Similar to eukaryotes, many prokaryotes compartmentalize their cytosol to carry out specialized metabolic reactions, prevent toxicity and store nutrients. This is achieved through two main classes of protein organelles, namely, bacterial microcompartments (BMCs) and encapsulin nanocompartments. Human-associated microbes play a vital role in health and disease and preliminary studies suggest that hundreds of commensal and pathogenic bacteria encode uncharacterized protein organelle systems. Some of these protein organelles have been proposed to contribute towards microbial virulence while others are hypothesized to allow more rapid colonization of challenging environments like the human host.
However, no in-depth analysis of protein organelles encoded by the human gut microbiome has been carried out. In addition, the molecular and physiological functions of most protein organelle systems have not been explored while their contributions towards human health and disease are poorly understood.
The overall goal of this project is to perform a comprehensive survey of protein organelle operons encoded in the human gut microbiome, followed by the molecular and physiological characterization of selected systems involved in host-microbe interactions.
To achieve this goal, we will first assemble metagenomes from microbiomes of healthy individuals. This data will then be used for in depth sequence analysis aimed at identifying genetic signatures of protein organelle operons using an array of bioinformatic and genome-mining tools. We will analyze the distribution and diversity of protein organelles in the microbiomes of healthy individuals and correlate this data with known molecular functions of certain protein organelle systems, potentially leading to new insights into the importance of these systems for a healthy gut. In addition, select protein organelle operons of unknown function will be studied in depth through an array of genetic, biochemical, imaging and structural biology techniques.
This project will lead to new fundamental insights into protein organelle-mediated host microbe interactions, the functioning of complex protein assemblies and lay the groundwork for exploring future therapeutic avenues aimed at disrupting protein organelle function to reduce microbial fitness and thus pathogenicity in the human gut.