Cardiotoxicity during invasive pneumococcal disease

Abstract

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and sepsis, with adult hospitalization linked to approximately 19% incidence of an adverse cardiac event (e.g., heart failure, arrhythmia, infarction). Herein, we review the specific host-pathogen interactions that contribute to cardiac dysfunction during invasive pneumococcal disease: (1) cell wall-mediated inhibition of cardiomyocyte contractility; (2) the new observation that S. pneumoniae is capable of translocation into the myocardium and within the heart, forming discrete, nonpurulent, microscopic lesions that are filled with pneumococci; and (3) the bacterial virulence determinants, pneumolysin and hydrogen peroxide, that are most likely responsible for cardiomyocyte cell death. Pneumococcal invasion of heart tissue is dependent on the bacterial adhesin choline-binding protein A that binds to laminin receptor on vascular endothelial cells and binding of phosphorylcholine residues on pneumococcal cell wall to platelet-activating factor receptor. These are the same interactions responsible for pneumococcal translocation across the blood-brain barrier during the development of meningitis. We discuss these interactions and how their neutralization, either with antibody or therapeutic agents that modulate platelet-activating factor receptor expression, may confer protection against cardiac damage and meningitis. Considerable collagen deposition was observed in hearts of mice that had recovered from invasive pneumococcal disease. We discuss the possibility that cardiac scar formation after severe pneumococcal infection may explain why individuals who are hospitalized for pneumonia are at greater risk for sudden death up to 1 year after infection.

Keywords: Streptococcus pneumoniae; heart failure; invasion; invasive pneumococcal disease; pathogenesis.

Figure 1.

Translocation across vascular endothelial cells requires platelet-activating factor receptor (PAFR)/lipoteichoic acid–bound phosphorylcholine (ChoP) and choline-binding protein A (CbpA)/laminin receptor (LR) interactions. To translocate across the vascular endothelium, Streptococcus pneumoniae (Spn) first binds LR with its adhesin CbpA. This facilitates the interaction of bacterial cell wall ChoP residues on teichoic and lipoteichoic acid with PAFR on endothelial cells. Activation of this G protein–coupled receptor results in the phosphorylation (P) and activation of β-arrestin. The activation of β-arrestin (β-arr), a scaffold protein, leads to clathrin recruitment and the uptake of the pneumococcus or cell wall fragment in a clathrin-coated vesicle. This vesicle either fuses with lysosomes, killing internalized bacteria, or is recycled to the surface, allowing, in some instances, release of live pneumococci to the basolateral side.

Figure 2.

Streptococcus pneumoniae cardiac microlesion formation and subsequent cardiac scarring. (A) Hematoxylin and eosin–stained mouse cardiac section showing an S. pneumoniae cardiac microlesion adjacent to a blood vessel. Individual diplococci can be seen within the lesion and in adjacent cardiomyocytes. Scale bar = 20 μm. (B) Picro Sirius Red–stained mouse cardiac tissue section after antibiotic treatment highlights collagen deposition (red) and is indicative of scar formation. Scale bar = 50 μm.