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ABSTRACT: TLR2 and TLR4 are crucial for recognition of Chlamydia pneumoniae in vivo, since infected TLR2/4 double-deficient mice are unable to control the infection as evidenced by severe loss of body weight and progressive lethal pneumonia. Unexpectedly, these mice display higher pulmonary levels of the protective cytokine IFNγ than wild type mice. We show here, that antigen-specific CD4(+) T-cells are responsible for the observed IFNγ-secretion in vivo and their frequency is higher in TLR2/4 double-deficient than in wild type mice. The capacity of TLR2/4 double-deficient dendritic cells to re-stimulate CD4(+) T-cells did not differ from wild type dendritic cells. However, the frequency of CD4(+)CD25(+)Foxp3(+) T-cells was considerably higher in wild type compared to TLR2/4 double-deficient mice and was inversely related to the number of IFNγ-secreting CD4(+) effector T-cells. Despite increased IFNγ-levels, at least one IFNγ-mediated response, protective NO-secretion, could not be induced in the absence of TLR2 and 4. In summary, CD4(+)CD25(+)Foxp3(+) regulatory T-cells fail to expand in the absence of TLR2 and TLR4 during pulmonary infection with C. pneumoniae, which in turn enhances the frequency of CD4(+)IFNγ(+) effector T-cells. Failure of IFNγ to induce NO in TLR2/4 double-deficient cells represents one possible mechanism why TLR2/4 double-deficient mice are unable to control pneumonia caused by C. pneumoniae and succumb to the infection.
PLoS ONE 01/2011; 6(11):e26101. · 4.09 Impact Factor
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ABSTRACT: Chlamydophila pneumoniae was shown to prevent IFN gamma-inducible upregulation of MHC-class II molecules by secreting chlamydial protease-like activity factor (CPAF) into the cytosol of those host cells which support the complete bacterial replication cycle. CPAF acts by degrading upstream stimulatory factor 1 (USF-1). However, in cells like bone marrow-derived macrophages (BMM), which restrict chlamydial replication, we show that CPAF expression is barely detectable and the expression of USF-1 is induced upon infection with C. pneumoniae. Nevertheless, the infection still reduced base line and prevented IFN gamma-inducible MHC-class II expression. Similar results were obtained with heat-inactivated C. pneumoniae. In contrast, reduction of MHC-class II molecules was not observed in MyD88-deficient BMM. Reduction of IFN gamma-inducible MHC-class II expression by C. pneumoniae in BMM was mediated in part by the MAP-kinase p38. Infection of murine embryonic fibroblasts (MEF) with C. pneumoniae, which allow chlamydial replication, induced the expression of CPAF and decreased USF-1 and MHC-class II expression. Treatment of these cells with heat-inactivated C. pneumoniae reduced USF-1 and MHC-class II expression to a much lower extent. In summary, C. pneumoniae downregulates MHC-class II expression by two cell type-specific mechanisms which are either CPAF-independent and MyD88-dependent like in BMM or CPAF-dependent like in MEFs.
Molecular Microbiology 03/2010; 76(3):648-61. · 5.01 Impact Factor
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ABSTRACT: Innate immune cells produce NO via inducible NO synthase (iNOS) in response to certain infections or upon stimulation with cytokines such as IFN-gamma and TNF. NO plays an important role in host defense against intracellular bacteria including Chlamydophila pneumoniae as a result of its microbicidal activity. In MyD88-deficient mice, which succumb to C. pneumoniae infection, iNOS induction is impaired 6 days postinfection, although pulmonary levels of IFN-gamma and TNF are elevated as in wild-type mice at this time-point. Here, we demonstrate that induction of iNOS in macrophages upon C. pneumoniae infection is controlled by MyD88 via two pathways: NF-kappaB activation and phosphorylation of the MAPK JNK, which leads to the nuclear translocation of c-Jun, one of the two components of the AP-1 complex. In addition, phosphorylation of STAT1 and expression of IFN regulatory factor 1 (IRF-1) were delayed in the absence of MyD88 after C. pneumoniae infection but not after IFN-gamma stimulation. Taken together, our data show that for optimal induction of iNOS during C. pneumoniae infection, the concerted action of the MyD88-dependent transcription factors NF-kappaB and AP-1 and of the MyD88-independent transcription factors phosphorylated STAT1 and IRF-1 is required.
Journal of Leukocyte Biology 10/2008; 84(6):1585-93. · 4.99 Impact Factor
