Chlamydia-driven ISG15 expression dampens the immune response of epithelial cells independently of ISGylation

Excessive inflammation upon C. trachomatis infection can cause severe damages in the female genital tract. This obligate intracellular bacterium develops mainly in epithelial cells, whose innate response contributes to the overall inflammatory response to infection. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) stimulates interferon γ (IFNγ) production and is required for bacterial clearance in several infectious contexts. Here, we describe and investigate the consequences of the increase in ISG15 expression by epithelial cells infected with C. trachomatis . Infection of HeLa cells and primary ecto-cervical epithelial cells resulted in a transcriptional up-regulation of ISG15 expression. This did not involve the canonical IFN-I signaling pathway and depended instead on the activation of the STING/TBK1/IRF3 pathway. Absence or reduction of ISG15 synthesis led to increased production of several cytokines and chemokines including interleukin (IL) 6 and IL8, implicating that ISG15 normally dampens the immune response induced by C. trachomatis infection in epithelial cells. ISG15 exerted its control from an intracellular location, but without involving ISGylation. Finally, higher levels of inflammation and delayed bacterial clearance were observed in the genital tracts of ISG15-KO mice infected by C. trachomatis compared to wild type animals, however IFNγ production was unchanged. Altogether, our data show that ISG15 expression acts as a brake on the immune response to C. trachomatis infection in epithelial cells and limits bacterial burden and inflammation in mice. ### Competing Interest Statement The authors have declared no competing interest.