Chlamydial pathogenesis, microbiome pathogen interactions and pathogen discovery

Chlamydiae are obligate intracellular parasites that live inside eukaryotic cells. The human chlamydial disease burden is massive and increasing, and pathogens in the genus Chlamydia are the most common infectious agents of blindness and bacterial sexually transmitted infections. Reasons these infections are so common include that no anti-chlamydial vaccines have been developed and infection does not usually elicit lasting immunity. How these pathogens cause disease and evade immunity is poorly understood because chlamydiae were intractable to genetic manipulation until recently. However, the last few years have seen many firsts in chlamydial genetics including transformation, allelic exchange and mutagenesis; the pathogenesis of these organisms can now be investigated using classical bacterial genetic strategies. My lab is using these new tools, and developing improved tools to understand the molecular basis of how highly similar Chlamydia species infect different hosts and how the same Chlamydia isolates infect different tissues (eye, urogenital tract, GI tract, lungs). More recently, we began studying interactions of C. trachomatis with the urogenital and gastrointestinal microbiomes. This work revealed an unexpectedly diverse male urogenital tract microbiota. We are now investigating if the composition of genital and gastrointestinal microbiomes is pertinent to C. trachomatis susceptibility and transmission in humans, and if some of the novel microorganisms we have recently identified are pathogens themselves, using a combination of metagenomic, immunological and epidemiological approaches.

Specific projects currently active in my laboratory include:

1. Identification of C. muridarum genes that dictate host tropism: We model human chlamydial in disease in mice using the mouse-adapted strain C. muridarum because the C. trachomatis strains that infect humans are quickly cleared in mice. A long-standing goal of the lab is to identify C. muridarum pathogenic determinants that that this pathogen uses to survive in mice and the cognate host immune defenses mechanisms these determinants counter. The longer goal of this work is develop better mouse models of human chlamydial infection and disease which we can use to evaluate new anti-chlamydial vaccines and therapeutics.

2. Identification of determinants of chlamydial pathogenesis. Most chlamydial genes are highly conserved, even in pathogenically distinct species. Core genes mediate shared aspects of chlamydial intracellular biology whereas species and strain specific-virulence factors may mediate niche specialization. We are using mutagenesis, forward genetic screens, and various reverse genetic approaches  to identify virulence factors that mediate chlamydial resistance to pro-apoptotic stimuli, cell-autonomous immunity and which help these pathogens invade different tissues. Separately, we are developing tools for manipulation of essential chlamydia genes that dictate broadly conserved aspects of chlamydial pathogenesis and intracellular biology.

3. Microbiome of the human urogenital tract and pathogen discovery: The male urogenital tract has classically been thought to be sterile. Results from our and other groups challenge this idea and suggest that uncharacterized microorganisms that colonize the urogenital and GI tracts and may be relevant to diseases of known (such as Chlamydia) and unknown etiologies. We are currently investigating the hypotheses that specific urethral microbiomes promote susceptibility to chlamydial infection and disease and that idiopathic urethritis is caused by novel urogenital microorganisms by comparing the microbiomes hundreds of men who do and do not have urethritis before and after antibiotic treatment. Separately, we are interested in how microbiomes of various body sites influence susceptibility to pathogens.

I currently direct a large case/control clinical study which is assessing if novel pathogens are linked to a common but undefined urogenital syndrome, idiopathic urethritis, in men. More broadly, I am interested in improving the standard of care for urogenital tract infections. Finally, I study factors that could modulate susceptibility to Chlamydia infection, detrimental outcomes of these infections, and the mechanisms of immune protection against Chlamydia and other urogenital tract pathogens.