CAREER: Understanding and Harnessing Host-derived Small RNAs Against Opportunistic Pathogens

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Complex communities of microbes colonize all living creatures. These communities comprise a microbiome. Communication between the host and various microbiomes help to maintain human health. Disrupting this communication can lead to infection and disease. Recently, studies have implicated small RNA molecules (sRNA) as key communication molecules. Understanding how different types of sRNAs regulate pathogens in oral and respiratory systems is the focus of this project. The research program will be integrated with an education and outreach plan. These efforts will prepare under-represented high-school students and undergraduates to pursue careers in STEM. They will also integrate authentic hands-on experiments into undergraduate courses and develop low-cost biology kits and virtual teaching methods to reach students in remote areas. This project will address the knowledge gap in understanding the roles played by host-derived extracellular sRNAs in host-microbiota interactions. There is a lack of enabling methodologies to unlock the functions of host sRNAs largely due to three limitations. First, native sRNAs are highly susceptible to degradation. Second, it is difficult to distinguish the origins of short sRNA fragments between host and bacteria. Third, host sRNAs are present inside bacteria at very low levels. The long-term project goal is to achieve in-depth understanding of host-derived sRNAs as a new class of defense molecules targeting opportunistic pathogens, and, furthermore, to repurpose host sRNAs as potential antimicrobial agents. To achieve this goal, this project will (1) optimize sRNA stability and functions by incorporating chemically modified nucleotides and define structure-function relationships, (2) employ structural modeling, bacterial genetics, and biochemical assays to dissect how host sRNAs are internalized by oral and airway opportunistic bacteria, and (3) develop a powerful methodology to uncover hitherto unknown host sRNAs with antimicrobial activities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.