Defining the Ocular Microbiome and Immune Landscape of Trachoma-Endemic Populations to Inform Disease Risk - PROJECT SUMMARY Trachoma caused by Chlamydia trachomatis (Ct) is the leading cause of infectious blindness in the world today, with >100M people at risk of impaired vision or blindness. Despite the World Health Organization’s SAFE program (Surgery, Antibiotics, Facial cleanliness, and Environmental improvement) to eradicate blinding disease by 2020, countries like Ethiopia that have received many years of azithromycin mass drug administration (MDA) for ‘A’ remain hyperendemic for trachoma with high rates of Ct infection. In other countries like Fiji, trachoma screening is inadequate, but rates are also high. The high prevalence of trachoma in Ethiopia and Fiji motivates the present study, which aims to characterize factors that contribute to trachoma pathogenesis and persistence. There are currently no studies that use metagenomic shotgun sequencing (MSS) to explore species comprising ocular microbiomes, and associated microbial metabolic pathways and resistomes (i.e., the collection of antibiotic resistance genes (ARGs)), and host-immune responses in trachoma-endemic populations. Assessing ocular resistomes is of particular importance given the rise in antibiotic-resistant pathogens globally and continued use of azithromycin for MDA in trachoma populations. It is likely that the ocular microbiome in these populations consists of pathogenic microbes that, along with Ct, impact ocular immune responses, and fuel inflammation and trachomatous disease development and progression. The overarching goal of this research is to compare ocular microbiomes and host immune responses among our Ethiopia and Fiji cohorts with and without trachoma using 850+ conjunctival samples. This will allow for the creation of Ct infection and trachoma disease models to support the near future development of novel diagnostics and conjunctival therapeutics for disease management. In Aim 1, MSS will be applied to define the ocular microbiomes for the Ethiopia and Fiji cohorts and develop ocular Community State Types (CSTs) that correlate with the features of pathogenic versus healthy microbiomes, including age, Ct infection status, microbial diversity and composition, and acute and chronic trachoma in these geographically diverse populations. In Aim 2, conjunctival host-immune responses will be studied and integrated with microbiome and participant metadata to develop a model of infection and trachoma disease risk. The successful completion of these aims will help to elucidate the role of the microbiome in trachoma pathogenesis and ultimately contribute to improved management and eradication of blinding trachoma. This research will leverage an interdisciplinary mentorship team from the University of California at San Francisco and at Berkeley, and Emory University, with expertise in Ct and bacterial pathogenesis, multi- omic analyses for complex diseases, host-immune responses, antimicrobial resistance, and mathematical modelling of microbiome data. This work complements the proposed training plan and will teach me how to bridge infectious diseases, global health, and bioinformatics to develop novel diagnostic tools and therapeutics for a diversity of infectious diseases nationally and globally as a future physician-scientist investigator.
