Mechanistic Insights Into Cardiac Dysfunction And Remodeling Associated With Invasive Pneumococcal Pathogenesis

Background: One-in-four adults hospitalized for community-acquired pneumonia (CAP) experiences a major adverse cardiac event (MACE). Pneumonia survivors, in particular those who experienced invasive pneumococcal disease, are also at elevated risk for MACE in convalescence. Although Streptococcus pneumoniae ( Spn )-mediated cardiac dysfunction is a well-established clinical problem, the mechanisms by which pneumonia impacts the long-term risk of MACE are poorly understood. Methods and Results: Each mouse was infected with 1 x 10 4 CFU of Spn , to model invasive pneumococcal disease (IPD). At 30 hours post-infection, mice were administered Ampicillin (50mg/kg) every 12 hours for 3 days. After that, animals were given Ampicillin (1mg/ml) ad libitum in drinking water for 4 days. Three weeks post-infection phase, Spn -rescued animals’ demonstrated marked cardiac dysfunction as reflected by significantly reduced ejection fraction (EF), and fractional shortening (FS). Cardiac injury was confirmed to have occurred by measurement of increased expression of ANP, BNP (q-PCR), and levels of serum Troponin-I as measured by ELISA. Trichrome-stained heart sections demonstrated fibrotic remodeling in the Spn -rescued animals. To gain insight into mechanisms, we analyzed whether Spn alters cardiac immune cell infiltration and pro-inflammatory S100A8/A9-TLR-NLRP3-IL-1β signaling axis in vivo . Indeed, Spn -rescued (with antibiotic) animals showed an increased percentage of TLR-2/4+, NLRP3+, and phosphor-NFkB+ myeloid/neutrophils in the heart. Importantly, these findings were corroborated using human blood samples collected from patients with IPD. Pharmacological blocking of S100A8/A9-TLR-NLRP3-IL-1β signaling axis by S100A9 inhibitor largely reduced Spn -induced detrimental cardiac pathologies in convalescence. Conclusion: Our results suggest chronic activation of the pro-inflammatory S100A8/A9-TLR2/4-NLRP3-IL-1β pathway in Spn -infected hearts that persists even after antibiotic clearance of bacterial infection. Targeting the S100A8/9-NLRP3-IL-1β signaling circuit reduced chronic inflammation and fibrosis in our mice model and therefore is potentially a novel strategy to mitigate the Spn-mediated cardiac dysfunction.