STAT1 regulates IFN-alpha beta- and IFN-gamma-dependent control of infection with Chlamydia pneumoniae by nonhemopoietic cells
Rothfuchs, A.Gigliotti.; Trumstedt, C.; Mattei, F.; Schiavoni, G.; Hidmark, A.; Wigzell, H.; Rottenberg, Mín.E.
Journal of Immunology 176(11): 6982-6990
2006
ISSN/ISBN: 0022-1767 PMID: 16709859 Document Number: 603020
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 STATI(-/-) mice were even more susceptible to C pneumoniae than IFN-gamma(-/-) or IFN-gamma R-/- mice. Phosphorylation of STAT1. was detected in the lungs of C pneumoniae-infected wild-type, IFN-gamma R-/-, and IFN-alpha beta R-/- mice, but not in mice lacking both IFN-alpha beta R and IFN-gamma R. In line with this, IFN-alpha beta R-/-/IFN-gamma R-/- mice showed increased susceptibility to infection compared with IFN-gamma R-/- mice. However, C pneumoniae-infected IFN-aj3R-1- or IFN regulatory factor 3(-/-) mice showed no increased susceptibility and similar IFN-gamma expression compared with wild-type mice. CD4(+) or CD8(+) cells released IFN-gamma 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-alpha beta and IFN-gamma on nonhemopoietic cells, resulting in protection against C pneumoniae.