Cardiac Microlesions Form During Severe Bacteremic Enterococcus faecalis Infection

Enterococci, such as Enterococcus faecalis, are a significant cause of hospital-acquired bacteremia and mortality among the elderly and patients with comorbid conditions in the healthcare setting. In this study, the novel discovery is made that cardiac microlesions form during severe bacteremic E. faecalis infection in mice. The cardiac microlesions were identical in appearance to those previously observed to form by Streptococcus pneumoniae during invasive pneumococcal disease (IPD) in mice, non-human primates, and humans. However, E. faecalis does not encode the virulence determinants implicated in pneumococcal microlesion formation, suggesting that formation is through an alternative pathway. In previous work, we showed that E. faecalis DsbA is required for the post-translational disulfide bond formation and stability of EntV, a secreted E. faecalis bacteriocin. Here, the role of DsbA in E. faecalis pathogenicity was explored. DsbA was discovered to be required for E. faecalis virulence in a C. elegans model and, importantly, was necessary for efficient cardiac microlesion formation. By investigating the cardiac host response, it was discovered that E. faecalis promotes cardiomyocyte necroptotic cell death at sites of microlesion formation. Additionally, by examining the cytokines induced by exposure of E. faecalis to cardiomyocytes, it was revealed that loss of DsbA caused a pro-inflammatory response unlike the wild type strain, which suppressed the immune response. In conclusion, we establish that E. faecalis is capable of forming cardiac microlesions and identify features of both the bacterial and host responses that are mechanistically involved. Significance StatementE. faecalis is a bacterium capable of causing serious disease in humans, including endocarditis, an infection on the surface of the heart valves with a high mortality rate. In this work, we document for the first time that E. faecalis is capable of also causing an invasive infection of the heart, forming cardiac microlesions in a mouse model of severe bloodstream infection. Additionally, a contributing bacterial factor is identified and the immune response of heart cells to infection with E. faecalis is characterized. Overall, this work makes a significant contribution to the field of infectious diseases by identifying a new enterococcal disease pathology, cardiac microlesion formation, which was previously known to occur only with IPD.