Many intracellular pathogens have evolved to evade immune responses and establish a secure niche inside host cells. One such stealth pathogen is the obligate intracellular bacterium Coxiella burnetii, the causative agent of Q-fever. Coxiella translocates an array of bacterial proteins (effectors) into the host cell through a type IVB secretion system (T4BSS) that mediates suppression of pathogen sensing and innate immunity. Yet, at a systemic level, immunocompetent hosts often restrict pathogens through Th1-mediated and cell-autonomous immunity through the expression of immune-inducible genes. However, the expression and regulation of chemokines, particularly, the CXC-ligands (CXCL9,-10,-11) that are considered biomarkers of Q-fever, is poorly understood. We observed minimal to no CXCL10 transcript levels during Coxiella infection. However, Coxiella-infected cells robustly augmented IFN{gamma}-activated expression of CXCL10 in both phagocytic and non-phagocytic cells, and this process was dependent on viability and T4BSS in epithelial cells. This phenomenon extends to other highly pro-inflammatory cytokines and other pathogens including Salmonella, Mycobacteria (H37Ra) and Toxoplasma. Synergistic increase in CXCL10 expression in Coxiella-infected, IFN{gamma}-activated cells requires ISRE and NF-{kappa}B transcriptional elements in the promoter, and the transcription factors STAT1, STAT3 and IRF9. Inhibition of STAT3 by small molecule inhibitors potently decreased the excess promoter activity of CXCL10. In addition, treatment of Coxiella-infected cells with IFN{gamma} is associated with decreased expression of SOCS1, a negative regulator of the IFN{gamma} signaling axis and relatively higher detection of extracellular bacteria. Altogether, these data demonstrate that intracellular pathogens including those conventionally considered to be immunologically silent, robustly synergize with IFN{gamma} signaling, with STAT3 activation emerging to be a nodal point for promoting both persistent infection as well as synergism in the expression of immune genes.
Valli Ramamoorthy, M., Kadavil Baburaj, B., Jayan, D., Ganesan, S.
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