly inhibited SARS-CoV-2 infection of both hPSC-LOs and hPSC-COs. Together, these data demonstrate that hPSC-LOs and hPSC-COs infected by SARS-CoV-2 can serve as disease models to study SARS-CoV-2 infection and provide a valuable resource for drug screening to identify candidate COVID-19 therapeutics.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/virology , Colon/cytology , Drug Evaluation, Preclinical/methods , Lung/cytology , Organoids/drug effects , Organoids/virology , SARS-CoV-2/drug effects , Animals , COVID-19/drug therapy , COVID-19/prevention & control , Colon/drug effects , Colon/virology , Drug Approval , Female , Heterografts/drug effects , Humans , In Vitro Techniques , Lung/drug effects , Lung/virology , Male , Mice , Organoids/cytology , Organoids/metabolism , SARS-CoV-2/genetics , United States , United States Food and Drug Administration , Viral Tropism , Virus Internalization/drug effects
10.
Int J Mol Sci ; 22(3)2021 Jan 28.
Article in English | MEDLINE | ID: covidwho-1055070

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) was identified as the main host cell receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its subsequent infection. In some coronavirus disease 2019 (COVID-19) patients, it has been reported that the nervous tissues and the eyes were also affected. However, evidence supporting that the retina is a target tissue for SARS-CoV-2 infection is still lacking. This present study aimed to investigate whether ACE2 expression plays a role in human retinal neurons during SARS-CoV-2 infection. Human induced pluripotent stem cell (hiPSC)-derived retinal organoids and monolayer cultures derived from dissociated retinal organoids were generated. To validate the potential entry of SARS-CoV-2 infection in the retina, we showed that hiPSC-derived retinal organoids and monolayer cultures endogenously express ACE2 and transmembrane serine protease 2 (TMPRSS2) on the mRNA level. Immunofluorescence staining confirmed the protein expression of ACE2 and TMPRSS2 in retinal organoids and monolayer cultures. Furthermore, using the SARS-CoV-2 pseudovirus spike protein with GFP expression system, we found that retinal organoids and monolayer cultures can potentially be infected by the SARS-CoV-2 pseudovirus. Collectively, our findings highlighted the potential of iPSC-derived retinal organoids as the models for ACE2 receptor-based SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Gene Expression , Induced Pluripotent Stem Cells/cytology , Retina/cytology , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Cell Culture Techniques , Cell Line , Humans , Induced Pluripotent Stem Cells/metabolism , Organoids/cytology , Organoids/metabolism , Retina/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Virus Internalization
11.
Int J Mol Sci ; 22(3)2021 Jan 26.
Article in English | MEDLINE | ID: covidwho-1050617

ABSTRACT

A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients' CNS and serve as a platform for therapeutic development and personalized precision medicine.


Subject(s)
Central Nervous System Diseases/drug therapy , Drug Discovery/methods , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/drug effects , Tissue Engineering/methods , Animals , COVID-19/drug therapy , COVID-19/pathology , Central Nervous System Diseases/pathology , Drug Discovery/instrumentation , Drug Evaluation, Preclinical/instrumentation , Drug Evaluation, Preclinical/methods , Humans , Induced Pluripotent Stem Cells/pathology , Lab-On-A-Chip Devices , Organoids/cytology , Organoids/drug effects , Organoids/pathology , Tissue Engineering/instrumentation , Zika Virus Infection/drug therapy , Zika Virus Infection/pathology
12.
Nat Med ; 27(1): 125-135, 2021 01.
Article in English | MEDLINE | ID: covidwho-1023963

ABSTRACT

Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.


Subject(s)
Influenza Vaccines/immunology , Palatine Tonsil/immunology , Adjuvants, Immunologic , B-Lymphocytes/cytology , B-Lymphocytes/immunology , COVID-19 Vaccines/immunology , Germinal Center/cytology , Hemagglutinin Glycoproteins, Influenza Virus , Humans , In Vitro Techniques , Lymphoid Tissue/immunology , Measles-Mumps-Rubella Vaccine/immunology , Organoids/cytology , Organoids/immunology , Rabies Vaccines/immunology , T-Lymphocytes/immunology
13.
Nature ; 588(7839): 670-675, 2020 12.
Article in English | MEDLINE | ID: covidwho-943910

ABSTRACT

The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5+ cells in basal organoids revealed a distinct population of ITGA6+ITGB4+ mitotic cells, whose offspring further segregated into a TNFRSF12Ahi subfraction that comprised about ten per cent of KRT5+ basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia.


Subject(s)
COVID-19/virology , Lung/cytology , Models, Biological , Organoids/cytology , Organoids/virology , SARS-CoV-2/physiology , Tissue Culture Techniques , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/metabolism , Alveolar Epithelial Cells/virology , COVID-19/metabolism , COVID-19/pathology , Cell Differentiation , Cell Division , Clone Cells/cytology , Clone Cells/metabolism , Clone Cells/virology , Humans , In Vitro Techniques , Influenza A Virus, H1N1 Subtype/growth & development , Influenza A Virus, H1N1 Subtype/physiology , Integrin alpha6/analysis , Integrin beta4/analysis , Keratin-5/analysis , Organoids/metabolism , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS-CoV-2/growth & development , Single-Cell Analysis , TWEAK Receptor/analysis
14.
Curr Protoc Stem Cell Biol ; 54(1): e118, 2020 09.
Article in English | MEDLINE | ID: covidwho-635380

ABSTRACT

The normal development of the pulmonary system is critical to transitioning from placental-dependent fetal life to alveolar-dependent newborn life. Human lung development and disease have been difficult to study due to the lack of an in vitro model system containing cells from the large airways and distal alveolus. This article describes a system that allows human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) to differentiate and form three-dimensional (3D) structures that emulate the development, cytoarchitecture, and function of the lung ("organoids"), containing epithelial and mesenchymal cell populations, and including the production of surfactant and presence of ciliated cells. The organoids can also be invested with mesoderm derivatives, differentiated from the same human pluripotent stem cells, such as alveolar macrophages and vasculature. Such lung organoids may be used to study the impact of environmental modifiers and perturbagens (toxins, microbial or viral pathogens, alterations in microbiome) or the efficacy and safety of drugs, biologics, and gene transfer. © 2020 Wiley Periodicals LLC. Basic Protocol: hESC/hiPSC dissection, definitive endoderm formation, and lung progenitor cell induction.


Subject(s)
Coronavirus Infections/pathology , Lung/cytology , Organoids/cytology , Pneumonia, Viral/pathology , Respiratory Tract Infections/pathology , Betacoronavirus , COVID-19 , Cell Culture Techniques , Cell Differentiation , Coronavirus Infections/therapy , Endoderm/cytology , Human Embryonic Stem Cells/cytology , Humans , Induced Pluripotent Stem Cells/cytology , Lung/growth & development , Lung/physiology , Models, Biological , Pandemics , Patient-Specific Modeling , Pneumonia, Viral/therapy , Respiratory Tract Infections/therapy , SARS-CoV-2 , Time-Lapse Imaging
15.
Theranostics ; 10(16): 7034-7052, 2020.
Article in English | MEDLINE | ID: covidwho-638462

ABSTRACT

This review provides an update for the international research community on the cell modeling tools that could accelerate the understanding of SARS-CoV-2 infection mechanisms and could thus speed up the development of vaccines and therapeutic agents against COVID-19. Many bioengineering groups are actively developing frontier tools that are capable of providing realistic three-dimensional (3D) models for biological research, including cell culture scaffolds, microfluidic chambers for the culture of tissue equivalents and organoids, and implantable windows for intravital imaging. Here, we review the most innovative study models based on these bioengineering tools in the context of virology and vaccinology. To make it easier for scientists working on SARS-CoV-2 to identify and apply specific tools, we discuss how they could accelerate the discovery and preclinical development of antiviral drugs and vaccines, compared to conventional models.


Subject(s)
Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Betacoronavirus , Coronavirus Infections/drug therapy , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/prevention & control , Viral Vaccines/isolation & purification , Viral Vaccines/pharmacology , Betacoronavirus/chemistry , Betacoronavirus/genetics , Betacoronavirus/immunology , Bioengineering/methods , Bioengineering/trends , Bioreactors , COVID-19 , COVID-19 Vaccines , Cell Culture Techniques , Computer Simulation , Coronavirus Infections/immunology , Drug Discovery/methods , Drug Discovery/trends , Drug Evaluation/methods , Drug Evaluation/trends , Drug Resistance, Viral , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Models, Biological , Organoids/cytology , Organoids/virology , Pneumonia, Viral/immunology , SARS-CoV-2 , Theranostic Nanomedicine
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