A dynamic insight into the interaction of Chlamydia trachomatis with host cells

Infection by the bacteria Chlamydia trachomatis, or chlamydia, imparts a large burden on society, particularly amongst young adults. It contributes significantly to the prevalence of sexually transmitted diseases and is a key cause of infertility and preventable blindness. Unlike many other types of bacteria, chlamydia cannot replicate outside of a cell. It is obligated to enter a cell in order to reproduce. As a result, it has evolved the ability to manipulate the environment of the host cell to keep the cell alive for the appropriate length of time; because if the host cell dies too quickly, the chlamydia will also die. In order to develop strategies to tackle this major public health problem, we will need to have a better understanding of what happens to the host cell and to the chlamydia during the infection process. Thus we will use a powerful new technique, which will allow us to accurately determine what happens to host cell and chlamydia proteins, as well as how they interact with each other, over the course of the infectious life cycle. In addition, we want to identify whether the chlamydia prevents the body's immune system or defence mechanisms working properly We think that the chlamydia may influence the types of proteins on the surface of the cell, and change the way the immune system cells react to an infection, so that the bacteria can persist. In order to study this, we will compare the proteins on the cell surface before and after infection. Both these approaches will help us better understand how chlamydia successfully enters cells, replicates and manipulates its environment. This knowledge is critical if we are to devise strategies to prevent humans succumbing to the infection and most importantly, the irreversible damage to the body that results in blindness and infertility.

Chlamydia trachomatis (CT) infection imparts a large burden on the human population, particularly amongst young adults, contributing significantly to the prevalence of sexually transmitted diseases, infertility and preventable blindness. CT is an obligate intracellular bacterium that is exquisitely adapted to manipulate the environment of the host cell. In contrast to gene expression studies, there is no information on the global protein changes that occur during the infectious process. Thus, we will utilise a powerful multiplexed proteomic technique that allows the relative abundance of chlamydia and host proteins to be determined accurately over the course of the infectious life cycle in both human epithelial and dendritic cells. This approach will provide the first opportunity to interrogate the chlamydia and host protein responses in tandem and provide a dynamic insight into the chlamydia-host interaction. A quantitative proteomics approach provides the opportunity to interrogate the biology of CT which has not been readily amenable to genetic manipulation approaches.
CT infection is also characterised by silent infection and inappropriate or inadequate cellular immunity to prevent reinfection. The plasma membrane provides a critical nexus with immune system cells and we hypothesize that changes in host cell plasma membrane proteins induced by CT infection may be critical in the modulation of immune responses. To address this, we will compare proteomic changes in the surface exposed membrane of human epithelial and dendritic cells infected CT. Both these approaches will identify pathways in the host cell response that that may be critical for either CT replication, induction of inflammatory responses and deviation of immune system responses. Most importantly, this study will inform potential approaches to prevent successful Chlamydia infection and its inflammatory sequelae in humans.

Who will benefit from this research and how?

The immediate academic beneficiaries from this research would be the chlamydia research community. We will be providing important datasets of both the chlamydial proteome from disease relevant chlamydia strains and in addition a careful description of the host cell proteome response to these pathogens. However, if these results improve our understanding of the mechanisms underlying Chlamydia pathogenesis, it is certainly not too far-fetched to imagine that, the human population could directly benefit from improved diagnostics and treatment options and preventative measures that may occur as a result of these findings. The identification of novel chlamydia molecules that modulate the host cells will progress our understanding of immune response pathways and eventually inform interventions to treat or prevent inflammation and scarring associated with infection, thus impacting on human health.

Societal impact
Chlamydia infection is currently a large burden to human health. It is the leading cause of preventable blindness and one of the major causes of infertility. Thus, any progress made within the context of this project, that improves therapeutic and preventative strategies for chlamydia infection and treatment, no matter how small, would have significant impact. Although a significant reduction in incidence of trachoma and sexually transmitted chlamydia infection could be achieved by improvement in living conditions and a change in sexual behaviour. This must be accompanied by research that increases the understanding of the underlying mechanisms of chlamydia infection and the pathogenic process to enable the development of complementary strategies to combat the disease.