Individuals hospitalized for community-acquired pneumonia (CAP) are at increased risk for sudden death as a result of adverse cardiac events. During hospitalization for CAP up to 1/5 of individuals >65 years of age experience some form of adverse cardiac event including arrhythmias, congestive heart failure, or myocardial infarction. Following successful resolution of the infection, individuals hospitalized for CAP remain at high-risk for sudden cardiac-related death for up to 1 year post-infection. Thus events occurring during pneumonia either aggravate existing cardiovascular conditions or directly affect cardiac function. Streptococcus pneumoniae (the pneumococcus) is the leading cause of CAP and infectious-related death among the elderly (>65 years). In past studies, we have determined that pneumococcal cell wall released during infection damages cardiomyocytes in a Platelet activating factor (PAFr)-dependent manner, inhibiting their ability to contract and leading to death of challenged mice. Recently, we have determined that statins (i.e. HMG-CoA reductase inhibitors) protect lung cells from damage during pneumonia by inhibiting PAFr expression and blocking lytic pore-formation by the pneumococcal toxin pneumolysin. For this reason, we hypothesize that statin therapy will also protect cardiomyocytes from cell wall and pneumolysin mediated damage during pneumonia and prevent the occurrence of adverse cardiac events. In support of this hypothesis we have collected data showing that statins reduced the ability of live bacteria and S. pneumoniae components to adhere to and kill vascular endothelial cells. Furthermore, that mice administered statins for 1 week were protected against heart failure and death following intravenous challenge with purified pneumococcal cell wall. Thus experimental evidence suggests that statins have strong potential to be used as a therapeutic agent against adverse cardiac events during pneumonia. To rigorously test whether statins protect cardiomyocyte function during pneumonia. We will:
Aim 1 : Determine impact of statin therapy on pneumolysin-mediated cardiomyocyte damage. We will examine the effect of statins on cardiomyocyte damage during infection with wild type and pneumolysin deficient bacteria, asses cardiomyocyte function in vivo and ex vivo following exposure to pneumolysin, and examine cardiomyocyte caspase-independent apoptosis, the pathway normally triggered by pneumolysin.
Aim 2 : Determine the impact of statin therapy on cardiomyocyte cell wall uptake. We will determine the impact of statins on cardiomyocyte PAFr expression and cell wall uptake in vitro and vivo, we will determine the impact of statin therapy on heart function following challenge with cell wall collected from wild type and ethanolamine grown bacteria, the latter which does not interact with PAFr, we will determine the impact of cell wall and statins on cardiomyocyte gene expression.
Individuals hospitalized for community-acquired pneumonia (CAP) are at increased risk for sudden death as a result of adverse cardiac events that are in part the result of noxious agents released by bacteria during the infection. Our published data suggests that statins are capable of protecting host cells against Streptococcus pneumoniae cell wall and the toxin pneumolysin. The goal of this proposal is to test if statins protect mice against heart damage during pneumonia.
| Brown, Armand O; Millett, Elizabeth R C; Quint, Jennifer K et al. (2015) Cardiotoxicity during invasive pneumococcal disease. Am J Respir Crit Care Med 191:739-45 |
| Brown, Armand O; Orihuela, Carlos J (2015) Visualization of Streptococcus pneumoniae within Cardiac Microlesions and Subsequent Cardiac Remodeling. J Vis Exp : |
| Brown, Armand O; Mann, Beth; Gao, Geli et al. (2014) Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function. PLoS Pathog 10:e1004383 |
| Boyd, Angela R; Hinojosa, Cecilia A; Rodriguez, Perla J et al. (2012) Impact of oral simvastatin therapy on acute lung injury in mice during pneumococcal pneumonia. BMC Microbiol 12:73 |
| Perry, Theodore W; Pugh, Mary Jo V; Waterer, Grant W et al. (2011) Incidence of cardiovascular events after hospital admission for pneumonia. Am J Med 124:244-51 |
