Project Team
Petter Brodin MD, PhD, Professor of Pediatric immunology, Karolinska Institutet and Imperial College London, UK
Judith Bruchfeld MD, Chief Physician at Karolinska University Hospital and a docent in Infectious Diseases at Karolinska Institutet’s Department of Medicine. Leads a multidisciplinary clinical team with vast experience in caring for patients with severe LongCOVID in Stockholm, Sweden.
Giorgio Casari, PhD, Full Professor of Genetics, School of Medicine, San Raffaele University, Milan, and other collaborators within the COVID-HGE network.
Jean-Laurent Casanova, MD, PhD, Professor, Rockefeller University; Investigator, Howard Hughes Medical Institute
Project lead Dr. Petter Brodin
Project Summary:
To determine the underlying genetic causes and other modifying factors—including sex hormones and immune parameters—that impact restrained T cell responses to SARS-CoV-2 in Long COVID. The study is being performed in a cohort of more than 500 severe and uniquely well-characterized Long COVID patients who developed persistent organ dysfunction or disease following mild to moderate COVID-19. By combining whole-genome sequencing with advanced human tissue models, the researchers are identifying the biological mechanisms that predispose certain individuals to persistent SARS-CoV-2 infection and chronic disease, with the goal of informing future diagnostics and targeted therapies.
Project Background:
Most people successfully eliminate SARS-CoV-2 after infection, yet a subset of individuals develop Long COVID, suggesting that inherited differences in antiviral immunity may influence disease susceptibility. To identify these differences, the research team is performing whole-genome sequencing to discover rare genetic variants enriched in patients with severe Long COVID compared with large populations of SARS-CoV-2-infected individuals who recovered without developing the condition. Early findings indicate that many candidate variants do not occur in genes traditionally associated with white blood cell function, raising the possibility that impaired antiviral defenses within barrier tissues—rather than immune cells alone—may contribute to viral persistence.
Data on the study presented by Dr. Peter Brodin at the PolyBio 2026 Symposium.
To test this hypothesis, the team is engineering candidate genetic variants into human intestinal organoids and barrier epithelial models to determine how they alter antiviral signaling pathways, including Toll-like receptor (TLR) responses, and whether they impair the ability of tissues to eliminate persistent virus. This integrated approach combines large-scale human genomics with functional tissue biology to uncover the mechanisms underlying Long COVID and identify new targets for precision diagnostics and therapeutic intervention.
The current project is expanding on these findings to search for genetic mechanisms underlying impaired cellular immune responses to SARS-CoV-2 infections. The team is performing whole genome sequencing and variant analyses in relation to >3000 whole genomes obtained from patients with variable presentations following SARS-CoV-2 infection within the global COVID Human Genetic Effort Consortium. The genetic analyses are being combined with other forms of research including immune cell profiling and experiments in lymphoid organoid cultures.
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