Project Team

Akiko Iwasaki, PhD: Sterling Professor of Immunobiology and Professor of Dermatology and of Molecular, Cellular, and Developmental Biology and of Epidemiology (Microbial Diseases), Yale University School of Medicine; Investigator, Howard Hughes Medical Institute

Richard A. Flavell, PhD, FRS: Sterling Professor of Immunobiology at Yale University School of Medicine, and an Investigator of the Howard Hughes Medical Institute

Craig Wilen, MD, PhD: Associate Professor Term; Medical Director, Immune Monitoring Core Facility, Yale School of Medicine

Anna Pyle, PhD: Sterling Professor of Molecular, Cellular, and Developmental Biology and Professor of Chemistry

Scott Handley, PhD: Professor of Pathology and Immunology, Washington University School of Medicine St. Louis

Project summary:

Project co-lead Dr. Anna Pyle

The project is using a mouse model of persistent SARS-CoV-2 infection to determine mechanisms by which the virus or its proteins can persist for long periods of time in tissue and blood. Specifically, the team is:

1. Characterizing viral RNA in a humanized mouse model of Long COVID: The team has developed a mouse model with human characteristics. They are isolating single cells from various organs of these infected mice at different time points and using advanced techniques to identify the precise nature of persistent viral RNA in different cell types. From viral RNA-positive tissues, they are performing further experiments to identify the location of the RNA and its impact on host gene expression patterns.

2. Testing therapeutics to eliminate viral RNA in the humanized mice: The team will perform experiments to determine what therapeutics (e.g., antivirals, antisense oligonucleotides, innate immune stimuli such as SRL) may best eliminate persistent virus.

3. Defining the nature and location of vRNA in human tissues: The team is working to obtain human tissues and will use advanced technologies including hybrid-capture vRNA sequencing and spatial transcriptomics to identify the location and nature of persistent viral RNA and associated gene expression changes.

Project background:

Project co-lead Dr. Akiko Iwasaki

SARS-CoV-2 persistence has been observed in a diverse number of tissue samples collected via autopsy studies and tissue biopsy studies. Some teams have also identified persistent viral RNA or proteins in blood samples collected from Long COVID or post-COVID patients months or years after initial SARS-CoV-2 infection. However, the exact nature of the viral RNA that gives rise to prolonged presence remains unclear. In this project, the team is isolating and sequencing viral RNA from animal models and human tissues to probe the cellular and molecular mechanisms of SARS-CoV-2 persistence and potential virus elimination.