Molecular dissection of cell death-mediated inflammation as a driver of virus-induced ME/CFS

Programmed cell death is a key bodily defence mechanism following infections such as SARS-CoV-2; as part of the immune response, it enables the targeted elimination of infected cells, thereby limiting the spread of pathogens. However, programmed cell death can simultaneously release pro-inflammatory molecules and signals that damage tissue. This process triggers sustained immune activation, which may contribute to the pathogenesis of post-viral illnesses and the development of characteristic long-term sequelae. Yet, it remains unclear how these cell death mechanisms sustain disease-relevant chronic inflammatory responses, in which organs these processes occur, and how they contribute to the multisystemic symptoms of ME/CFS. The aim is to characterise the causal links between virus-induced cell death, chronic inflammation, and disease-specific symptoms. To this end, the investigators combine a preclinical in-vivo model of post-COVID syndrome with genetic functional analyses, advanced whole-body and intravital imaging, and the analysis of longitudinal blood samples from patients with post-COVID ME/CFS. This approach links molecular processes at the cellular level with organ changes, functional effects, and clinical courses, thereby enabling the differentiation of causal signalling pathways from correlative findings. The focus lies on signalling pathways involved in programmed cell death and associated inflammatory responses linked to post-COVID ME/CFS. A two-stage imaging approach allows, for the first time, the systematic mapping of cell death and inflammation signatures throughout the entire organism. The identification of these signatures is being validated in a clinical ME/CFS cohort to pinpoint disease-relevant blood and tissue markers as well as potentially druggable signalling pathways. The project aims to provide fundamental mechanistic insights into the pathogenesis of post-infectious diseases. It lays the foundation for mechanism-based diagnostics, improved patient stratification, and the targeted repurposing of cell-death-modulating and anti-inflammatory treatments for ME/CFS and post-COVID syndrome.