Innate memory signaling in airway epithelial cells

SUMMARY Staphylococcus aureus is an important Gram positive pathogen of the airway. It is of great concern due to its significant morbidity, mortality and antibiotic resistance, and has been acknowledged as a high priority target for new research from major international research and government bodies. The long term goal of our research is to understand the host-pathogen interactions between S. aureus and the host in the context of the airway infection. The objective of this proposal is to determine the signaling mechanisms and specific cell types behind the ability of S. aureus to evoke trained immunity in the airway epithelium. Our rationale underlying this proposal builds upon our significant in vitro and in vivo preliminary data that demonstrates only viable S. aureus is able to evoke trained immunity in the airway and this is driven by airway epithelial cells that demonstrate alterations in DNA modification, glycolysis and metabolism. Understanding these concepts in the context of infection will provide a greater understanding of host resistance mechanisms that may be adapted to new therapeutic concepts for at-risk patient populations for prophylactic use. Our specific aims investigate training of the innate immune system to S. aureus, with a focus on airway epithelial cells. In Aim 1 we will determine the factor of S. aureus that drives trained immunity and that sensing results in epigenetic changes to the chromatin architecture. Our goal for Aim 2 is to identify, using single cell sequencing, the specific epithelial subset that drives trained immunity and demonstrate its role through cell-specific knockout mice. This research is innovative as it combines next-generation sequencing approaches scRNA-seq and ATAC-seq with powerful mouse models to define the sensing and roles of airway epithelial subsets in trained immunity in the airway. The proposed research is significant, as it will further investigate our novel observation that airway epithelial cells are involved in trained immunity and will be the first study to attribute specific bacterial factors trained immunity. We will be able to further dissect this response to specific cell subsets. The results will have an important positive impact immediately because they will establish a better understanding of how the host innate immune system can be altered to better defend against this important pathogen, and long-term, because it lays the groundwork to potentially target specific aspects of the innate immune system to prevent infections in at-risk patient populations. Project Number: 1R21AI188124-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Dane Parker | Institution: RUTGERS BIOMEDICAL AND HEALTH SCIENCES, Newark, NJ | Award Amount: $235,500 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 RCCS-C (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI18812401A1