Impact of ocular microbiome, immune response and Chlamydiae on trachoma following MDA

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PROJECT SUMMARY Chlamydia trachomatis (Ct) is the leading cause of infectious blindness in the world today. The World Health Organization (WHO) estimates that there are over 142 million people at risk of irreversible loss of sight. This figure likely underestimates the true numbers as it is difficult to account for all communities that are affected globally. The ocular disease caused by Ct is called trachoma and carries an annual price tag of approximately $8 billion from lost productivity. The highest concentrations of this neglected disease include 37 countries in Africa, the Middle East, Asia, and Central and South America along with Australia. Africa has over 89% of the world’s known trachoma cases, reflecting a major region of health disparity. The WHO developed the SAFE strategy to eliminate trachoma as a public health problem by the year 2020. SAFE stands for: Surgery to correct in-turned eyelashes (known as Trachomatous Trichiasis or TT); Antibiotics to treat Ct; Facial cleanliness to improve hygiene, and Environmental improvements to reduce transmission. The A part of SAFE includes Mass Drug Administration (MDA) with azithromycin and has been used in many countries. Ten endemic or hypoendemic countries have been validated by WHO as being trachoma free. However, 6 endemic and 38 hyperendemic countries have not, although they have received 5 to over 10 rounds of MDA. The highest burden of disease is in Ethiopia and South Sudan where ~30-50% of children under 10 years of age have active trachoma, and the reasons for this remain unclear. Trachoma as a public health concern will not be eliminated until we understand why there is ongoing active trachoma following multiple rounds of MDA in hyperendemic countries. Our unifying hypothesis, therefore, is that the natural history of trachoma is defined by the interaction of the ocular microbiome, immune responses and pathogen populations (both Ct and non-Ct) that are influenced by MDA. While there is a growing body of research on the ocular microbiome, few studies have evaluated differences in microbiota composition between healthy and trachomatous eyes and none have looked at the influence of Ct infection. We will employ metagenome shotgun sequencing (MSS) to understand healthy, dysbiotic and chlamydial-associated microbiota in addition to immune responses and pathogen genomic characteristics for a cohort residing in the trachoma hyperendemic Amhara Region of Ethiopia. We aim to: 1) Examine Ct infections based on whole genome sequencing; 2) Identify taxonomic diversity and abundance of ocular microbiota among subjects with and without Chlamydia and their association with trachomatous disease; and 3) Determine host microbiota/immune response profiles associated with and without Chlamydia, and develop models to predict trachoma post MDA. This work will naturally transition to improving chlamydial diagnostics that utilize MSS methods, and developing interventions that, given the ineffective antibiotic regimens to date, may include novel therapeutic strategies and/or revised treatment duration to decrease and eliminate hyperendemic trachoma among at risk populations in Africa that have the greatest need for intervention.