Characterizing the immune response to Chlamydia trachomatis

Isaac Bernstein-Hanley	Jörn Coers	Wendy Loomis	Nadia Roan

Chlamydia trachomatis is the most common bacterial cause of sexually transmitted disease in the developed world and the leading cause of preventable blindness worldwide. It is an obligate intracellular bacterium that infects the epithelial cells of either the conjunctivae or the genital tract. Chlamydia species have a unique lifestyle, consisting of two distinct developmental forms: the metabolically inert, infectious elementary body (EB) that can survive outside the host cell and the non-infectious, replicative reticulate body (RB) that is found exclusively within a specialized vacuole called an inclusion. Although the organism is strictly confined to a host cell vacuole throughout replication, we have found that CD8+ T-cells are stimulated in mice infected with C. trachomatis. We have cultured these CD8+ T-cells and can demonstrate that they recognize and lyse cells infected with C. trachomatis. When these cultured CD8+ T-cells are adoptively transferred into infected mice, a reduction in Chlamydia load within the mice can be measured. We are working to understand how T cells are stimulated in the genital tract in response to infection with C. trachomatis. We also are beginning to gain insight into what types of T cell responses lead to resolution of infection and what types of T cell responses fail to clear the organism and result in pathology.

The response of CD8+ T cells suggests that a subset of C. trachomatis proteins cross the vacuolar membrane and have access to the cytosol of host cells. We are beginning to identify some of these proteins that may be used by C. trachomatis for nutrient acquisition, modification of or maintenance of the vacuolar environment, or alteration of host cell structures or functions. This work may lead to insights into the pathogenesis of this unique organism.

In collaboration with William Dietrich’s lab we have taken a more global approach to understand the genetic basis of resistance and susceptibility to C. trachomatis. Using a forward genetic screen, we were able to map and identify first a locus, and then a specific gene, Irgb10, that mediates resistance of mice to C. trachomatis. Irgb10 is an interferon-inducible GTPase and it appears that interferon-inducible gene products are key signals in controlling intracellular replication of C. trachomatis and other bacterial pathogens. We are now pursuing this work as a project sponsored by the “immune circuits” group at the Broad Institute; using a large-scale shRNA screen to uncover host genes (and pathways) responsible for interferon-inducible control.