Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function

PLoS Pathogens, Sep 2014

Hospitalization of the elderly for invasive pneumococcal disease is frequently accompanied by the occurrence of an adverse cardiac event; these are primarily new or worsened heart failure and cardiac arrhythmia. Herein, we describe previously unrecognized microscopic lesions (microlesions) formed within the myocardium of mice, rhesus macaques, and humans during bacteremic Streptococcus pneumoniae infection. In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1β was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring. Bacterial translocation into the heart tissue required the pneumococcal adhesin CbpA and the host ligands Laminin receptor (LR) and Platelet-activating factor receptor. Immunization of mice with a fusion construct of CbpA or the LR binding domain of CbpA with the pneumolysin toxoid L460D protected against microlesion formation. We conclude that microlesion formation may contribute to the acute and long-term adverse cardiac events seen in humans with IPD.

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Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function

et al. (2014) Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function. PLoS Pathog 10(9): e1004383. doi:10.1371/journal.ppat.1004383 Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function Armand O. Brown 0 Beth Mann 0 Geli Gao 0 Jane S. Hankins 0 Jessica Humann 0 Jonathan Giardina 0 Paola Faverio 0 Marcos I. Restrepo 0 Ganesh V. Halade 0 Eric M. Mortensen 0 Merry L. Lindsey 0 Martha Hanes 0 Kyle I. Happel 0 Steve Nelson 0 Gregory J. Bagby 0 Jose A. Lorent 0 Pablo Cardinal 0 Rosario Granados 0 Andres Esteban 0 Claude J. LeSaux 0 Elaine I. Tuomanen 0 Carlos J. Orihuela 0 Michael R. Wessels, Boston Children's Hospital, United States of America 0 1 Dept. of Microbiology and Immunology, University of Texas Health Science Center at San Antonio , San Antonio, Texas , United States of America, 2 Dept. of Infectious Diseases, St. Jude Children's Research Hospital , Memphis , Tennessee, United States of America, 3 Dept. of Hematology, St. Jude Children's Research Hospital , Memphis , Tennessee, United States of America, 4 University of Milan Bicocca and Dept. of Respiratory Medicine, San Gerardo Hospital , Monza , Italy , 5 Dept. of Medicine, South Texas Veterans Health Care System and University of Texas Health Science Center at San Antonio , San Antonio, Texas , United States of America, 6 Division of Cardiovascular Disease, Dept. of Medicine, The University of Alabama at Birmingham , Birmingham , Alabama, United States of America, 7 Medical Service, Veterans Affairs North Texas Health Care System and Dept. of Internal Medicine and Clinical Sciences, University of Texas Southwestern Medical Center , Dallas, Texas , United States of America, 8 Dept. of Physiology and Biophysics University of Mississippi Medical Center, Jackson, Mississippi, United States of America, 9 Dept. of Laboratory Animal Resources. University of Texas Health Science Center at San Antonio , San Antonio, Texas , United States of America, 10 Dept. of Physiology and Section of Pulmonary/Critical Care Medicine. Louisiana State University Health Sciences Center , New Orleans , Louisiana, United States of America, 11 CIBER de Enfermedades Respiratorias, Hospital Universitario de Getafe , Madrid , Spain , 12 Division of Cardiology, Dept. of Medicine, University of Texas Health Science Center at San Antonio , San Antonio, Texas , United States of America Hospitalization of the elderly for invasive pneumococcal disease is frequently accompanied by the occurrence of an adverse cardiac event; these are primarily new or worsened heart failure and cardiac arrhythmia. Herein, we describe previously unrecognized microscopic lesions (microlesions) formed within the myocardium of mice, rhesus macaques, and humans during bacteremic Streptococcus pneumoniae infection. In mice, invasive pneumococcal disease (IPD) severity correlated with levels of serum troponin, a marker for cardiac damage, the development of aberrant cardiac electrophysiology, and the number and size of cardiac microlesions. Microlesions were prominent in the ventricles, vacuolar in appearance with extracellular pneumococci, and remarkable due to the absence of infiltrating immune cells. The pore-forming toxin pneumolysin was required for microlesion formation but Interleukin-1b was not detected at the microlesion site ruling out pneumolysin-mediated pyroptosis as a cause of cell death. Antibiotic treatment resulted in maturing of the lesions over one week with robust immune cell infiltration and collagen deposition suggestive of long-term cardiac scarring. Bacterial translocation into the heart tissue required the pneumococcal adhesin CbpA and the host ligands Laminin receptor (LR) and Platelet-activating factor receptor. Immunization of mice with a fusion construct of CbpA or the LR binding domain of CbpA with the pneumolysin toxoid L460D protected against microlesion formation. We conclude that microlesion formation may contribute to the acute and long-term adverse cardiac events seen in humans with IPD. - Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This study was supported by grants from the American Heart Association IRG14560023 and National Institute of Health (NIH) HL108054 to CJO. Support was also obtained from NIH AI27913 and the American Lebanese Syrian Associated Charities to EIT, NIH 268201000036C (N01-HV-00244) for the San Antonio Cardiovascular Proteomics Center and HL075360 and the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development Award 5I01BX000505 to MLL, NIH AT006704 to GVH, NIH AA009803 to SN, NIH HL096054 to MIR, and RR00164 for the Tulane National Primate Research Center. The funders had no role in study design, data collecti (...truncated)


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Armand O. Brown, Beth Mann, Geli Gao, Jane S. Hankins, Jessica Humann, Jonathan Giardina, Paola Faverio, Marcos I. Restrepo, Ganesh V. Halade, Eric M. Mortensen, Merry L. Lindsey, Martha Hanes, Kyle I. Happel, Steve Nelson, Gregory J. Bagby, Jose A. Lorent, Pablo Cardinal, Rosario Granados, Andres Esteban, Claude J. LeSaux, Elaine I. Tuomanen, Carlos J. Orihuela. Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function, PLoS Pathogens, 2014, 9, DOI: 10.1371/journal.ppat.1004383