title: Streptococcus pneumoniae translocates into the myocardium and forms unique microlesions that disrupt cardiac function.
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.
authors.affiliation: Dept. of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Armand O
authors.initials: AO
authors.lastname: Brown
authors.affiliation: Dept. of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Beth
authors.initials: B
authors.lastname: Mann
authors.affiliation: Dept. of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Geli
authors.initials: G
authors.lastname: Gao
authors.affiliation: Dept. of Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Jane S
authors.initials: JS
authors.lastname: Hankins
authors.affiliation: Dept. of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Humann
authors.affiliation: Dept. of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Giardina
authors.affiliation: University of Milan Bicocca and Dept. of Respiratory Medicine, San Gerardo Hospital, Monza, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Faverio
authors.affiliation: 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.
authors.forename: Marcos I
authors.initials: MI
authors.lastname: Restrepo
authors.affiliation: Division of Cardiovascular Disease, Dept. of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Halade
authors.affiliation: 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.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Mortensen
authors.affiliation: Dept. of Physiology and Biophysics University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
authors.affiliation: Dept. of Laboratory Animal Resources. University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Martha
authors.initials: M
authors.lastname: Hanes
authors.affiliation: Dept. of Physiology and Section of Pulmonary/Critical Care Medicine. Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Kyle I
authors.initials: KI
authors.lastname: Happel
authors.affiliation: Dept. of Physiology and Section of Pulmonary/Critical Care Medicine. Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Steve
authors.initials: S
authors.lastname: Nelson
authors.affiliation: Dept. of Physiology and Section of Pulmonary/Critical Care Medicine. Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Bagby
authors.affiliation: CIBER de Enfermedades Respiratorias, Hospital Universitario de Getafe, Madrid, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Lorent
authors.affiliation: CIBER de Enfermedades Respiratorias, Hospital Universitario de Getafe, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Cardinal
authors.affiliation: CIBER de Enfermedades Respiratorias, Hospital Universitario de Getafe, Madrid, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Granados
authors.affiliation: CIBER de Enfermedades Respiratorias, Hospital Universitario de Getafe, Madrid, Spain.
authors.forename: Andres
authors.initials: A
authors.lastname: Esteban
authors.affiliation: Division of Cardiology, Dept. of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Claude J
authors.initials: CJ
authors.lastname: LeSaux
authors.affiliation: Dept. of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Elaine I
authors.initials: EI
authors.lastname: Tuomanen
authors.affiliation: Dept. of Microbiology and Immunology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Orihuela
mesh_terms: D018829:Adhesins, Bacterial / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D005260:Female; D007114:Immunization; D053583:Interleukin-1beta / Q000378:metabolism; D008251:Macaca / Q000382:microbiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000276:immunology / Q000473:pathology*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D011008:Pneumococcal Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D017474:Receptors, Laminin / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*; D013301:Streptolysins / Q000378:metabolism
chemical_list: D018829:Adhesins, Bacterial; D001426:Bacterial Proteins; C490083:CbpA protein, bacteria; D053583:Interleukin-1beta; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D017474:Receptors, Laminin; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; C039351:platelet activating factor receptor