Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria (original) (raw)
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Journal of immunology (Baltimore, Md. : 1950), 2006
STAT1 mediates signaling in response to IFN-alpha, -beta, and -gamma, cytokines required for protective immunity against several viral, bacterial, and eukaryotic pathogens. The protective role of STAT1 in the control of intranasal infection with the obligate intracellular bacterium Chlamydia pneumoniae was analyzed. IFN-gamma-/- or IFN-gamma receptor (R)-/- mice were highly susceptible to infection with C. pneumoniae. We found that STAT1-/- mice were even more susceptible to C. pneumoniae than IFN-gamma-/- or IFN-gammaR-/- mice. Phosphorylation of STAT1 was detected in the lungs of C. pneumoniae-infected wild-type, IFN-gammaR-/-, and IFN-alphabetaR-/- mice, but not in mice lacking both IFN-alphabetaR and IFN-gammaR. In line with this, IFN-alphabetaR-/-/IFN-gammaR-/- mice showed increased susceptibility to infection compared with IFN-gammaR-/- mice. However, C. pneumoniae-infected IFN-alphabetaR-/- or IFN regulatory factor 3-/- mice showed no increased susceptibility and similar IFN-...
The Journal of Immunology, 2006
STAT1 mediates signaling in response to IFN-␣, -, and -␥, cytokines required for protective immunity against several viral, bacterial, and eukaryotic pathogens. The protective role of STAT1 in the control of intranasal infection with the obligate intracellular bacterium Chlamydia pneumoniae was analyzed. IFN-␥ ؊/؊ or IFN-␥ receptor (R) ؊/؊ mice were highly susceptible to infection with C. pneumoniae. We found that STAT1 ؊/؊ mice were even more susceptible to C. pneumoniae than IFN-␥ ؊/؊ or IFN-␥R ؊/؊ mice. Phosphorylation of STAT1 was detected in the lungs of C. pneumoniae-infected wild-type, IFN-␥R ؊/؊ , and IFN-␣R ؊/؊ mice, but not in mice lacking both IFN-␣R and IFN-␥R. In line with this, IFN-␣R ؊/؊ /IFN-␥R ؊/؊ mice showed increased susceptibility to infection compared with IFN-␥R ؊/؊ mice. However, C. pneumoniae-infected IFN-␣R ؊/؊ or IFN regulatory factor 3 ؊/؊ mice showed no increased susceptibility and similar IFN-␥ expression compared with wild-type mice. CD4 ؉ or CD8 ؉ cells released IFN-␥ in vivo and conferred protection against C. pneumoniae in a STAT1-independent manner. In contrast, STAT1 mediated a nonredundant protective role of nonhemopoietic cells but not of hemopoietic cells. Nonhemopoietic cells accounted for the expression of STAT1-mediated indoleamine 2, 3-dioxygenase and the p47 GTPase LRG-47, but not inducible NO synthase mRNA. In summary, we demonstrate that STAT1 mediates a cooperative effect of IFN-␣ and IFN-␥ on nonhemopoietic cells, resulting in protection against C. pneumoniae. The Journal of Immunology, 2006, 176: 6982-6990. IFN-␥ cooperate in protection against C. pneumoniae through their ability to activate STAT1. STAT1 was not required for CD4 ϩ or
Journal of immunology (Baltimore, Md. : 1950), 2008
Type I IFNs (IFNIs) have pleiotropic functions in regulating host innate and adaptive immune responses to pathogens. To elucidate the role of IFNIs in host resistance to chlamydial infection in vivo, we compared IFN-alpha/beta receptor knockout (IFNAR(-/-)) and wild-type control mice in susceptibility to Chlamydia trachomatis mouse pneumonitis (Chlamydia muridarum) lung infection. We found that the IFNAR(-/-) mice were significantly more resistant to C. muridarum infection showing less bacterial burden and bodyweight loss, and milder pathological changes. However, IFN-gamma response, which is believed to be critical in host defense against chlamydial infection, was similar between the wild-type and IFNAR(-/-) mice. More importantly, TUNEL analysis showed less macrophage apoptosis in IFNAR(-/-) mice, which was consistent with lower expressions of IFNI-induced apoptotic factors, TRAIL, Daxx, and PKR. Furthermore, depletion of lung macrophages with dichloromethylene diphosphonate-lipos...
Role of IRAK4 and IRF3 in the control of intracellular infection with Chlamydia pneumoniae
Journal of Leukocyte Biology, 2007
TLR signal transduction involves a MyD88-mediated pathway, which leads to recruitment of the IL-1 receptor (IL-1R)-associated kinase 4 (IRAK4) and Toll/IL-1R translation initiation region domain-containing adaptor-inducing IFN--mediated pathway, resulting in the activation of IFN regulatory factor (IRF)3. Both pathways can lead to expression of IFN-. TLR-dependent and -independent signals converge in the TNF receptor-associated factor 6 (TRAF6) adaptor, which mediates the activation of NF-〉. Infection of murine bone marrowderived macrophages (BMM) with Chlamydia pneumoniae induces IFN-␣/-and NF-〉-dependent expression of IFN-␥, which in turn, will control bacterial growth. The role of IRAK4 and IRF3 in the regulation of IFN-␣/ expression and NF-〉 activation was studied in C. pneumoniae-infected BMM. We found that levels of IFN-␣, IFN-, and IFN-␥ mRNA were reduced in infected IRAK4 ؊/؊ BMM compared with wild-type (WT) controls. BMM also showed an IRAK4-dependent growth control of C. pneumoniae.