Components of the Host-Pathogen Interface and Their Role in Chlamydial Intracellular Pathogenesis

Abstract

Intracellular bacteria such as Chlamydia inhabit a single-membrane vacuolar compartment termed the “inclusion”. Chlamydia inclusions offer an escape from host immune defenses and a dedicated spaces for replication. Viable inclusion membranes must be modified by Chlamydia to sequester nutrients and camouflage themselves from host immune defenses that otherwise sense, contain, or eradicate microbial invaders. C. trachomatis, a human-adapted pathogen responsible for widespread sexually transmitted disease, forms inclusions that are protected from gamma-interferon (IFNγ)-induced cell-autonomous immunity. However, it is largely unknown how the unique architecture of host and bacterial components that localize to inclusion membranes impact chlamydial pathogenesis during IFNγ-stimulated conditions. This dissertation details a novel C. trachomatis secreted effector, the gamma resistance determinant or “GarD”, that shields inclusions from cell-autonomous immunity. Specifically, GarD forms a perimeter on inclusion membranes to prevent attack by the IFNγ-inducible enzyme RNF213, which labels GarD-less inclusions with linear poly-ubiquitin protein chains as a signal for elimination. Therefore, GarD operates as an essential antagonist of RNF213-mediated ubiquitylation and allows C. trachomatis to endure human cell-autonomous defenses. Future and ongoing work considers the mechanics of how GarD, RNF213 and additional bacterial and host cell factors affect pathogenesis of Chlamydia species in mammals. Overall, the novel GarD-RNF213 axis is an important expansion of our knowledge of chlamydial pathogenesis and immune responses to vacuole-residing pathogens.