S100A8/9-NLRP3-mediated chronic unresolved inflammation drives cardiac pathologies following invasive pneumococcal disease
Year: 2025
Type: article
Abstract: Streptococcus pneumoniae (Spn) is the leading cause of community-acquired pneumonia (CAP). A quarter of hospitalized patients with CAP experience a major adverse cardiac event (MACE), raising their mortality by four to five times compared with pneumonia alone. Patients with CAP continue to face a significantly greater risk of MACE and cardiovascular-associated death during convalescence. However, the reasons responsible for this remain unclear. To elucidate the molecular mechanism(s) of Spn-induced MACE in convalescence, a mouse model of Spn infection and antibiotic rescue was employed. A marked decline in ejection fraction persisting at least 3 weeks after bacterial eradication with antibiotics was observed. Evidence of enduring cardiac injury was observed at the molecular, biochemical and histology levels. Blood analysis from patients with invasive pneumococcal disease confirmed unresolved inflammation in these individuals. Here we mechanistically identified that S100A8/A9-TLR4-NLRP3-mediated unresolved inflammation drives cardiac pathologies in Spn convalescent mice. This inflammation was central to the cardiac pathology because interventions with broad-spectrum immunosuppressive hydrocortisone or specific inhibitors of S100A9 (paquinimod) essentially rescued the Spn-induced cardiac pathologies. These results provide critical preclinical data and rationale for a clinical investigation into immunosuppressive interventions for managing Spn-mediated cardiac pathologies in convalescence.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,490
Awards: G1922333041, G211428442, G2483483994, G3106197723, G3224460447, G3718510750, G381310454, G3979542943, Novel Mechanisms of Cardiac Function and Dysfunction, Novel Mechanisms of Cardiac Function and Dysfunction, G4761140184, G5000467770, Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart, G5398536189, Cell-specific role of HIPK2 in cardiac pathophysiology: Focus on fibrosis and inflammation, Cardiomyocyte self-defense against Streptococcus pneumoniae, G6913808315, G7069741293, G7091973078, The Significance of Fibroblast and myeloid-Specific PD-L1 in Cardiac Pathophysiology post ischemic injury, Signaling Mechanisms Governing Myocardial Fibrosis in Diseased Heart, G869213283, G8966236800, Mechanosignaling regulates macrophage immunometabolism, Molecular mechanisms underlying organ penetration in disseminated pneumococcal infection, Novel strategies to mitigate cardiac damage and dysfunction following invasive pneumococcal disease
OpenAlex ID: W4415024347