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

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. LeSauxElaine I. Tuomanen, Carlos J. Orihuela

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalPLoS pathogens
Volume10
Issue number9
DOIs
StatePublished - Sep 1 2014

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Streptococcus pneumoniae
Laminin Receptors
Myocardium
Cardiac Electrophysiology
Toxoids
Bacterial Translocation
Pneumococcal Infections
Troponin
Macaca mulatta
Interleukin-1
Cicatrix
Cardiac Arrhythmias
Cause of Death
Immunization
Hospitalization
Cell Death
Collagen
Heart Failure
Anti-Bacterial Agents
Ligands

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

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

In: PLoS pathogens, Vol. 10, No. 9, 01.09.2014.

Research output: Contribution to journalArticle

Brown, AO, Mann, B, Gao, G, Hankins, JS, Humann, J, Giardina, J, Faverio, P, Restrepo, MI, Halade, GV, Mortensen, EM, Lindsey, ML, Hanes, M, Happel, KI, Nelson, S, Bagby, GJ, Lorent, JA, Cardinal, P, Granados, R, Esteban, A, LeSaux, CJ, Tuomanen, EI & Orihuela, CJ 2014, 'Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function', PLoS pathogens, vol. 10, no. 9. https://doi.org/10.1371/journal.ppat.1004383
Brown, Armand O. ; Mann, Beth ; Gao, Geli ; Hankins, Jane S. ; Humann, Jessica ; Giardina, Jonathan ; Faverio, Paola ; Restrepo, Marcos I. ; Halade, Ganesh V. ; Mortensen, Eric M. ; Lindsey, Merry L. ; Hanes, Martha ; Happel, Kyle I. ; Nelson, Steve ; Bagby, Gregory J. ; Lorent, Jose A. ; Cardinal, Pablo ; Granados, Rosario ; Esteban, Andres ; LeSaux, Claude J. ; Tuomanen, Elaine I. ; Orihuela, Carlos J. / Streptococcus pneumoniae Translocates into the Myocardium and Forms Unique Microlesions That Disrupt Cardiac Function. In: PLoS pathogens. 2014 ; Vol. 10, No. 9.
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AU - Brown, Armand O.

AU - Mann, Beth

AU - Gao, Geli

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AU - Humann, Jessica

AU - Giardina, Jonathan

AU - Faverio, Paola

AU - Restrepo, Marcos I.

AU - Halade, Ganesh V.

AU - Mortensen, Eric M.

AU - Lindsey, Merry L.

AU - Hanes, Martha

AU - Happel, Kyle I.

AU - Nelson, Steve

AU - Bagby, Gregory J.

AU - Lorent, Jose A.

AU - Cardinal, Pablo

AU - Granados, Rosario

AU - Esteban, Andres

AU - LeSaux, Claude J.

AU - Tuomanen, Elaine I.

AU - Orihuela, Carlos J.

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N2 - 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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