Inclusion integrity – Storming the membranous sanctuary of Chlamydia

Many clinically important pathogens can invade human cells and can evade their defenses by hiding within pathogen-containing vacuoles (PCVs). Hence, it may be feasible to combat such microbes by deliberately destabilizing their PCVs.

To promote progress towards such a novel therapeutic concept, I propose a 5-year research program in which my group at Umeå University will uncover the molecular basis of PCV integrity and means for and the impact of PCV destabilization.

We will focus on the inclusion, the PCV of Chlamydia trachomatis, a leading bacterial cause of ocular and urogenital infections.

To identify the host-derived and bacterial factors that maintain the integrity of the inclusion, we will conduct genome-wide genetic screens.

We will further use a proteomic and lipidomic approach to test our hypothesis that the integrity of the inclusion is determined by its composition, and this in turn by its interactions with host organelles.

Exploiting this mechanistic knowledge, we will then strive to identify pharmacologic means for inclusion destabilization.

Finally, we will use a microscopic approach to determine the host cell response to inclusion damage and the consequences for the bacteria, thereby revealing the benefit that can be achieved by targeting PCVs.

By filling significant knowledge gaps in the field of host-pathogen interaction, I expect this project to pave the way for the future design of innovative antimicrobials for our battle against intracellular infections.