Timothy Henrich MD, MMSc, Associate Professor of Medicine, University of California San Francisco
Henry VanBrocklin PhD, Professor of Radiology and Biomedical Imaging, University of California San Francisco
Michael Peluso MD, MPH, DTMH, Assistant Adjunct Professor of Infectious Diseases, University of California San Francisco
Robert Flavel MD, PhD, Chief of Molecular Imaging and Therapeutics Clinical Section in the Department of Radiology and Biomedical Imaging, University of California San Francisco
Steven Deeks, MD, Professor of Medicine in Residence, University of California San Francisco
Ramsey Badawi PhD, Professor of Radiology and Biomedical Engineering, University of California Davis
Simon Cherry PhD, Professor of Biomedical Engineering, University of California Davis
This study is the first in the world to use advanced imaging technologies to identify deep tissue SARS-CoV-2 reservoirs and T cell activity in LongCovid study participants. Specifically the team will use longitudinal ImmunoPET-CT imaging of radiolabeled SARS-CoV-2-specific monoclonal antibodies (mAbs) to identify SARS-CoV-2 tissue reservoirs in individuals with Long COVID. The project team is also using ImmunoPET-CT imaging to identify the spatial and temporal dynamics of tissue-based T cell activity in Long COVID study participants.
Tissue biopsy samples from the lymph node and gut will also be collected from Long COVID study participants undergoing imaging. These tissue samples will be analyzed for SARS-CoV-2 RNA, spike, and nucleocapsid proteins, other chronic viruses (e.g., Epstein-Barr virus and cytomegalovirus), and cellular immune responses. Data collected on the tissue samples will be correlated with the imaging data, so that potential viral reservoirs and T cell activity in study participants can be validated by overlapping methods.
PET scanning (positron emission tomography) is a medical imaging technique in which a biologically meaningful substance, like an antibody, is “tagged” with a very small amount of rapidly decaying radiation. When the substance is injected, it travels to wherever it normally would within the body. The PET scanner is very sensitive camera that can detect and localize the tiny amount of energy that is emitted by the radioactive decay. In this project, the team will take a monoclonal antibody (a medication that specifically targets the SARS-CoV-2 spike protein wherever it might be in the body) and “tag” it with a tiny amount of radioactivity (called radiotracers). They will then safely inject the tagged monoclonal antibody into participants with Long COVID. The tagged monoclonal antibody will diffuse throughout the participants’ bodies, and if it encounters the SARS-CoV-2 spike protein, it will selectively bind it. Wherever this binding occurs its tagged radiotracer will become trapped and rapidly decay. This can be detected in 3-dimensions by the PET scanner’s ultra-sensitive camera. The PET scanner camera documents the location of these tagged antibodies, which can be used to infer the location of the SARS-CoV-2 spike protein in the patients’ tissue. In other words, the PET scanner is able to triangulate the specific location of any SARS-CoV-2 viral reservoir sites within the body. The same series of events will occur for T cell imaging, except the team uses a different radiotracer.
The project collaborative team is uniquely positioned to perform a SARS-CoV-2 deep tissue reservoir and T cell imaging study. They have deep expertise in nuclear medicine, viral persistence, immunology, and in-depth tissue-based studies of viral infection and immune responses. They were one of the first teams in the world to successfully apply a virus-specific immunoPET approach to identify deep-tissue viral reservoirs in individuals with HIV. The findings were recently published in Nature Communications and covered here on the BBC’s Science in Action program, where project team member Dr. Tim Hendrich explains how the approach can be iterated to study deep-tissue SARS-CoV-2 reservoirs in Long COVID.
A major strength of the project is that it pushes the boundaries of how imaging technologies can be used to identify persistent pathogens in the human body. The EXPLORER PET scanner that will be used in this study is the first FDA-approved full-body PET scanner and was created by two members of the project team. The scanner has an effective sensitivity for total-body imaging that is 40-fold higher than current commercial scanners and is expected to revolutionize how PET imaging can be used in both biomedical research and ultimately in clinical practice. This video provides more information on the EXPLORER PET scanner and its innovative features.
If the project team can successfully image SARS-CoV-2 reservoirs in patients with Long COVID, they can begin to radiolabel therapeutics that target other pathogens implicated in human chronic disease. This would greatly increase the general understanding of pathogen persistence throughout the human body, with strong implications for cancer, Alzheimer’s disease, and other conditions increasingly tied to persistent viral or bacterial activity in tissue.