Research Initiatives on COVID-19 in the Division of Translational Toxicology

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

Our current work focuses on investigating specific cellular functions that have been demonstrated to be relevant to respiratory viral infection, including (influenza and SARS-CoV-2), susceptibility and pathogenesis by evaluating inflammatory and innate and adaptive immune responses. We are using an in vitro human whole blood assay system that can examine the impact of environmental factors, such as polyaromatic compounds, on lymphocyte cytotoxicity as well as selected immune functions from the same cell cultures and using multiple donors. To provide direct relevance to respiratory viral infections, we have incorporated evaluation of immune responses to viral antigens. To investigate interindividual susceptibility factors, human donors with a prior history of respiratory viral disease have been screened using the in vitro assays for immune response and challenged with viral antigens to provide information on the potential interactions with age, gender, and ethnicity. We have screened 200 donors and are evaluating the correlation between the independent variables of demographics and Covid history with immune endpoints. A second analysis strategy will examine the correlation between blood antibody levels and immune cell population counts/cytotoxicity, cytokine/chemokine production, and NK function. We have also partnered with collaborators in the Program on Reproductive Health and the Environment at the University of California San Francisco to develop a systematic evidence map of environmental factors that may impact the immune response to SARS-CoV-2. The protocol has been published and the team is currently evaluating results. Study 2. Programs of work under development focus on addressing the key challenges affecting the uptake of MPS models for SARS-CoV-2 research, as identified by the MPSCoRe working group membership. The MPSCoRe working group identified a variety of scientific challenges, including model complexity and incorporation of innate and adaptive immune responses, and practical challenges, such as the need for model standardization, interlaboratory characterization, and defined performance criteria, and access to appropriate biosafety-level facilities, funding streams, and repositories of human tissues and cell sources. The University of Pittsburgh has developed a MPS Database (MPSDb), which aggregates MPS data with linked preclinical and clinical databases for analysis in the context of human exposure. NICEATM provided support for the development of a COVID-19 portal within the MPSDb, which provides links to COVID-19 disease information from Government and literature sources. This includes links to disease statistics, strategic responses, funding information, COVID-19 literature hubs and other scientific literature sites pre-queried forCOVID-19. Most recently, NICEATM has supported the further development of the COVID-19 portal to include an iPSC repository with details about cell sourcing and protocols. NICEATM is also working with NIAID and providing input and guidance on the overall design and coordination for a validation study of a MPS to evaluate the potential efficacy of prospective COVID-19 therapeutics prior to their study in a clinical setting. NICEATM and NC3Rs co-host an annual Summer Webinar Series (virtual, once per month) for the MPSCoRe working group members. Each agenda featured talks from two working group members and/or other invited MPS stakeholders or COVID researchers. On May 31-June 1, 2023 NICEATM and the MPSCoRe WG held a virtual workshop on Advancing Research and Regulatory Acceptance of Microphysiological Systems for Infectious Disease Applications. Study 3. Building an AOP network modeling COVID-19 pathogenesis relies on interdisciplinary collaborative effort, synergizing exchange between experts from different fields to translate complex biology into messages understandable across disciplines. Currently, more than 60 scientists coming from 40 organizations are participating in the CIAO project. NICEATM is co-leading an effort to develop and publish an AOP for Neuro-COVID. Moreover, NICEATM is co-leading a systematic review-driven approach to facilitate data identification and analysis within CIAO and more generally into the AOP framework.