Genetic and immunological determinants of severe post-acute COVID-19-syndrome

During the pandemic we have collaborated within the COVID-Human Genetic Effort since Feb. 2020 and studied the SARS-CoV-2 virus, the immune response it elicits and its variation among young and old, men and women with vastly different disease manifestations.

We have described novel immunological mechanisms in severe COVID-19 pneumonia and we also described the Multisystem Inflammatory Syndrome (MIS-C) in children infected with SARS-CoV-2.

Now we lead a subgroup of COVID-HGE to study post-acute COVID-19 syndromes (PACS) and we apply for support to investigate four hypothetical mechanisms of disease.

By focusing on previously healthy individuals with severe PACS and objective measures of disease after PCR-verified infection, we maximize our chances of understanding the mechanisms of disease.

We aim to test four, non exclusive hypotheses for PACS; I) viral persistence due to an inadequate adaptive immune response to SARS-CoV-2, II) Superantigen-mediated stimulation of T-cells leading to autoimmunity, III) Delayed-onset anti-IFN-I autoantibodies that hamper antiviral defenses and, IV) bioenergetic perturbation of cellular metabolism during SARS-CoV-2 infection leading to post-exertional malaise.

To test each of these hypotheses, we will perform systems-level analyses and bioenergetic measurements of blood immune cells in combination with whole genome sequencing from patients with severe PACS and hope to unravel pathogenic pathways that can guide future treatment strategies.