title: The transcriptional programme of human heart valves reveals the natural history of infective endocarditis.
abstract: Infective endocarditis (IE) is an infectious disease that is mainly caused by Staphylococcus aureus and Streptococcus sp. It usually leads to valvular destruction and vegetation formation. Its pathophysiology is badly understood and likely involves immune and coagulation systems with close interactions with the microorganism. Our objective was to evaluate host response by comparing transcriptional profiles of cardiac valves from IE patients with controls. Hierarchical clustering revealed a signature of IE consisting of 146 genes. Among the 89 up-regulated genes, we identified two genes strongly associated with IE: metalloproteinase 12 (MMP-12) and aquaporin-9, a member of the aquaglyceroporin membrane channel family. The up-regulation of MMP-12 gene is strengthened by the down-modulation of the gene encoding its inhibitor TIMP3. In addition, MMP-12 was expressed in macrophages infiltrating EI valves. We also found that aquaporin-9 was expressed in endothelial cells lining neo-vessel lumen, suggesting that aquaporin-9 might be associated with neovascularization of infected valves leading to tissue oedema secondary to the inflammatory process. The Gene Ontology annotation and the resulting functional classification showed that most up-regulated genes account for recruitment of inflammatory cells in vegetations, angiogenesis and remodelling of endocardium tissue. A network analysis confirmed the involvement of molecules related to the remodelling of endocardium tissue and angiogenesis in IE. It also evidenced the role of caspases, especially that of caspase-9 and intrinsic apoptotic pathway in IE. Based on this study we propose a scenario for the natural history of IE in humans. Some parameters identified in this work could become tools for measuring the disease activity and should be tested as biomarkers for diagnosis or prognosis assessment in future studies.
authors.affiliation: Unité de Recherche sur les Maladies Infectieuses Transmissibles et Emergentes, Faculté de Médecine, Centre National de la Recherche Scientifique Unité Mixte de Recherche 6236, Université de la Méditerranée, Marseille, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Benoit
authors.forename: Franck
authors.initials: F
authors.lastname: Thuny
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Priol
authors.forename: Hubert
authors.initials: H
authors.lastname: Lepidi
authors.forename: Sonia
authors.initials: S
authors.lastname: Bastonero
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Casalta
authors.forename: Frédéric
authors.initials: F
authors.lastname: Collart
authors.forename: Christian
authors.initials: C
authors.lastname: Capo
authors.forename: Didier
authors.initials: D
authors.lastname: Raoult
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Mege
mesh_terms: D000328:Adult; D000368:Aged; D015536:Down-Regulation; D004697:Endocarditis, Bacterial / Q000235:genetics* / Q000382:microbiology; D020869:Gene Expression Profiling; D006351:Heart Valves / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D013211:Staphylococcus aureus / Q000472:pathogenicity; D013291:Streptococcus / Q000472:pathogenicity; D014158:Transcription, Genetic; D015854:Up-Regulation