NCI-CAD SIGNED

Project "NCI-CAD" data sheet

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 Project objective

Incidences of sexually transmitted diseases (STI) have increased during the past decades with a concomitant rapid spread of antibiotic resistant bacteria. Chlamydia trachomatis is the most frequent cause of bacterial STIs. These infections often remain asymptomatic and are consequently not diagnosed and treated, resulting in the subsequent development of severe chronic pathologies and an enormous economic burden for health systems. The reason for the asymptomatic nature of chlamydial infection is currently unknown.

My laboratory made the intriguing observation that exposure of polymorphonuclear neutrophils (PMNs), a major subset of innate immune cells and cause of inflammation and tissue damage, to C. trachomatis causes PMNs to become unresponsive to a broad range of stimuli, including Chlamydia themselves. We identified a chlamydial secreted protease (CPAF) to be the bacterial effector responsible for preventing the activation of the non-stimulated PMNs. Chlamydia not only survive PMN exposure but can also surprisingly exploit the PMN itself as host cell for replication. Unexpectedly, the chlamydial secreted deubiquitinase Cdu1 is required for intracellular adaptation of Chlamydia, indicating that PMNs may posses antibacterial cell-autonomous defence strategies based on the host ubiquitin system.

It remains completely unclear how PMNs are converted to host cells for obligate intracellular bacteria. This proposal therefore aims to comprehensively investigate the mechanism of PMN reprogramming from a short-lived major immune effector cells to a host cell for Chlamydia replication and development. PMN paralysis offers an unexpected explanation for the asymptomatic nature of these infections. Furthermore, chlamydial factors involved in PMN reprogramming provide prime targets to rearm the patient’s immune response to effectively resolve Chlamydia infections.