The Adverse Outcome Pathway Framework Applied to Neurological Symptoms of COVID-19.

Several reports have shown that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the potential to also be neurotropic. However, the mechanisms by which SARS-CoV-2 induces neurologic injury, including neurological and/or psychological symptoms, remain unclear. In this review, the available knowledge on the neurobiological mechanisms underlying COVID-19 was organized using the AOP framework. Four AOPs leading to neurological adverse outcomes (AO), anosmia, encephalitis, stroke, and seizure, were developed. Biological key events (KEs) identified to induce these AOs included binding to ACE2, blood-brain barrier (BBB) disruption, hypoxia, neuroinflammation, and oxidative stress. The modularity of AOPs allows the construction of AOP networks to visualize core pathways and recognize neuroinflammation and BBB disruption as shared mechanisms. Furthermore, the impact on the neurological AOPs of COVID-19 by modulating and multiscale factors such as age, psychological stress, nutrition, poverty, and food insecurity was discussed. Organizing the existing knowledge along an AOP framework can represent a valuable tool to understand disease mechanisms and identify data gaps and potentially contribute to treatment, and prevention. This AOP-aligned approach also facilitates synergy between experts from different backgrounds, while the fast-evolving and disruptive nature of COVID-19 emphasizes the need for interdisciplinarity and cross-community research.

ADRD and COVID-19: A multi-scale framework for elucidating and addressing mechanisms and outcomes

Background The COVID-19 pandemic has disproportionately impacted vulnerable populations. The elderly, including individuals with Alzheimer's Disease and Related Dementias (ADRD) are at an increased risk due to a variety of factors ranging from the molecular, to the physiological and social domains. Here we describe the development of a neural network-inspired, expanded Adverse Outcome Pathways (AOP) approach to examine the relations, outcomes and potential interventions across scales at the intersections of these acute and long-term health crises. Method Using an Adverse Outcome Pathway (AOP) approach we compared key events and their relationships in COVID-19 and ADRD. However, whereas current AOP approaches are often limited and centralized around the molecular domain we expand these to encompass a range of domains across scales such as the neuropsychological and social factors. Inspired by neural network modeling approaches we also extend the traditional AOP framework to explicitly include: inhibitory and excitatory mechanisms, causal recurrence, strength of interactions and advantageous pathways. Result By including an analysis that spans molecular pathways, system level vulnerabilities, psychological, environmental and social factors we are able to assess commonalities of events (e.g., macrophage activation, systemic inflammation, environmental exposures and disproportionately affected racial/ethnic communities). In addition, by utilizing higher order and systems perspectives, we were able to better identify mechanistic differences (e.g., vulnerabilities of specific brain regions, timescale of bio-cognitive consequences, sex-gender differences), as well as chart interactions resulting in comorbidities and resilience factors. Conclusion In recent years the global ADRD research field has strongly shifted to a conceptual framework that recognizes the essential role of interactions between levels of biosocial organization. The COVID-19 pandemic has also revealed the crucial biopsychosocial connections of disease vulnerability, resistance and management. AOPs are powerful tools in clarifying key linkages in these multifactorial diseases. However, AOPs have also showed their limitation by biasing molecular events as the prime initiating events. Our hybrid approach integrates multiscale elements to more effectively develop a mechanistic framework and identify pathways to health. Taken together, this new approach can help bridge the divide across bio-molecular events and higher level factors such as health disparities in COVID and the ADRD spectrum.

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.

The Absence and Need for Certified Xenofree iPSC Culture Conditions in Disease Modeling: From Alzheimer's to COVID-19

Human-induced pluripotent stem cells (iPSCs) and their differentiated derivatives are a powerful way to study disease processes and healthy function in conditions ranging from Alzheimer's disease (AD) to COVID-19. However, these models often remain limited due to their contamination with non-human animal-derived components. As such, there is a need for a major shift to entirely xenofree methodologies so experimental conditions are free of non-human animal contaminants. Here, we evaluate the availability of xenofree stem cell lines and the extent of xenogenicity in major public sources of AD and control cell lines that could also be used in COVID-19 iPSC-related research. In order to assess the extent of xenogenicity, we analyzed three primary catalogs of stem cell repositories for AD and control cell lines. The iPSC catalogs were chosen based on their efforts to create accessible, high quality cell lines and recognition of the need to improve reproducibility in stem cell research. These public collections included the Coriell Institute for Medical Research, the California Institute for Regenerative Medicine (CIRM), and the European Bank for induced Pluripotent Stem Cells (EBiSC). Over 300 cell lines were reviewed in this study. Although all cells were obtained from human donors, none of the collections were determined to meet fully verifiable xenofree criteria. A large numbers of cell lines were generated with one or more known xenogenic components (e.g., fetal bovine serum, Matrigel). Others lines were classified as 'suspected exposure to xenogenic components', based on the composition of the culture reagent and/or lack of manufacturer product information to verify whether animal-free reagents were used (e.g., Eagle's Minimum Essential Medium). Even CIRM, a repository clearly dedicated to producing xenofree cell lines, included Vitronectin (VTN-N) Recombinant Human Protein that was manufactured using Casein Peptone Type I derived from bovine milk. The results show that major stem cell collections -- despite substantial efforts to improve accessibility, consistency and reproducibility -- either fail to be xenofree or make it difficult to establish truly xenofree research conditions. The absence of xenofree resources fundamentally undermines the clinical, scientific and ethical integrity of stem cell research and raises specific concerns for readiness to study AD and COVID-19 using iPSCs. There is a clear need for xenofree sources, not only for clinical applications but also for the discovery and testing phases of research. This will likely require the development of open and transparent xenofree certification. By establishing truly xenofree research criteria, the field can build a foundation for accurately and effectively studying conditions that affect large parts of the population, including AD and COVID-19. Xenofree conditions for the study of long-term sequelae will be important in COVID-19 research as sources for iPSC cells from recovered and vaccinated individuals become available. Beyond population impact studies, having a xenofree platform could help lay the groundwork for safe and effective personalized medicine.