Versatile β-Catenin Is Crucial for SARS-CoV-2 Infection

Chatterjee, Sanchari; Keshry, Supriya Suman; Ghosh, Soumyajit; Ray, Amrita; Chattopadhyay, Soma

doi:10.1128/spectrum.01670-22

Cited by 16 publications

(23 citation statements)

References 7 publications

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Section: Discussionmentioning

confidence: 65%

“…Besides this, blockade of β-catenin/CBP reversed pulmonary fibrosis (46), which is a central COVID-19 complication (47). A recent study confirmed overall higher β-catenin levels in SARS-CoV-2 infected patients and targeting reduced virus shedding in vitro (48). A limitation of our study is that the machine learning procedure bases on screening data of the four initial screens which were at hand when we developed the computational method.…”

Section: Discussionmentioning

confidence: 90%

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Machine learning on large scale perturbation screens for SARS-CoV-2 host factors identifies β-catenin/CBP inhibitor PRI-724 as a potent antiviral

Kelch

Vera-Guapi

Beder

et al. 2023

Preprint

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Expanding antiviral treatment options against SARS-CoV-2 remains crucial as the virus evolves rapidly and drug resistant strains have emerged. Broad spectrum host-directed antivirals (HDA) are promising therapeutic options, however the robust identification of relevant host factors by CRISPR/Cas9 or RNA interference screens remains challenging due to low consistency in the resulting hits. To address this issue, we employed machine learning based on experimental data from knockout screens and a drug screen. As gold standard, we assembled perturbed genes reducing virus replication or protecting the host cells. The machines based their predictions on features describing cellular localization, protein domains, annotated gene sets from Gene Ontology, gene and protein sequences, and experimental data from proteomics, phospho-proteomics, protein interaction and transcriptomic profiles of SARS-CoV-2 infected cells. The models reached a remarkable performance with a balanced accuracy of 0.82 (knockout based classifier) and 0.71 (drugs screen based classifier), suggesting patterns of intrinsic data consistency. The predicted host dependency factors were enriched in sets of genes particularly coding for development, morphogenesis, and neural related processes. Focusing on development and morphogenesis-associated gene sets, we found β-catenin to be central and selected PRI-724, a canonical β-catenin/CBP disruptor, as a potential HDA. PRI-724 limited infection with SARS-CoV-2 variants, SARS-CoV-1, MERS-CoV and IAV in different cell line models. We detected a concentration-dependent reduction in CPE development, viral RNA replication, and infectious virus production in SARS-CoV-2 and SARS-CoV-1-infected cells. Independent of virus infection, PRI-724 treatment caused cell cycle deregulation which substantiates its potential as a broad spectrum antiviral. Our proposed machine learning concept may support focusing and accelerating the discovery of host dependency factors and the design of antiviral therapies.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 90%

Machine learning on large scale perturbation screens for SARS-CoV-2 host factors identifies β-catenin/CBP inhibitor PRI-724 as a potent antiviral

Kelch

Vera-Guapi

Beder

et al. 2023

Preprint

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“…Enrichment analysis results showed that the host proteins interacting with the S1 protein are closely related to cell adhesion and connection, protein metabolism, and transport processes and participate in receptor interaction, apoptosis, and autophagy signaling pathways ( Figure 4 A,B and Supplementary Tables S2 and S3 ). Among the identified candidates, several proteins such as integrin, beta-catenin, nectin, otogelin, and shroom3 belong to adhesive components [ 12 , 13 , 14 ], which are potentially important factors for host cell attachment and infection progression during IBV infection.…”

Section: Discussionmentioning

confidence: 99%

Identification of Host Proteins Interacting with IBV S1 Based on Tracheal Organ Culture

Zhang

Cai

et al. 2023

Viruses

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Infectious bronchitis virus (IBV) belongs to the gamma-coronavirus genus of Coronaviridae and causes serious infectious diseases in the poultry industry. However, only a few IBV strains can infect avian passage cell lines, seriously hindering the progress of basic research on IBV pathogenesis. Whereas IBV field strains can replicate in tracheal ring organ culture (TOC) without any previous adaptation in chicken embryos or primary cells. In this study, to investigate the potential use of TOC as an in vitro infection model for the study of IBV-host interaction, we first established a chicken embryo TOC culture system and carried out an investigation on the IBV replication kinetics in the system. We found that the selected strains of the IBV GI-1, GI-7, GI-13, GI-19, and GI-22 genotypes could successfully replicate in TOC and bring about damage to the infected trachea. Next, we identified host proteins of the chicken embryo trachea that interact with the IBV S1 protein by immunoprecipitation and protein mass spectrometry. A total of 127 candidate proteins were initially identified with major involvement in cell adhesion pathways and apoptosis- and autophagy-related pathways. The heat shock protein 70 (HSP70) was selected for further investigation in the interaction with IBV viral proteins. Our results showed that HSP70 interacted with IBV S1 in both TOC and CEK cells, whereas HSP70 overexpression inhibited viral replication. This study indicates that TOC is a good system for the elucidation of IBV-host interactions and HSP70 is a potential host antiviral factor.

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“…The viral copy number was determined for the above-mentioned samples by generating the standard curve of the SARS-CoV-2 N gene. The percentage of copy number/ml was calculated from the corresponding Ct values of all the samples 20 .…”

Section: Rna Extraction and Qrt-pcrmentioning

confidence: 99%

SELEX based aptamers with diagnostic and entry inhibitor therapeutic potential for SARS-CoV-2

Halder¹,

Thakur

Keshry

et al. 2023

Preprint

Self Cite

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Frequent mutation and variable immunological protection against vaccination is a common feature for COVID-19 pandemic. Early detection and confinement remain key to controlling further spread of infection. In response, we have developed an aptamer-based system that possesses both diagnostic and therapeutic potential towards the virus. A random aptamer library (~ 1017 molecules) was screened using systematic evolution of ligands by exponential enrichment (SELEX) and aptamer R was identified as a potent binder for the SARS-CoV-2 spike receptor binding domain (RBD) using in vitro binding assay. Using a pseudotyped viral entry assay we have shown that aptamer R specifically inhibited the entry of a SARS-CoV-2 pseudotyped virus in HEK293T-ACE2 cells but did not inhibit the entry of a Vesicular Stomatitis Virus (VSV) glycoprotein (G) pseudotyped virus, hence establishing its specificity towards SARS-CoV-2 spike protein. The antiviral potential of aptamers R and J (same central sequence as R but lacking flanked primer regions) was tested and showed 95.4% and 82.5% inhibition, respectively, against the SARS-CoV-2 virus. Finally, intermolecular interactions between the aptamers and the RBD domain were analyzed using in silico docking and molecular dynamics simulations that provided additional insight into the binding and inhibitory action of aptamers R and J.

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Versatile β-Catenin Is Crucial for SARS-CoV-2 Infection

Cited by 16 publications

References 7 publications

Machine learning on large scale perturbation screens for SARS-CoV-2 host factors identifies β-catenin/CBP inhibitor PRI-724 as a potent antiviral

Machine learning on large scale perturbation screens for SARS-CoV-2 host factors identifies β-catenin/CBP inhibitor PRI-724 as a potent antiviral

Identification of Host Proteins Interacting with IBV S1 Based on Tracheal Organ Culture

SELEX based aptamers with diagnostic and entry inhibitor therapeutic potential for SARS-CoV-2

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