The Role of macrophages in cardiac end organ damage associated to acute respiratory disease syndrome and post-acute infection syndrome

• Applicant: Dr. Jana Grune
• Subject Area: Clinical Infectiology and Tropical Medicine ; Pneumology, Thoracic Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 553344285

The Coronavirus disease 2019 (COVID-19) pandemic, triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has magnified a longstanding clinical problem that is now reaching unprecedented levels: post-acute infection syndromes (PAIS). PAIS manifests in a significant portion of patients who continue to experience symptoms three months after the acute phase of infection has subsided. While pathogen-specific PAISs have been documented for years (e.g. Ebola, Dengue, Influenza), it is the SARS-CoV-2 pandemic that has brought attention to millions of patients suffering from PAIS in Germany and worldwide. Bacterial or viral acute respiratory distress syndrome (ARDS) is often associated with strong immune responses. Importantly, this immune response is not restricted to lung tissue, but can also afflict secondary organs beyond the lung. For instance, patients with bacterial lung infections frequently co-develop acute kidney injury, acute cardiac events or even neurological disorders. In line, data from us demonstrate secondary organ damage in the heart long-term after bacterial infection. We have recently identified pro-inflammatory macrophages as a cellular component of infection-associated cardiac remodeling, exhibiting pro-thrombotic and pro-inflammatory phenotypes in the context of acute ARDS. Of note, impaired macrophage dynamics were also found in a murine model of sterile ARDS and remained dysregulated even after the acute disease was resolved, suggesting that the hosts’ own immune response is a driver of PAIS development. In this proposal, we aim to mechanistically understand PAIS, with a focus on post-COVID-syndrome (PCS) and PAIS in the context of community-acquired pneumonia (CAP). By employing three independent mouse models of hyperinflammatory ARDS (bacterial, viral, sterile), we aim to gain a mechanistic understanding of PAIS by i) characterizing remote end-organ damage in acute ARDS, and ii) understanding the role of ARDS-related secondary organ damage in the pathogenesis of PAIS. We hypothesize that remote organ damage in acute ARDS predisposes for PAIS development later. Based on our data from sterile ARDS, we assume that the hosts’ own immune response, evident as sterile inflammation and thrombo-inflammation starring myeloid cell expansion, is a driver of ARDS-related remote organ damage and later PAIS development. Vice versa, inhibition of the hosts’ immune response will prevent remote organ damage, PAIS development and improve ARDS outcomes.

• DFG Programme: Research Grants