Project Team
Richard Scheuermann, PhD, Director of the JCVI La Jolla Campus & Informatics, the J. Craig Venter Institute
Christopher Dupont, PhD, Professor in Genomic Medicine, Environment & Sustainability, and Synthetic Biology, the J. Craig Venter Institute
Gene S. Tan PhD, Assistant Professor in the Infectious Disease Group, the J. Craig Venter Institute
David Price MD PhD, Chair of Infection and Immunity, Cardiff University
Helen Davies MD, Consultant Respiratory Physician and Clinical Lead of Post Covid Respiratory Clinic, University Hospital of Wales, Cardiff
Marcus Buggert, MSc, PhD, Assistant Professor, Department of Medicine, Karolinska Institutet
Soo Aleman, MD, PhD, Associate professor, Department of Infectious Diseases, Karolinska Institutet
Amy Proal, PhD, President, Research Director, PolyBio Research Foundation
Project Summary:
Project team member Dr. Gene Tan
A multi-site collaborative study to identify infectious, immune and microbiome abnormalities that contribute to pulmonary symptoms in individuals with Long COVID. Long COVID lung tissue, bronchoalveolar lavage fluid (BALF), and blood are being collected & analyzed by cutting-edge methods for immune cell activity and the SARS-CoV-2 virus (with assays that allow for detection of replicating virus and expressed proteins). A series of experiments will also determine if activation of B and T cells in the lung environment and blood are responsive to viruses capable of emerging from latency (such as Epstein-Barr virus) and/or are targeting human tissue (‘autoimmunity’). The microbial composition and activity of the lower respiratory tract (ie the lung microbiome) will be characterized from BALF, and associated with the potential persistence of SARS-CoV-2 in lung tissue using machine learning.
Advanced sequencing techniques will additionally be used to characterize lung tissue damage and remodeling associated with alveolar and vascular endothelial cell dysregulation. Blood samples will be deeply analyzed to characterize components of the immune response including complement and natural killer cell activation. Fluorescence microscopy will be used to identify and quantify fibrin-amyloid microclots in both blood and lung tissue samples. A series of advanced neutralization assays using viral pseudoparticles will determine if suboptimal antibody responses in blood correlate with potential SARS-CoV-2 persistence or other pathology in the lung environment.
Additional Project Information:
This study is the first in the world to concurrently collect lung tissue, BALF samples, and blood from patients with Long COVID. It is designed to comprehensively study core “root cause” drivers of pulmonary symptoms and disease in Long COVID via state-of-the-art ‘omics technologies in conjunction with high-definition experimental immunology. Each project component is being performed by an investigator with pioneering expertise in its use. Four central and non-exclusive hypotheses are being investigated, namely that Long COVID pulmonary symptoms and disease are driven by: (i) persistence of the SARS-CoV-2 virus in lung tissue reservoirs; (ii) lower respiratory tract microbiome dysbiosis and/or reactivation of latent viral pathogens such as Epstein-Barr virus; (iii) lung tissue damage and remodeling associated with alveolar and vascular endothelial cell dysregulation and fibrin/amyloid microclots; and (iv) suboptimal lung tissue-resident immunity including alterations in B and T cell signaling.
The comprehensive datasets generated by the study will elucidate key biological trends in Long COVID. The technologies and methods used in the study are not just cutting-edge; they are also being combined in a novel fashion to push the boundaries of how advanced technologies can best be employed in the overall study of human chronic disease. The findings should set the stage for Long COVID clinical trials of antivirals, microbiome-based therapeutics, anticoagulants, and immunotherapies.