Project description
The role of neutrophils in chlamydia
Polymorphonuclear neutrophils (PMNs) constitute the first line of innate defence against pathogens. However, in the case of chlamydia, a common sexually transmitted infection caused by the bacterium Chlamydia trachomatis, PMNs seem to be unresponsive. Moreover, bacteria exploit PMNs as intracellular sites for replication. The key objective of the EU-funded NCI-CAD project is to investigate the mechanism by which PMNs subject to this role change from effectors to infection facilitators. Results have important consequences for the understanding of the asymptomatic nature of chlamydia and may lead to novel interventions against infections.
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.
Fields of science
Not validated
Not validated
Keywords
Programme(s)
Topic(s)
Funding Scheme
ERC-ADG - Advanced GrantHost institution
97070 Wuerzburg
Germany