title: Hepatic induction of cholesterol biosynthesis reflects a remote adaptive response to pneumococcal pneumonia.
abstract: Community-acquired pneumonia presents a spectrum of clinical phenotypes, from lobar pneumonia to septic shock, while mechanisms underlying progression are incompletely understood. In a transcriptomic and metabolomic study across tissues, we examined serotype-specific regulation of signaling and metabolic pathways in C57BL/6 mice intratracheally instilled with either serotype 19F Streptococcus pneumoniae (S19; causing lobar pneumonia), or serotype 2 S. pneumoniae (S2; causing septic pneumococcal disease,) or vehicle (Todd-Hewitt broth). Samples of lung, liver, and blood were collected at 6 and 24 h postinfection and subjected to microarray analysis and mass spectrometry. Results comprise a preferential induction of cholesterol biosynthesis in lobar pneumonia at low-infection doses (10(5) colony forming units/mouse) leading to increased plasma cholesterol (vehicle: 1.8±0.12 mM, S2: 2.3±0.10 mM, S19: 2.9±0.15 mM; P<0.05, comparing S19 to vehicle and S2). This induction was pneumolysin dependent, as a pneumolysin-deficient strain of serotype 19F failed to induce cholesterol biosynthesis (S19ΔPLY: 1.9±0.03 mM). Preincubation of pneumolysin with purified cholesterol or plasma from hypercholesterolemic mice prior to intratracheal instillation protected against lung barrier dysfunction and alveolar macrophage necrosis. Cholesterol may attenuate disease severity by neutralizing pneumolysin in the alveolar compartment and thus prevent septic disease progression.
authors.affiliation: Department of Anaesthesiology and Intensive Care Therapy, Jena University Hospital, Jena, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Weber
authors.forename: Sandro
authors.initials: S
authors.lastname: Lambeck
authors.forename: Nadine
authors.initials: N
authors.lastname: Ding
authors.forename: Stefanie
authors.initials: S
authors.lastname: Henken
authors.forename: Matthias
authors.initials: M
authors.lastname: Kohl
authors.forename: Hans P
authors.initials: HP
authors.lastname: Deigner
authors.forename: David P
authors.initials: DP
authors.lastname: Enot
authors.forename: Emeka I
authors.initials: EI
authors.lastname: Igwe
authors.forename: Lucien
authors.initials: L
authors.lastname: Frappart
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehntopf
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Claus
authors.forename: Thomas
authors.initials: T
authors.lastname: Kamradt
authors.forename: Debra
authors.initials: D
authors.lastname: Weih
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.forename: David E
authors.initials: DE
authors.lastname: Briles
authors.forename: Abiodun D
authors.initials: AD
authors.lastname: Ogunniyi
authors.forename: James C
authors.initials: JC
authors.lastname: Paton
authors.forename: Ulrich A
authors.initials: UA
authors.lastname: Maus
authors.forename: Michael
authors.initials: M
authors.lastname: Bauer
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis* / Q000494:pharmacology; D005260:Female; D008099:Liver / Q000378:metabolism*; D016676:Macrophages, Alveolar / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000503:physiopathology*; D040081:Protein Array Analysis; D013301:Streptolysins / Q000235:genetics / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D002784:Cholesterol