Novel strategies to mitigate cardiac damage and dysfunction following invasive pneumococcal disease

About This Grant

One-in-four adults hospitalized for community-acquired pneumonia (CAP) experiences a major adverse cardiac event (MACE). Critically, individuals who experience MACE are 4-5 times more likely to die than those with pneumonia alone. Hospitalization for CAP is also tied to a greater risk of MACE (up to 10-fold within 30 days of hospitalization) and cardiovascular (CV)-associated death in convalescence for at least 5 years. Thus, pneumonia damages the heart and this is linked to MACE and CV-associated death during and after hospitalization. Of note, studies on Streptococcus pneumoniae (Spn), a Gram-positive bacterium and the leading cause of CAP, have historically focused on events that occur in the respiratory and nervous systems. Indeed, although Spn-mediated cardiac damage/dysfunction is now well-established clinical problem, no specific treatment is available to combat this devastating condition. To address this unmet medical need, we will focus on identifying potential mitigation strategies to alleviate the cardiac damage following pneumococcal disease. Our preliminary studies have revealed the excessive recruitment of multiple components of the S100A8/9- NLRP3-IL-1β signaling circuit in the heart of Spn-infected animals. Therefore, aim 1 will test the hypothesis that the S100A8/9-NLRP3-IL-1β signaling circuit is critical to mediate Spn-induced excessive cardiac inflammation, adverse remodeling, and dysfunction. These studies will be accomplished by employing a combination of mouse genetic models (S100A9 and NLRP3 knockouts (KOs)) and pharmacological agents (S100A9 inhibitor (Paquinimod, in vivo), and NLRP3 inhibitor (CY-09, in vivo)). Although macrophages (MΦs) are heterogeneous, a distinction has emerged between circulating monocyte-derived C-C chemokine receptor 2+ (CCR2+) MΦs that prolong inflammation (detrimental), versus tissue-resident or circulating CCR2- MΦs, which are critical to resolve inflammation and promote healing (protective). Our preliminary studies revealed excessive cardiac recruitment of proinflammatory CCR2+ MΦs in Spn-infected hearts, which persist in the myocardium even after antibiotic clearance of the infection. Hence, Aim 2 will test the hypothesis that Spn promotes adverse cardiac remodeling by excessive recruitment of proinflammatory CCR2+ MΦs. CCR2 KO mouse model and novel anti-CCR2 monoclonal antibody (MC-21) will be employed to determine whether inhibiting the CCR2+ axis attenuates the Spn-mediated adverse myocardial remodeling. Thus, proposed studies will identify novel mechanisms by which detrimental profibrotic and prolonged inflammation could be selectively targeted without hampering the repairing/healing mechanisms. The human relevance of critical findings from the mouse model will be accessed with blood samples from CAP patients. The interventional studies for mitigation approaches with the mouse model will be further validated in the human cardiac tissue chip (heart-on-a-chip) model. We are confident that accomplishing the proposed studies will put us in an ideal situation to carry out a modes clinical trial to alleviate the cardiac burden of CAP patients.