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At least 109 records · Page 6

All sources NASA NTRS DOE OSTI

DOE OSTI2023

Site specific N- and O-glycosylation mapping of the spike proteins of SARS-CoV-2 variants of concern

Abstract The glycosylation on the spike (S) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, modulates the viral infection by altering conformational dynamics, receptor interaction and host immune responses. Several variants of concern (VOCs) of SARS-CoV-2 have evolved during the pandemic, and crucial mutations on the S protein of the virus have led to increased transmissibility and immune escape. In this study, we compare the site-specific glycosylation and overall glycomic profiles of the wild type Wuhan-Hu-1 strain (WT) S protein and five VOCs of SARS-CoV-2: Alpha, Beta, Gamma, Delta and Omicron. Interestingly, both N- and O-glycosylation sites on the S protein are highly conserved among the spike mutant variants, particularly at the sites on the receptor-binding domain (RBD). The conservation of glycosylation sites is noteworthy, as over 2 million SARS-CoV-2 S protein sequences have been reported with various amino acid mutations. Our detailed profiling of the glycosylation at each of the individual sites of the S protein across the variants revealed intriguing possible association of glycosylation pattern on the variants and their previously reported infectivity. While the sites are conserved, we observed changes in the N- and O-glycosylation profile across the variants. The newly emerged variants, which showed higher resistance to neutralizing antibodies and vaccines, displayed a decrease in the overall abundance of complex-type glycans with both fucosylation and sialylation and an increase in the oligomannose-type glycans across the sites. Among the variants, the glycosylation sites with significant changes in glycan profile were observed at both the N -terminal domain and RBD of S protein, with Omicron showing the highest deviation. The increase in oligomannose-type happens sequentially from Alpha through Delta. Interestingly, Omicron does not contain more oligomannose-type glycans compared to Delta but does contain more compared to the WT and other VOCs. O-glycosylation at the RBD showed lower occupancy in the VOCs in comparison to the WT. Our study on the sites and pattern of glycosylation on the SARS-CoV-2 S proteins across the VOCs may help to understand how the virus evolved to trick the host immune system. Our study also highlights how the SARS-CoV-2 virus has conserved both N - and O - glycosylation sites on the S protein of the most successful variants even after undergoing extensive mutations, suggesting a correlation between infectivity/ transmissibility and glycosylation.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin-converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryo–electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains locked into their inaccessible down state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Characterization of Materials Used as Face Coverings for Respiratory Protection

Use of masks is a primary tool to prevent the spread of the novel COVID-19 virus resulting from unintentional close contact with infected individuals. However, detailed characterization of the chemical properties and physical structure of common mask materials is lacking in the current literature. In this study, a series of commercial masks and potential mask materials, including 3M Particulate Respirator 8210 N95, a material provided by Oak Ridge National Laboratory Carbon Fiber Technology Facility (ORNL/CFTF), and a Filti Face Mask Material, were characterized by a suite of techniques, including scanning electron microscopy, X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. Wetting properties of the mask materials were quantified by measurements of contact angle with a saliva substitute. Mask pass-through experiments were performed using a dispersed metal oxide nanoparticle suspension to model the SARS-CoV-2 virus, with quantification via spatially resolved X-ray fluorescence mapping. Notably, all mask materials tested provided a strong barrier against respiratory droplet breakthrough. The comparisons and characterizations provided in this study provide useful information when evaluating mask materials for respiratory protection.

36 MATERIALS SCIENCE↗

DOE OSTI2024

Light-Induced Transformation of Virus-Like Particles on TiO 2

Titanium dioxide (TiO 2 ) shows significant potential as a self-cleaning material to inactivate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and prevent virus transmission. This study provides insights into the impact of UV-A light on the photocatalytic inactivation of adsorbed SARS-CoV-2 virus-like particles (VLPs) on a TiO 2 surface at the molecular and atomic levels. X-ray photoelectron spectroscopy, combined with density functional theory calculations, reveals that spike proteins can adsorb on TiO 2 predominantly via their amine and amide functional groups in their amino acids blocks. We employ atomic force microscopy and grazing-incidence small-angle X-ray scattering (GISAXS) to investigate the molecular-scale morphological changes during the inactivation of VLPs on TiO 2 under light irradiation. Notably, in situ measurements reveal photoinduced morphological changes of VLPs, resulting in increased particle diameters. These results suggest that the denaturation of structural proteins induced by UV irradiation and oxidation of the virus structure through photocatalytic reactions can take place on the TiO 2 surface. The in situ GISAXS measurements under an N 2 atmosphere reveal that the virus morphology remains intact under UV light. This provides evidence that the presence of both oxygen and UV light is necessary to initiate photocatalytic reactions on the surface and subsequently inactivate the adsorbed viruses. The chemical insights into the virus inactivation process obtained in this study contribute significantly to the development of solid materials for the inactivation of enveloped viruses.

36 MATERIALS SCIENCE↗

DOE OSTI2020

COVID-19 biomarkers based on respiratory microbiome content

COVID-19 patient care management would greatly benefit from new tools that enable accurate assessment of disease severity and stage, potentially enabling a personalized medicine approach. Detection of the SARS-CoV-2 virus itself, or even quantitation of viral loads, is not sufficient for accurate assessment of disease state beyond diagnosis of infection [eg, doi:10.1093/cid/ciaa344]. Levels of usual suspect protein biomarkers associated with host response to infection [eg, C-reactive protein (CRP); cytokines like IL-6, TNF-alpha, and IL-10; complement proteins like C3a and C5a], and of individual blood cell types (eg, leukocytes, lymphocytes, and subsets thereof), show limited correlation with disease severity and stage, with high patient-to-patient and study-to-study variability [eg, doi:10.1093/cid/ciaa248]. High-dimensional panels of biomarkers should have greater predictive power and resilience to unavoidable sources of variability; however, their assembly from proteins and cell types is extremely difficult, due to technical limitations in analyte measurement, especially with regard to starting material requirements and detection sensitivity. Host response profiling through Next Generation Sequencing (NGS) of gene expression patterns (ie, RNA-Seq) is a promising approach, but at the time of this project there were only two publicly available datasets of relevance [doi:10.1093/cid/ciaa203, doi:10.1080/22221751.2020.1747363], and close inspection of them revealed that each had at least one major flaw that severely undermined its value in supporting robust analysis of host response to SARS-CoV- 2 infection. However, the first of these studies [doi:10.1093/cid/ciaa203] fortuitously collected NGS data not only from host cells, but also from bacteria present in bronchoalveolar lavage fluid (BALF) recovered from COVID-19 patients; and because the respiratory microbiome (in terms of bacterial species content) is far less complex than the human transcriptome, the NGS data collected were sufficient to provide coverage depth supporting robust analysis. Surprisingly, the authors of the study did not carry out a detailed analysis of these data and their potential for revealing important new information about COVID-19. Therefore, we carried out a meta-analysis of the dataset as a first step in evaluating the potential for profiling of respiratory microbiome dynamics as a means of accurately assessing COVID-19 disease state.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Vaccination compartmental epidemiological models for the delta and omicron SARS-CoV-2 variants

We explore the inclusion of vaccination in compartmental epidemiological models concerning the delta and omicron variants of the SARS-CoV-2 virus that caused the COVID-19 pandemic. We expand on our earlier compartmental-model work by incorporating vaccinated populations. We present two classes of models that differ depending on the immunological properties of the variant. The first one is for the delta variant, where we do not follow the dynamics of the vaccinated individuals since infections of vaccinated individuals were rare. The second one for the far more contagious omicron variant incorporates the evolution of the infections within the vaccinated cohort. We explore comparisons with available data involving two possible classes of counts, fatalities and hospitalizations. We present our results for two regions, Andalusia and Switzerland (including the Principality of Liechtenstein), where the necessary data are available. In the majority of the considered cases, the models are found to yield good agreement with the data and have a reasonable predictive capability beyond their training window, rendering them potentially useful tools for the interpretation of the COVID-19 and further pandemic waves, and for the design of intervention strategies during these waves.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Effect of Delta and Omicron Mutations on the RBD-SD1 Domain of the Spike Protein in SARS-CoV-2 and the Omicron Mutations on RBD-ACE2 Interface Complex

The receptor-binding domain (RBD) is the essential part in the Spike-protein (S-protein) of SARS-CoV-2 virus that directly binds to the human ACE2 receptor, making it a key target for many vaccines and therapies. Therefore, any mutations at this domain could affect the efficacy of these treatments as well as the viral-cell entry mechanism. We introduce ab initio DFT-based computational study that mainly focuses on two parts: (1) Mutations effects of both Delta and Omicron variants in the RBD-SD1 domain. (2) Impact of Omicron RBD mutations on the structure and properties of the RBD-ACE2 interface system. The in-depth analysis is based on the novel concept of amino acid-amino acid bond pair units (AABPU) that reveal the differences between the Delta and/or Omicron mutations and its corresponding wild-type strain in terms of the role played by non-local amino acid interactions, their 3D shapes and sizes, as well as contribution to hydrogen bonding and partial charge distributions. Our results also show that the interaction of Omicron RBD with ACE2 significantly increased its bonding between amino acids at the interface providing information on the implications of penetration of S-protein into ACE2, and thus offering a possible explanation for its high infectivity. Our findings enable us to present, in more conspicuous atomic level detail, the effect of specific mutations that may help in predicting and/or mitigating the next variant of concern.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2023

AI-Accelerated Design of Targeted Covalent Inhibitors for SARS-CoV-2

Direct-acting antivirals for the treatment of the COVID-19 pandemic caused by the SARS-CoV-2 virus are needed to complement vaccination efforts. Given the ongoing emergence of new variants, automated experimentation, and active learning based fast workflows for antiviral lead discovery remain critical to our ability to address the pandemic’s evolution in a timely manner. While several such pipelines have been introduced to discover candidates with noncovalent interactions with the main protease (M pro ), here we developed a closed-loop artificial intelligence pipeline to design electrophilic warhead-based covalent candidates. Here, this work introduces a deep learning-assisted automated computational workflow to introduce linkers and an electrophilic “warhead” to design covalent candidates and incorporates cutting-edge experimental techniques for validation. Using this process, promising candidates in the library were screened, and several potential hits were identified and tested experimentally using native mass spectrometry and fluorescence resonance energy transfer (FRET)-based screening assays. We identified four chloroacetamide-based covalent inhibitors of M pro with micromolar affinities (K I of 5.27 μM) using our pipeline. Experimentally resolved binding modes for each compound were determined using room-temperature X-ray crystallography, which is consistent with the predicted poses. The induced conformational changes based on molecular dynamics simulations further suggest that the dynamics may be an important factor to further improve selectivity, thereby effectively lowering KI and reducing toxicity. These results demonstrate the utility of our modular and data-driven approach for potent and selective covalent inhibitor discovery and provide a platform to apply it to other emerging targets.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Low rotational barriers for the most dynamically active methyl groups in the proposed antiviral drugs for treatment of SARS-CoV-2, apilimod and tetrandrine

A recent screening study highlighted a molecular compound, apilimod, for its efficacy against the SARS-CoV-2 virus, while another compound, tetrandrine, demonstrated a remarkable synergy with the benchmark antiviral drug, remdesivir. In this work, we find that because of significantly reduced potential energy barriers, which also give rise to pronounced quantum effects, the rotational dynamics of the most dynamically active methyl groups in apilimod and tetrandrine are much faster than those in remdesivir. Because dynamics of methyl groups are essential for biochemical activity, screening studies based on the computed potential energy profiles may help identify promising candidates within a given class of drugs.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Conducting polymer-based electrochemical sensors: Progress, challenges, and future perspectives

Conducting polymers are promising due to their unique properties, such as excellent electrical and optical properties, physical and chemical stability, high conductivity, and effective redox properties with high-temperature stability and biocompatibility. Due to these properties, conducting polymers are useful in diverse applications like sensors, batteries, oil industries, biosensors, biomedicines, catalysis, cancer treatment, etc. This review article aims to discuss the recent trends and analysis of conducting polymer-based electrochemical sensors in diverse areas with all required sensor characteristics, such as the derived limit of detection, utilized techniques for the sensing analysis and derived linear dynamic range with the stability of the sensors. Conducting polymers and their nanocomposites-based electrochemical sensors have demonstrated exceptional capabilities towards detecting various biomolecules, heavy metals, pesticides, and viruses like SARS-COV-2. Incorporation of redox mediators, use of conducting hydrogels, and molecular imprinting are promising strategies for better performance of the derived sensor. The article has demonstrated the existing challenges and limitations and provided solutions in the field. In the future, conducting polymers-based electrochemical sensors can be utilized in wearable sensors and integrated with IoT devices for better reach in real-time applications. They can also be made more accessible with precise control and data output by following specific methodologies. Utilizing green and sustainable conducting polymers can be crucial in advancing eco-friendly practices in the future. Conducting polymer-based electrochemical sensors has affectivity in neurochemical and pathogen sensing, which is essential for brain function and mental health.

42 ENGINEERING↗

DOE OSTI2023

Protection against Chemical Warfare Agents and Biological Threats Using Metal–Organic Frameworks as Active Layers

The SARS-CoV-2 pandemic outbreak and the unfortunate misuse of toxic chemical warfare agents (CWAs) highlight the importance of developing functional materials to protect against these chemical and pathogen threats. Metal–organic frameworks (MOFs), which comprise a tunable class of crystalline porous materials built from inorganic nodes and organic linkers, have emerged as a class of heterogeneous catalysts capable of rapid detoxification of multiple classes of these harmful chemical or biological hazards. In particular, zirconium-based MOFs (Zr-MOFs) feature Lewis acidic nodes that serve as active sites for a wide range of catalytic reactions, including the hydrolysis of organophosphorus nerve agents within seconds in basic aqueous solutions. In addition, postsynthetic modification of Zr-MOFs enables the release of active species capable of reacting with and deactivating harmful pathogens. Despite this impressive performance, utilizing Zr- MOFs in powder form is not practical for application in masks or protective uniforms. To address this challenge, our team sought to develop MOF/fiber composite systems that could be adapted for use under realistic operating conditions to protect civilians, military personnel, and first responders from harmful pathogens and chemical warfare agents. Over the last several years, our group has designed and fabricated reactive and biocidal MOF/fiber composites that effectively capture and deactivate these toxic species. In this Account, we describe the evolution of these porous and reactive MOF/fiber composites and focus on key design challenges and considerations. First, we devised a scalable method for the integration of Zr-MOFs onto textile substrates using aqueous precursor solutions and without using pretreated textiles, highlighting the potential scalability of this method. Moving beyond standard textiles, we also developed a microbial synthesis strategy to prepare hierarchically porous MOF/bacterial cellulose nanofiber composite sponges that can both capture and detoxify nerve agents when exposed to contaminated gas flows. The mass loading of the MOF in the nanofibrous composite sponge is up to 90%, affording higher work capacities compared to those of textile-fiber-based composites with relatively lower MOF loadings. Next, we demonstrated that heterogeneous polymeric bases are suitable replacements for volatile liquid bases typically used in solution-phase reactions, and we showed that these composite systems are capable of effectively hydrolyzing nerve agents in the solid state by using only water that is present as humidity. Moreover, incorporating a reactive dye precursor into the composite affords a dual function sensing and detoxifying material that changes color from white to orange upon reaction with the byproduct following nerve agent hydrolysis, demonstrating the versatility of this platform for use in decontamination applications. We then created chlorine-loaded MOF/fiber composites that act as biocidal and reactive textiles that are capable of not only detoxifying sulfur-mustard-based chemical warfare agents and simulants but also deactivating both bacteria and the SARS-CoV-2 virus within minutes of exposure. Lastly, we synthesized a mixed-metal Ti/Zr-MOF coating on cotton fibers to afford a photoactive biocidal cloth that shows fast and broad-spectrum biocidal performance against viruses and Gram-positive and Gram-negative bacteria under visible light irradiation. Given the tunable, multifunctional nature of these MOF/fiber composites, we believe that this Account will offer new insights for the rational design and preparation of functional MOF/fiber composites and pave the way toward the development of next-generation reactive and protective textiles.

36 MATERIALS SCIENCE↗

DOE OSTI2022

Impact of Remdesivir Incorporation along the Primer Strand on SARS-CoV-2 RNA-Dependent RNA Polymerase

Remdesivir was the first antiviral drug that received emergency use authorization from the United States Food and Drug Administration and is now formally approved to treat COVID-19. Remdesivir is a nucleotide analogue that targets the RNA-dependent RNA polymerase (RdRp) of coronaviruses, including SARS-CoV-2. The solution of multiple RdRp structures has been one of the main axes of research in the race against the SARS-CoV-2 virus. Several hypotheses of the mechanism of inhibition of RdRp by remdesivir have been proposed, although open questions remain. This work uses molecular dynamics simulations to explore the impact of remdesivir and two analogues as incoming nucleotides and of up to four incorporations of remdesivir along the primer strand on RdRp. The simulation results suggest that the overall structure and the dynamical behavior of RdRp are destabilized by remdesivir and the two analogues in the incoming position. The incorporation of remdesivir along the primer strand impacts specific non-bonded interactions between the nascent RNA and the polymerase subunit, as well as the overall dynamical networks on RdRp. The strongest impact on the structure and dynamics are observed after three incorporations, when remdesivir is located at position -A3, in agreement with previously reported experimental and computational results. Our results provide atomic-level details of the role played by remdesivir on the disruption of RNA synthesis by RdRp and the main drivers of these disruptions.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2020

Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of “undruggability” for an intracellular target. Structural studies reveal extensive protein–WDB002 and protein–protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise “undruggable” targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Experimental evaluation of respiratory droplet spread to rooms connected by a central ventilation system

This article presents results from an experimental study to ascertain the transmissibility of the SARS-CoV-2 virus between rooms in a building that are connected by a central ventilation system. Respiratory droplet surrogates made of mucus and virus mimics were released in one room in a test building and measurements of concentration levels were made in other rooms connected via the ventilation system. The paper presents experimental results for different ventilation system configurations, including ventilation rate, filtration level (up to MERV-13), and fractional outdoor air intake. The most important finding is that respiratory droplets can and do transit through central ventilation systems, suggesting a mechanism for viral transmission (and COVID-19 specifically) within the built environment in reasonable agreement with well-mixed models. We also find the deposition of these droplets on room walls to be negligibly small. Furthermore, the energy use impact of the different configuration settings is also quantified to help inform intelligent building operation that can simultaneously address energy use and occupant health.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Control of airborne infectious disease in buildings: Evidence and research priorities

The evolution of SARS-CoV-2 virus has resulted in variants likely to be more readily transmitted through respiratory aerosols, underscoring the increased potential for indoor environmental controls to mitigate risk. Use of tight-fitting face masks to trap infectious aerosol in exhaled breath and reduce inhalation exposure to contaminated air is of critical importance for disease control. Administrative controls including the regulation of occupancy and interpersonal spacing are also important, while presenting social and economic challenges. Indoor engineering controls including ventilation, exhaust, air flow control, filtration, and disinfection by germicidal ultraviolet irradiation can reduce reliance on stringent occupancy restrictions. However, the effects of controls-individually and in combination-on reducing infectious aerosol transfer indoors remain to be clearly characterized to the extent needed to support widespread implementation by building operators. We review aerobiologic and epidemiologic evidence of indoor environmental controls against transmission and present a quantitative aerosol transfer scenario illustrating relative differences in exposure at close-interactive, room, and building scales. We identify an overarching need for investment to implement building controls and evaluate their effectiveness on infection in well-characterized and real-world settings, supported by specific, methodological advances. Finally, improved understanding of engineering control effectiveness guides implementation at scale while considering occupant comfort, operational challenges, and energy costs.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

GPU-Accelerated Drug Discovery with Docking on the Summit Supercomputer: Porting, Optimization, and Application to COVID-19 Research

Protein-ligand docking is an in silico tool used to screen potential drug compounds for their ability to bind to a given protein receptor within a drug-discovery campaign. Experimental drug screening is expensive and time consuming, and it is desirable to carry out large scale docking calculations in a high-throughput manner to narrow the experimental search space. Few of the existing computational docking tools were designed with high performance computing in mind. Therefore, optimizations to maximize use of high-performance computational resources available at leadership-class computing facilities enables these facilities to be leveraged for drug discovery. Here we present the porting, optimization, and validation of the AutoDock-GPU program for the Summit supercomputer, and its application to initial compound screening efforts to target proteins of the SARS-CoV-2 virus responsible for the current COVID-19 pandemic.

LeGrand, Scott↗

DOE OSTI2026

Iterative ML and Experiments for Emerging VOCs

SAND2026-17074O Iterative ML and Experiments for Emerging VOCs is a tool that analyzes and predicts the behaviors of SARS-CoV-2 variants. It processes experimental data on ACE2 (the receptor for the SARS-CoV-2 virus that allows it to infect the cell) and antibody binding using machine learning models, including neural networks, to forecast ACE2 interactions and variant expression. The tool employs transfer learning and global epistasis modeling, integrating public datasets with proprietary data to enhance prediction accuracy. Additionally, it fits concentration-response curves to determine dissociation constants and generates visualizations to support research findings, thereby aiding in the identification of new antibodies for emerging variants of concern. Sandia National Laboratories is a multimission laboratory managed and operated by National Technology & Engineering Solutions of Sandia, LLC, a wholly owned subsidiary of Honeywell International Inc., for the U.S. Department of Energy’s National Nuclear Security Administration under contract DE-NA0003525.

Sheffield, Thomas [Sandia National Lab. (SNL-NM), ↗

DOE OSTI2022

COVID-19 through Adverse Outcome Pathways: Building networks to better understand the disease – 3rd CIAO AOP Design Workshop

On April 28-29, 2021, 50 scientists from different fields of expertise met for the 3rd online CIAO workshop. The CIAO project “Modelling the Pathogenesis of COVID-19 using the Adverse Outcome Pathway (AOP) framework” aims at building a holistic assembly of the available scientific knowledge on COVID-19 using the AOP framework. An individual AOP depicts the disease progression from the initial contact with the SARS-CoV-2 virus through biological key events (KE) toward an adverse outcome such as respiratory distress, anosmia or multiorgan failure. Assembling the individual AOPs into a network highlights shared KEs as central biological nodes involved in multiple outcomes observed in COVID-19 patients. During the workshop, the KEs and AOPs established so far by the CIAO members were presented and positioned on a timeline of the disease course. Modulating factors influencing the progression and severity of the disease were also addressed as well as factors beyond purely biological phenomena. CIAO relies on an interdisciplinary crowdsourcing effort, therefore, approaches to expand the CIAO network by widening the crowd and reaching stakeholders were also discussed. To conclude the workshop, it was decided that the AOPs/KEs will be further consolidated, integrating virus variants and long COVID when relevant, while an outreach campaign will be launched to broaden the CIAO scientific crowd.

60 APPLIED LIFE SCIENCES↗