Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

Spalinger, Marianne R.; Hai, Rong; Jiang, Li; Santos, Alina N.; Nordgren, Tara M.; Tremblay, Michel L.; Eckmann, Lars; Hanson, Elaine; Scharl, Michael; Wu, Xiwei; Boland, Brigid S.; McCole, Declan F.

doi:10.1101/2020.12.09.416586

Cited by 8 publications

(4 citation statements)

References 52 publications

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“…T-cell protein tyrosine phosphatase, PTPN2, negatively regulates the antiviral response of MITA [89] and the JAK-STAT pathway of the innate immune system [90]. Knockout of PTPN2 results in systemic inflammatory responses in mice resulting in premature death [91], and a genetic polymorphism resulting in PTPN2 loss of function increases ACE2 expression, resulting in greater susceptibility to SARS-CoV-2 infection [77].…”

Section: Discussionmentioning

confidence: 99%

“…Nsp3 mediated modulation of ubiquitination has been shown to be important for IFN antagonism [32][33][34][35][36][37][38][39], and there is also evidence for Nsp5 mediated reduction of ubiquitination [45,47]. Finally, a group of proteins implicated in cytokine response was also strongly predicted to be cleaved (AIMP1, MAPK12, and PTPN2), which are involved in downstream signaling of multiple cytokines [74][75][76][77].…”

Section: Network Analysis and Pathways Of Interestmentioning

confidence: 98%

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Predicted Coronavirus Nsp5 Protease Cleavage Sites in the Human Proteome: A Resource for SARS-CoV-2 Research

Lacasse

et al. 2021

Preprint

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Background: The coronavirus nonstructural protein 5 (Nsp5) is a cysteine protease required for processing the viral polyprotein and is therefore crucial for viral replication. Nsp5 from several coronaviruses have also been found to cleave host proteins, disrupting molecular pathways involved in innate immunity. Nsp5 from the recently emerged SARS-CoV-2 virus interacts with and can cleave human proteins, which may be relevant to the pathogenesis of COVID-19. Based on the continuing global pandemic, and emerging understanding of coronavirus Nsp5-human protein interactions, we set out to predict what human proteins are cleaved by the coronavirus Nsp5 protease using a bioinformatics approach. Results: Using a previously developed neural network trained on coronavirus Nsp5 cleavage sites (NetCorona), we made predictions of Nsp5 cleavage sites in all human proteins. Structures of human proteins in the Protein Data Bank containing a predicted Nsp5 cleavage site were then examined, generating a list of 92 human proteins with a highly predicted and accessible cleavage site. Of those, 48 are expected to be found in the same cellular compartment as Nsp5. Analysis of this targeted list of proteins revealed molecular pathways susceptible to Nsp5 cleavage and therefore relevant to coronavirus infection, including pathways involved in mRNA processing, cytokine response, cytoskeleton organization, and apoptosis. Conclusions: This study combines predictions of Nsp5 cleavage sites in human proteins with protein structure information and protein network analysis. We predicted cleavage sites in proteins recently shown to be cleaved in vitro by SARS-CoV-2 Nsp5, and we discuss how other potentially cleaved proteins may be relevant to coronavirus mediated immune dysregulation. The data presented here will assist in the design of more targeted experiments, to determine the role of coronavirus Nsp5 cleavage of host proteins, which is relevant to understanding the molecular pathology of SARS-CoV-2 infection.

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Section: Discussionmentioning

confidence: 99%

Section: Network Analysis and Pathways Of Interestmentioning

confidence: 98%

Predicted Coronavirus Nsp5 Protease Cleavage Sites in the Human Proteome: A Resource for SARS-CoV-2 Research

Lacasse

et al. 2021

Preprint

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“…However preliminary data from the SECURE-IBD registry, though focused on a very small number of patients, showed no significant differences between tofacitinib-treated patients and other IBD patients in the occurrence of hospitalization, intensive care unit admission and severe COVID-19[ 64 ]. Moreover, recent preclinical evidence is emerging that tofacitinib treatment might in fact reduce ACE2 upregulation and ACE2-mediated intestinal viral uptake[ 65 ], and randomized clinical trials for the treatment of COVID-19 pneumonia are ongoing.…”

Section: Covid-19 In Ibd Patientsmentioning

confidence: 99%

Impact of COVID-19 on inflammatory bowel disease practice and perspectives for the future

Viganò¹,

Mulinacci²,

Palermo³

et al. 2021

WJG

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Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); since its first description in December 2019, it has rapidly spread to a global pandemic. Specific concerns have been raised concerning patients with inflammatory bowel diseases (IBD), which are chronic autoimmune inflammatory disorders of the gut that frequently require immunosuppressive and biological therapies to control their activity. Accumulating evidence has so far demonstrated that patients with IBD are not at increased risk of contracting severe acute respiratory syndrome coronavirus 2 infection. As for the general population, the identified risk factors for severe COVID-19 course among IBD patients have been established to be advanced age and the presence of comorbidities. Treatment with high-dose corticosteroids has also been associated with an increased risk of death in IBD patients with COVID-19. Information on COVID-19 is constantly evolving, with data growing at a rapid pace. This will guarantee better knowledge and stronger evidence to help physicians in the choice of the best therapeutic approach for each patient, concurrently controlling for the risk of IBD disease under treatment and the risk of COVID-19 adverse outcomes and balancing the two. Moreover, the impact of the enormous number of severe respiratory patients on healthcare systems and facilities has led to an unprecedented redeployment of healthcare resources, significantly impacting the care of patients with chronic diseases. In this newly changed environment, the primary aim is to avoid harm whilst still providing adequate management. Telemedicine has been applied and is strongly encouraged for patients without the necessity of infusion therapy and whose conditions are stable. The severe acute respiratory syndrome coronavirus 2 pandemic has already revolutionized the management of patients with chronic immune-mediated diseases such as IBD. Direct and indirect effects of the COVID-19 pandemic will be present for some time. This is the reason why continuous research, rapid solutions and constantly updated guidelines are of utmost importance. The aim of the present review is, therefore, to point out what has been learned so far as well as to pinpoint the unanswered questions and perspectives for the future.

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“…Dashti et al 26 also extracted the free-energy surfaces of the ryanodine receptor type 1 (RyR1) associated with the bound–unbound states (with the ATP, caffeine, and Ca ligands) using a master equation approach to find the probability of a transition between the two free-energy landscapes. Recently, deep learning methods have provided similar strategies to extract free-energy surfaces 27 , 28 . We note that replicating these methods might be cumbersome, and the bank of images required is very large.…”

Section: Introductionmentioning

confidence: 99%

A Bayesian approach to extracting free-energy profiles from cryo-electron microscopy experiments

Giraldo-Barreto

Ortiz

Thiede

et al. 2021

Sci Rep

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Cryo-electron microscopy (cryo-EM) extracts single-particle density projections of individual biomolecules. Although cryo-EM is widely used for 3D reconstruction, due to its single-particle nature it has the potential to provide information about a biomolecule’s conformational variability and underlying free-energy landscape. However, treating cryo-EM as a single-molecule technique is challenging because of the low signal-to-noise ratio (SNR) in individual particles. In this work, we propose the cryo-BIFE method (cryo-EM Bayesian Inference of Free-Energy profiles), which uses a path collective variable to extract free-energy profiles and their uncertainties from cryo-EM images. We test the framework on several synthetic systems where the imaging parameters and conditions were controlled. We found that for realistic cryo-EM environments and relevant biomolecular systems, it is possible to recover the underlying free energy, with the pose accuracy and SNR as crucial determinants. We then use the method to study the conformational transitions of a calcium-activated channel with real cryo-EM particles. Interestingly, we recover not only the most probable conformation (used to generate a high-resolution reconstruction of the calcium-bound state) but also a metastable state that corresponds to the calcium-unbound conformation. As expected for turnover transitions within the same sample, the activation barriers are on the order of $$k_BT$$ k B T . We expect our tool for extracting free-energy profiles from cryo-EM images to enable more complete characterization of the thermodynamic ensemble of biomolecules.

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Identification of a Novel Susceptibility Marker for SARS-CoV-2 Infection in Human Subjects and Risk Mitigation with a Clinically Approved JAK Inhibitor in Human/Mouse Cells

Cited by 8 publications

References 52 publications

Predicted Coronavirus Nsp5 Protease Cleavage Sites in the Human Proteome: A Resource for SARS-CoV-2 Research

Predicted Coronavirus Nsp5 Protease Cleavage Sites in the Human Proteome: A Resource for SARS-CoV-2 Research

Impact of COVID-19 on inflammatory bowel disease practice and perspectives for the future

A Bayesian approach to extracting free-energy profiles from cryo-electron microscopy experiments

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