All mammalian cells possess inherent defense mechanisms to fight intracellular bacteria. These include the tagging of the bacteria or the pathogen containing vacuole with ubiquitin, engulfment into autophagosomes and subsequent lysosomal destruction or host cell death triggered by the activation of the inflammasome or apoptosis signaling. Interferon is an important cytokine of the innate immune system to fight intracellular pathogens including Chlamydia. Interferon signaling alters the gene expression of multiple antibacterial and immunoregulatory genes which limit intracellular growth and boost bacterial-killing mechanisms.
Due to their obligate intracellular life style Chlamydia established multiple strategies to prevent recognition and autophagosomal destruction of the inclusion and to block host cell death. Recent studies highlighted the central role of the secreted deubiquitinase Cdu1 of Chlamydia trachomatis for the intracellular survival of the bacteria: the anti-apoptotic protein Mcl-1 is deubiquitinated and thereby stabilized by Cdu1 to block host cell apoptosis. Furthermore, Chlamydia lacking enzymatic active Cdu1 are more susceptible to Interferon γ-mediated defense.
Our research aims to understand how Chlamydia use their two deubiquitinases Cdu1 and Cdu2 to manipulate the host cell ubiquitin proteasome system to promote intracellular survival.