Sunday, May 18, 2025
5/18/2025
The impact of host RANKL signaling on Salmonella Typhimurium pathogenesis - PROJECT SUMMARY/ABSTRACT The proficiency of immune cells to react to environmental stimuli and mount specific responses are, in part, due to robust gene expression profiles that involve coordinated regulation. Monocytes are unique amongst immune cells in that they can also differentiate into osteoclasts (OCs) following exposure to the cytokine Receptor Activator of Nuclear factor KappaB-Ligand (RANKL). Once thought to be important only for the bone- resorbing function of OCs, RANKL is now known to regulate diverse facets of mammalian physiology outside of the skeleton, including processes such as secondary lymphoid organ development, intestinal homeostasis, and immune cell crosstalk, all of which are critical for host defenses against bacterial pathogens. Therefore, as monocyte lineage cells in many different tissues experience RANKL signaling and undergo profound transcriptional and epigenetic remodeling, RANKL has the potential to shape the outcome of infectious diseases. The broad goal of this proposal is to define how RANKL alters monocyte responses to bacterial pathogens. One model bacterial pathogen that replicates within monocytes during systemic dissemination is Salmonella enterica serovar Typhimurium (STm). In preliminary studies, we found that RANKL-treated monocytes harbor significantly higher numbers of intracellular STm. Moreover, these cells have decreased pro- inflammatory IL-1β production. Based on our preliminary findings and literature from the osteoimmunology field, the central hypothesis of this proposal is that RANKL signaling silences key monocyte effector genes to render cells more susceptible to intracellular infection. Therefore, we also predict that RANKL blockade will modify the outcome of infection in vivo. To test the hypothesis, Aim 1 will define how RANKL diminishes monocyte inflammatory responses to STm by elucidating the effects of RANKL signaling on monocyte IL-1β regulation and cell polarization. Aim 2 will explore how RANKL signaling increases STm replication in monocytes by examining STm virulence in the context of host intracellular cues including iron availability and phagolysosome formation. Aim 2 will also test how the RANKL signaling axis impacts STm disease in vivo using an FDA-approved RANKL- blocking antibody. Collectively, the Aims will define how RANKL-mediated cellular reprogramming alters the antibacterial and inflammatory properties of monocytes and modifies immune responses to STm. The proposed project will be completed in the Cassat laboratory at Vanderbilt University, a world-leading institution in biomedical research with a robust Medical Scientist Training Program (MSTP). The fellowship synergizes with the applicant’s goal to conduct independent research at the interface of innate immunity and cell biology. The training plan was designed to provide the applicant with foundational knowledge in host-pathogen interactions and immunology while integrating clinical programming throughout, equipping them with translatable expertise to conduct rigorous research focused on infection and immunity.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).