# S100A8/9-NLRP3-mediated chronic unresolved inflammation drives cardiac pathologies following invasive pneumococcal disease

## TL;DR

Pneumonia can cause lasting heart issues due to persistent inflammation, and targeting this inflammation could prevent heart damage after recovery.

## Contribution

The study identifies the S100A8/A9-TLR4-NLRP3 pathway as a novel driver of cardiac pathology following pneumococcal infection.

## Key findings

- Unresolved inflammation persists after bacterial eradication, leading to cardiac injury in mice.
- S100A8/A9-TLR4-NLRP3-mediated inflammation is central to post-pneumonia heart damage.
- Immunosuppressive treatments like hydrocortisone or paquinimod can rescue cardiac pathologies.

## 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.

Hospitalization for community-acquired pneumonia (CAP) can lead to serious heart problems, even after recovery. Researchers explored why this happens. They studied both humans and mice to understand the link between pneumonia and heart problems. The study involved 10 healthy adults and 7 pneumonia patients. Researchers collected blood samples to analyze immune responses. They also used mice to study heart changes after pneumonia. The focus was on inflammation and its role in heart damage. Findings showed that inflammation persists even after the infection clears, leading to heart issues. The study identified a specific inflammatory pathway (S100A8/A9-TLR4-NLRP3) as a key player in this process. The researchers concluded that targeting this inflammation could help prevent heart problems after pneumonia. Future treatments might focus on reducing inflammation to protect the heart in pneumonia survivors.