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 like sex hormones and interferon responses impacting restrained  T cell responses to SARS-CoV-2 & viral persistence in LongCOVID. The study is being performed in a group of > 500 severe and uniquely well characterized LongCOVID patients, with signs of organ dysfunction or disease after mild/moderate COVID-19.

Project background:

Figure from the project team showing clusters of memory CD8T cells

There is accumulating evidence of persistent SARS-CoV-2 virus in patients with LongCOVID. The project team has been studying a group of LongCOVID patients with clear signs of organ dysfunction or disease after mild/moderate COVID-19. They have found variable levels of circulating

SARS-CoV-2 spike protein in blood up to 1000 days following initial infection in a subset of these patients. They have also identified immune system correlates of this viral persistence in the form of monocyte immune cell activation and remodulation, cytokine upregulation, and altered adaptive immune responses. These include high levels of anti-RBD IgG titers but reduced expansion of CD8 memory T cells specific for SARS-CoV-2 in proportions. These results suggest that individuals who fail to mount a clonally expanded memory CD8+ T cell response to SARS-CoV-2 develop elevated anti-SARS-CoV-2 Spike IgG levels with time, likely as a consequence of viral persistence.

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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