Browsing by Author "Clerbaux, Laure Alix"
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- Beyond chemicals: opportunities and challenges of integrating non-chemical stressors in adverse outcome pathwaysPublication . Clerbaux, Laure Alix; Filipovska, Julija; Nymark, Penny; Chauhan, Vinita; Sewald, Katherina; Alb, Miriam; Sachana, Madgalini; Beronius, Anna; Amorim, Maria João; Wittwehr, ClemensThe adverse outcome pathways (AOPs) were developed to accelerate evidence-based chemical risk assessment by leveraging data from new approach methodologies. Thanks to their stressor-agnostic approach, AOPs were seen as instrumental in other fields. Here, we present AOPs that report non-chemical stressors along with the challenges encountered for their development. Challenges regarding AOPs linked to nanomaterials include non-specific molecular initiating events, limited understanding of nanomaterial biodistribution, and needs for adaptations of the in silico modeling and testing systems. Development of AOPs for radiation face challenges in how to incorporate ionizing events type, dose rate, energy deposition, and how to account for targeting multiple macromolecules. AOPs for COVID-19 required the inclusion of SARS-CoV-2-specific replicative steps to capture the essential events driving the disease. Developing AOPs to evaluate efficacy and toxicity of cell therapies necessitates addressing the cellular nature and the therapeutic function of the stressor. Finally, addressing toxicity of emerging biological stressors like microbial pesticides can learn from COVID-19 AOPs. We further discuss that the adaptations needed to expand AOP applicability beyond chemicals are mainly at the molecular and cellular levels while downstream key events at tissue or organ level, such as inflammation, are shared by many AOPs initiated by various stressors. In conclusion, although it is challenging to integrate non-chemical stressors within AOPs, this expands opportunities to account for real-world scenarios, to identify vulnerable individuals, and to bridge knowledge on mechanisms of adversity.
- Building an adverse outcome pathway network for COVID-19Publication . Nymark, Penny; Clerbaux, Laure Alix; Amorim, Maria João; Andronis, Christos; Bernardi, Francesca de; Bezemer, Gillina F. G.; Coecke, Sandra; Gavins, Felicity N. E.; Jacobson, Daniel; Lekka, Eftychia; Margiotta-Casaluci, Luigi; Martens, Marvin; Mayasich, Sally A.; Mortensen, Holly M.; Kim, Young Jun; Sachana, Magdalini; Tanabe, Shihori; Virvilis, Vassilis; Edwards, Stephen W.; Halappanavar, SabinaThe COVID-19 pandemic generated large amounts of data on the disease pathogenesis leading to a need for organizing the vast knowledge in a succinct manner. Between April 2020 and February 2023, the CIAO consortium exploited the Adverse Outcome Pathway (AOP) framework to comprehensively gather and systematically organize published scientific literature on COVID-19 pathology. The project considered 24 pathways relevant for COVID-19 by identifying essential key events (KEs) leading to 19 adverse outcomes observed in patients. While an individual AOP defines causally linked perturbed KEs towards an outcome, building an AOP network visually reflect the interrelatedness of the various pathways and outcomes. In this study, 17 of those COVID-19 AOPs were selected based on quality criteria to computationally derive an AOP network. This primary network highlighted the need to consider tissue specificity and helped to identify missing or redundant elements which were then manually implemented in the final network. Such a network enabled visualization of the complex interactions of the KEs leading to the various outcomes of the multifaceted COVID-19 and confirmed the central role of the inflammatory response in the disease. In addition, this study disclosed the importance of terminology harmonization and of tissue/organ specificity for network building. Furthermore the unequal completeness and quality of information contained in the AOPs highlighted the need for tighter implementation of the FAIR principles to improve AOP findability, accessibility, interoperability and re-usability. Finally, the study underlined that describing KEs specific to SARS-CoV-2 replication and discriminating physiological from pathological inflammation is necessary but requires adaptations to the framework. Hence, based on the challenges encountered, we proposed recommendations relevant for ongoing and future AOP-aligned consortia aiming to build computationally biologically meaningful AOP networks in the context of, but not limited to, viral diseases.
- Gut as an alternative entry route for SARS-CoV-2: current evidence and uncertainties of productive enteric infection in COVID-19Publication . Clerbaux, Laure Alix; Mayasich, Sally A.; Munoz Pineiro, Amalia; Soares, Helena; Petrillo, Mauro; Albertini, Maria Cristina; Lanthier, Nicolas; Grenga, Lucia; Amorim, Maria JoãoThe gut has been proposed as a potential alternative entry route for SARS-CoV-2. This was mainly based on the high levels of SARS-CoV-2 receptor expressed in the gastrointestinal (GI) tract, the observations of GI disorders (such as diarrhea) in some COVID-19 patients and the detection of SARS-CoV-2 RNA in feces. However, the underlying mechanisms remain poorly understood. It has been proposed that SARS-CoV-2 can productively infect enterocytes, damaging the intestinal barrier and contributing to inflammatory response, which might lead to GI manifestations, including diarrhea. Here, we report a methodological approach to assess the evidence supporting the sequence of events driving SARS-CoV-2 enteric infection up to gut adverse outcomes. Exploring evidence permits to highlight knowledge gaps and current inconsistencies in the literature and to guide further research. Based on the current insights on SARS-CoV-2 intestinal infection and transmission, we then discuss the potential implication on clinical practice, including on long COVID. A better understanding of the GI implication in COVID-19 is still needed to improve disease management and could help identify innovative therapies or preventive actions targeting the GI tract.
- Mechanisms leading to gut dysbiosis in COVID-19: current evidence and uncertainties based on adverse outcome pathwaysPublication . Clerbaux, Laure Alix; Fillipovska, Julija; Muñoz, Amalia; Petrillo, Mauro; Coecke, Sandra; Amorim, Maria João; Grenga, LuciaAlteration in gut microbiota has been associated with COVID-19. However, the underlying mechanisms remain poorly understood. Here, we outlined three potential interconnected mechanistic pathways leading to gut dysbiosis as an adverse outcome following SARS-CoV-2 presence in the gastrointestinal tract. Evidence from the literature and current uncertainties are reported for each step of the different pathways. One pathway investigates evidence that intestinal infection by SARS-CoV-2 inducing intestinal inflammation alters the gut microbiota. Another pathway links the binding of viral S protein to angiotensin-converting enzyme 2 (ACE2) to the dysregulation of this receptor, essential in intestinal homeostasis—notably for amino acid metabolism—leading to gut dysbiosis. Additionally, SARS-CoV-2 could induce gut dysbiosis by infecting intestinal bacteria. Assessing current evidence within the Adverse Outcome Pathway framework justifies confidence in the proposed mechanisms to support disease management and permits the identification of inconsistencies and knowledge gaps to orient further research.