Essential role of mitochondrial antiviral signaling, IFN regulatory factor (IRF)3, and IRF7 in Chlamydophila pneumoniae-mediated IFN-beta response and control of bacterial replication in human endothelial cells.
Chlamydophila pneumoniae infection of the vascular wall as well as activation of the transcription factor IFN regulatory factor (IRF)3 have been linked to development of chronic vascular lesions and atherosclerosis. The innate immune system detects invading pathogens by use of pattern recognition receptors, some of which are able to stimulate IRF3/7 activation and subsequent type I IFN production (e. g., IFN-beta). In this study, we show that infection of human endothelial cells with C. pneumoniae-induced production of IFN-beta, a cytokine that so far has been mainly associated with antiviral immunity. Moreover, C. pneumoniae infection led to IRF3 and IRF7 nuclear translocation in HUVECs and RNA interference experiments showed that IRF3 and IRF7 as well as the mitochondrial antiviral signaling (MAVS) were essential for IFN-beta induction. Finally, C. pneumoniae replication was enhanced in endothelial cells in which IRF3, IRF7, or MAVS expression was inhibited by small interfering RNA and attenuated by IFN-beta treatment. In conclusion, C. pneumoniae infection of endothelial cells activates an MAVS-, IRF3-, and IRF7-dependent signaling, which controls bacterial growth and might modulate development of vascular lesions.
Division of Infectious Diseases and Pulmonary Medicine, Department of Internal Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany.
Claudia
C
Buss
Bastian
B
Opitz
Andreas C
AC
Hocke
Juliane
J
Lippmann
Vincent
V
van Laak
Stefan
S
Hippenstiel
Matthias
M
Krüll
Norbert
N
Suttorp
Julia
J
Eitel
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D002478:Cells, Cultured; D016993:Chlamydophila pneumoniae / Q000254:growth & development* / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000502:physiology*; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007942:Leukemia, Experimental / Q000276:immunology / Q000382:microbiology / Q000821:virology; D024101:Mitochondrial Proteins / Q000502:physiology*; D008979:Moloney murine leukemia virus / Q000276:immunology; D034622:RNA Interference / Q000502:physiology*; D012367:RNA, Viral / Q000037:antagonists & inhibitors; D012192:Retroviridae Infections / Q000276:immunology / Q000382:microbiology / Q000821:virology; D015398:Signal Transduction / Q000276:immunology; D014412:Tumor Virus Infections / Q000276:immunology / Q000382:microbiology / Q000821:virology
D048868:Adaptor Proteins, Signal Transducing; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; C505371:MAVS protein, human; D024101:Mitochondrial Proteins; D012367:RNA, Viral; D016899:Interferon-beta