Probing NADase function of bacterial Toll/interleukin-1 receptor (TIR) proteins: Starting with a CURE (Course-based Undergraduate Research Experience)

The growing threat of antimicrobial resistance underlies the need for novel therapeutics that target specific bacterial virulence mechanisms. Bacterial Toll/interleukin-1 receptor (TIR) domain-containing proteins were originally characterized based on their roles in immune evasion. Early reports demonstrated the ability of bacterial TIRs to interact with TIR signaling domains in Toll-like receptor (TLR) signaling pathways and block downstream innate immune responses. Subsequently, bacterial TIRs were found to hydrolyze nicotinamide adenine dinucleotide (NAD+), a central player in cellular metabolism. The significance of the NADase activity of bacterial TIRs for bacterial function and survival is not clear, and it also is not known whether NADase activity plays a role in bacterial TIR interference with host innate immune responses. We hypothesize that bacterial TIR NADase activity alters metabolic and signaling responses within both bacteria and host cells to contribute to bacterial virulence and interference with host immune responses. To test this, we will 1) determine the effects of TcpC NADase activity on bacterial survival within model hosts, 2) identify novel host molecular pathways targeted by TcpC, and 3) develop course-based undergraduate research experiences (CUREs) for analysis of model host responses to TcpC and its NADase activity. This project will provide research experiences for a diverse group of students and will generate research findings that will inform development of therapeutics that can regulate growth and survival of bacteria, including pathogenic species, or can mimic the functions of bacterial TIRs to modulate immune responses for the treatment of immune disorders. Project Number: 1R16AI182345-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Michelle Snyder | Institution: TOWSON UNIVERSITY, TOWSON, MD | Award Amount: $149,620 | Activity Code: R16 | Study Section: Special Emphasis Panel[ZAI1 NKD-D (J1)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R16AI18234501A1