The role of interferons in the resistance to infection with Chlamydia pneumoniae

Abstract

Chlamydia pneumoniae is an obligate intracellular bacterial pathogen that infects the respiratory tract in human. IFN-gamma is an essential cytokine for the immune response triggered to limit infection with C. pneumoniae. C. pneumoniae infection of murine bone marrow-derived macrophages (BMM), induces IFN-alpha/betadependent IFN-gamma secretion leading to control of intracellular bacterial growth.

We studied the molecular details of chlamydial-induced IFN-alpha and IFN-gamma expression in BMM. We demonstrated that TLR4, but not TLR2, TLR6 or TLR9 is essential for control of C pneumoniae infection. We found that TLR4-MyD88IRAK4-dependent signalling is necessary for IFN-alpha and IFN-gamma mRNA expression, and protection against infection of BMM with C. pneumoniae. The transcription factor STAT1 mediates signalling in response to IFN-alpha/beta and IFN-gamma. In C. pneumoniae-infected BMM, phosphorylation of STAT1 is IFN-alpha/beta-dependent and necessary for increased IFN-gamma mRNA accumulation and bacterial growth control.

Enhancement of IFN-gamma mRNA levels and control of C. pneumoniae infection also required NF-kappaB activation. We showed that NF-kappaB activation is TRAF6-dependent, but independent on TLR4MyD88-IFN-alpah/beta-U/PSTAT I signalling in intracellular bacterial infection. The transcription factor IRF3 mediates IFN-beta synthesis. In C. pneumoniae-infected IRF3-/- BMM, the accumulation of IFN-beta mRNA was reduced, but however the IFN-alpha and IFN-gamma mRNA level and the susceptibility were not altered compared to the wild type. Surprisingly, IMP-/- BMM show higher loads of C. pneumoniae and no expression of IFN-alpha and IFN-gamma mRNA in comparison to the wild type BMM. In conclusion, we demonstrate that TLR4-MyD88-IFN-alpha/beta-STAT1-dependent signalling, as well as TLR4-independent, but TRAF6dependent NF-kappaB activation play a role in IFN-gamma expression and protection against C. pneumoniaeinfection in BMM.

We studied the protective role of STAT1 in mice infected intranasally with C. pneumoniae. STAT1 mediates an IFN-alpha/betaR and IFN-gammaR-dependent protection against C. pneumoniae infection in vivo. STAT1 phosphorylation is detected after chlamydial infection in IFN-alpha/betaR-/- and IFN-gammaR-/- mice, but not in IFN-alpha/betaR-/-IFN-gammaR-/- mice. T-cells release IFN-gamma and conferred protection against C pneumoniae in a STAT1 -independent fashion. STAT1 mediates microbicidal mechanisms of nonhematopoietic cells, leading to control of intracellular infection in vivo. Thus, STAT1 mediates a cooperative effect of IFN-alpha/beta and IFN-gamma on non-hematopoietic cells, resulting in protection against C. pneumoniae in pulmonary infection.