PROJECT ABSTRACT Our goal is to identify significant interactions between the host immune response and the metagenome in sarcoidosis. Sarcoidosis, a disease of unknown etiology, represents an unmet challenge in healthcare. Sarcoidosis is difficult to diagnose, treatments are ineffective, and in the United States it disproportionately afflicts African American women. The disease primarily affects the lungs, but can target the heart, skin, liver and other organ systems as well. Although the etiology remains unknown, dysregulation of T cell subsets in the immune response has been described. Our preliminary data reveal changes in the microbiome and immune regulatory elements as well distinct populations of miRNAs in sarcoidosis providing evidence for the involvement of both the microbiome and immunoregulation. Our hypothesis is that host-microbe interactions are key determinants of aberrant T- lymphocyte function in sarcoidosis. Aim 1 will investigate the role of the metagenome in sarcoidosis. Our preliminary data identifies distinct taxa in the metagenome of bronchoalveolar lavage samples from sarcoidosis subjects. We will use metagenomic shotgun sequencing to identify and quantitate the bacteria, viruses and fungi in sarcoid subjects and perform linear regression analysis to identify significant taxa that are associated with covariates in the metadata. We anticipate that our investigation will identify the composition of the metagenome and also identify biologic functions that are diagnostic of sarcoidosis. Aim 2 will analyze interactions between the host immune response and the metagenome. To investigate the regulatory T cell response in sarcodosis, we will perform RNAseq to identify modulated mRNA and also miRNA. The differentially expressed genes will be used in conjunction with the results of Aim 1 to identify mechanistic functions and to construct predictive models of sarcoidosis. Overall, we will address the interface between the microbiome and T-lymphocyte regulation using a systems biology approach to elucidate key mechanisms of host-microbe interactions contributing to pathology.