Hepatic induction of cholesterol biosynthesis reflects a remote adaptive response to pneumococcal pneumonia

Martina Weber, Sandro Lambeck, Nadine Ding, Stefanie Henken, Matthias Kohl, Hans P. Deigner, David P. Enot, Emeka I. Igwe, Lucien Frappart, Michael Kiehntopf, Ralf A. Claus, Thomas Kamradt, Debra Weih, Yoram Vodovotz, David E. Briles, Abiodun D. Ogunniyi, James C. Paton, Ulrich A. Maus, Michael Bauer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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 lowinfection doses (105 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.

Original languageEnglish
Pages (from-to)2424-2436
Number of pages13
JournalFASEB Journal
Volume26
Issue number6
DOIs
StatePublished - Jun 2012
Externally publishedYes

Keywords

  • Pathogen-host interaction
  • Pneumolysin
  • Sepsis

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