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

Mulay, Apoorva; Konda, Bindu; García, Gustavo; Yao, Changfu; Beil, Stephen; Villalba, Jaquelyn M.; Koziol, Colin; Sen, Chandani; Purkayastha, Arunima; Kolls, Jay K.; Pociask, Derek; Pessina, Patrizia; Aja, Julio Sainz de; Alba, Carolina García de; Kim, Carla F.; Gomperts, Brigitte N.; Arumugaswami, Vaithilingaraja; Stripp, Barry R.

doi:10.1016/j.celrep.2021.109055

Cited by 183 publications

(138 citation statements)

References 34 publications

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“…The authors conclude that the proximal airway components of the model are important for SARS-CoV-2 infectivity, while transdifferentiating alveolar epithelial cells subsequently recapitulate the host response (100). Multiple studies have reported the induction of an IFN response and upregulation of inflammatory (NF-κB) pathways upon SARS-CoV-2 infection in alveolar organoids (13,100,101,103). This characteristic allows to study IFN treatment, which has been administered to COVID-19 patients (255), in a physiologically relevant site.…”

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

confidence: 97%

“…The infection can propagate further as ACE2 and TMPRSS2 expression is found throughout the airway epithelium, particularly in ciliated and secretory cells (83, 92). Correspondingly, ciliated cells and goblet cells in the trachea and bronchi are efficiently infected by SARS-CoV-2, whereas basal cells are permissive for SARS-CoV-2 to a lower extent [ (13,14,82,93,94); Figure 1C]. The finding that SARS-CoV-2 does not infect ciliated cells of distal lung organoids but exhibits a strong tropism for club cells seems contradictory (95).…”

Section: Molecular Mechanisms Of Sars-cov-2 Infection In the Lungmentioning

confidence: 99%

“…The patient-to-patient variability can be captured by adult stem cell derived alveolar organoid models. Alveolar organoids have been generated from HTII-280 + -enriched ATII cells (101,103) or mixed alveolar epithelial cells (13,100). They maintain an ATII cell subpopulation during prolonged culture.…”

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

confidence: 99%

“…In the intact organoids, ACE2 entry receptor faces the lumen while the basolateral side is exposed to the external milieu. In order to infect the organoids with SARS-CoV-2, the apical side has to be exposed either by apical-out polarization in suspension (95) or mechanical and chemical dissociation for the infection as single cells (13,101) or as 2D monolayers (100). In contrast to hPSC-derived ATII cell monolayers, adult stem cell derived alveolar organoids nearly entirely lose the ATII cell population upon culture in 2D monolayers (100).…”

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

confidence: 99%

“…as remdesivir, camostat, imatinib, and Retro-2.1 and have helped elucidating the molecular mechanisms of host-pathogen interactions in more detail (10)(11)(12)(13)(14)(15). Increasing knowledge about the course of COVID-19 raised concerns regarding its longterm consequences.…”

Section: Introductionmentioning

confidence: 99%

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

confidence: 97%

Section: Molecular Mechanisms Of Sars-cov-2 Infection In the Lungmentioning

confidence: 99%

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

confidence: 99%

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

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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A Multifunctional Neutralizing Antibody‐Conjugated Nanoparticle Inhibits and Inactivates SARS‐CoV‐2

et al. 2021

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The outbreak of 2019 coronavirus disease (COVID‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has resulted in a global pandemic. Despite intensive research, the current treatment options show limited curative efficacies. Here the authors report a strategy incorporating neutralizing antibodies conjugated to the surface of a photothermal nanoparticle (NP) to capture and inactivate SARS‐CoV‐2. The NP is comprised of a semiconducting polymer core and a biocompatible polyethylene glycol surface decorated with high‐affinity neutralizing antibodies. The multifunctional NP efficiently captures SARS‐CoV‐2 pseudovirions and completely blocks viral infection to host cells in vitro through the surface neutralizing antibodies. In addition to virus capture and blocking function, the NP also possesses photothermal function to generate heat following irradiation for inactivation of virus. Importantly, the NPs described herein significantly outperform neutralizing antibodies at treating authentic SARS‐CoV‐2 infection in vivo. This multifunctional NP provides a flexible platform that can be readily adapted to other SARS‐CoV‐2 antibodies and extended to novel therapeutic proteins, thus it is expected to provide a broad range of protection against original SARS‐CoV‐2 and its variants.

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3D printed human organoids: High throughput system for drug screening and testing in current COVID‐19 pandemic

Parihar

Pandita

Khan

2022

Biotech & Bioengineering

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In the current pandemic, scenario the world is facing a huge shortage of effective drugs and other prophylactic medicine to treat patients which created havoc in several countries with poor resources. With limited demand and supply of effective drugs, researchers rushed to repurpose the existing approved drugs for the treatment of COVID‐19. The process of drug screening and testing is very costly and requires several steps for validation and treatment efficacy evaluation ranging from in‐vitro to in‐vivo setups. After these steps, a clinical trial is mandatory for the evaluation of treatment efficacy and side effects in humans. These processes enhance the overall cost and sometimes the lead molecule show adverse effects in humans and the trial ends up in the final stages. Recently with the advent of three‐dimensional (3D) organoid culture which mimics the human tissue exactly the process of drug screening and testing can be done in a faster and cost‐effective manner. Further 3D organoids prepared from stems cells taken from individuals can be beneficial for personalized drug therapy which could save millions of lives. This review discussed approaches and techniques for the synthesis of 3D‐printed human organoids for drug screening. The key findings of the usage of organoids for personalized medicine for the treatment of COVID‐19 have been discussed. In the end, the key challenges for the wide applicability of human organoids for drug screening with prospects of future orientation have been included.

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

Cited by 183 publications

References 34 publications

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

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

A Multifunctional Neutralizing Antibody‐Conjugated Nanoparticle Inhibits and Inactivates SARS‐CoV‐2

3D printed human organoids: High throughput system for drug screening and testing in current COVID‐19 pandemic

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