Pseudomonas aeruginosa pulmonary infection results in S100A8/A9-dependent cardiac dysfunction

Abstract

Pseudomonas aeruginosa ( P. a.) infection accounts for nearly 20% of all cases of hospital acquired pneumonia with mortality rates >30%. P. a. infection induces a robust inflammatory response, which ideally enhances bacterial clearance. Unfortunately, excessive inflammation can also have negative effects, and often leads to cardiac dysfunction with associated morbidity and mortality. However, it remains unclear how P. a. lung infection causes cardiac dysfunction. Using a murine pneumonia model, we found that P. a. infection of the lungs led to severe cardiac left ventricular dysfunction and electrical abnormalities. More specifically, we found that neutrophil recruitment and release of S100A8/A9 in the lungs activates the TLR4/RAGE signaling pathways, which in turn enhance systemic inflammation and subsequent cardiac dysfunction. Paradoxically, global deletion of S100A8/A9 did not improve but aggravated cardiac dysfunction and mortality likely due to uncontrolled bacterial burden in the lungs and heart. Our results indicate that P. a. infection induced release of S100A8/9 is double-edged, providing increased risk for cardiac dysfunction yet limiting P. a. growth.

Author summary

Over 5 million people develop pneumonia annually in the United States and is the 8 ^th leading cause of death worldwide. Surprisingly, up to 30% of patients admitted to the hospital for community acquired pneumonia develop cardiovascular complications but the mechanisms are not clearly understood. Pseudomonas aeruginosa (P.a.) infection is very common in hospital settings and accounts for up to 20% of all cases of hospital-acquired pneumonia with a mortality rate of ~30%. P.a. infection and severe lung and systemic inflammation increases levels of S100A8/9 (calprotectin) in the blood stream. Systemic inflammation or dissemination of pathogens into heart tissue can induce cardiac inflammation, cardiomyocyte death and cardiac dysfunction. We found that P.a. infection increases infiltration of inflammatory immune cells in the heart, leading to arrhythmia and left ventricular dysfunction. Our study provides evidence that S100A8/9 provides protection against bacterial infection yet when its production is uncontrolled it activates host immune responses leading to severe cardiovascular complications.