ABSTRACT: One-in-four adults hospitalized for community-acquired pneumonia (CAP) experiences a major adverse cardiac event (MACE). Individuals who experience MACE are 4-5 times more likely to die than those with pneumonia alone. Hospitalization for CAP is also tied to greater risk of MACE and cardiovascular-associated death in convalescence for at least 5 years. Thus, pneumonia damages the heart and this is linked to MACE and cardiovascular-associated death during and after hospitalization. Streptococcus pneumoniae (Spn), a Gram-positive bacterium, is the leading cause of CAP and invasive disease. During invasive pneumococcal disease (IPD), Spn in the bloodstream gains access to the myocardium, where they replicate, kill cardiomyocytes, and impair function. Notably, and in surviving animals that had been treated with antimicrobials, cardiac damage caused by Spn results in tissue remodeling that has long-term negative effects on heart function. Thus, pneumococci in the heart are direct effectors of cardiac damage and this helps to explain CAP-associated MACE. Our laboratory has been studying the molecular basis of cardiomyocyte damage by Spn for close to a decade. One key discovery we have made is that Spn that invade the heart are taken up by cardiomyocytes via clathrin-mediated endocytosis. Moreover, when pneumococci persist within these cells, their replication and production of pneumolysin and hydrogen peroxide results in the death of the cardiomyocyte. Accordingly, we have chosen to explore the importance of LC3-associated phagocytosis, a form of autophagy, on cardiomyocyte self-defense. Our preliminary results support the hypotheses that: 1) autophagy protects the heart during IPD; 2) autophagy contributes to the eradication of intracellular bacteria in the heart; 3) cardiomyocyte autophagy sustains cardiac function post-infection. Testing of these hypotheses via completion of the aims below will advance our understanding of the host-pathogen interactions that take place in the heart during IPD with the potential to influence future intervention strategies. We will: AIM 1: Determine the role of autophagy in protecting cardiomyocyte function and survivability following Spn uptake. This will be done in vitro using autophagy-deficient (ATG7 null) adult mouse cardiomyocytes and induced pluripotent stem cell (iPSC)-derived cardiomyocytes growing in a novel cardiac tissue chip infected with Spn. AIM 2: Determine the impact of autophagy on cardiac remodeling. This will be done in vivo using cardiomyocyte-specific ATG7 null mice infected with Spn. Cardiac function will be evaluated using echocardiography so that the extent of post-infection cardiac remodeling can be correlated to aberrant function.