Dissecting Mechanisms of Granuloma Macrophage Polarization and Granuloma Formation in Chronic Salmonella Infection

Project summaryIntracellular bacteria, most notably, Salmonella enterica and Mycobacterium tuberculosis, infect hundreds ofmillions of people and cause millions of deaths annually. These pathogens can establish chronic infections tosurvive long-term within host tissues. In chronic stage, many infected individuals are asymptomatic, but they canprogress to develop active disease. Currently there is a paucity of effective strategies to monitor and modulatedisease progression, reactivation risks, and therapy responsiveness for chronic bacterial infections. A keypathological feature common to many intracellular bacterial infections is granuloma, a complex and dynamictissue microstructure comprised of immune cells, particularly macrophages, and pathogens. Granulomaformation is thought to be an important immune response to control infection, but it also serves as a crucialmechanism for pathogen persistence. Our long-term goal is to identify common pathways involved in granulomaformation that would lead to fundamental advances in diagnostic and therapeutic modalities for chronic bacterialinfections. In the current proposal, we will take multipronged approaches to dissect mechanisms of host-pathogen interactions underpinning granuloma formation and control of chronic Salmonella infection. In Aim 1,we will define the mechanisms by which a critical host factor regulates granuloma formation and bacterialpersistence. The objective of Aim 2 is to identify the key pathways of granuloma formation manipulated by anovel Salmonella virulence factor. In Aim 3, we propose to construct an innovative reporter system consisting ofgenetically engineered mice and genetically engineered Salmonella to characterize development andmaintenance of granuloma macrophages.The proposed research is a component of a mentored career development plan for the candidate to acquire aunique interdisciplinary skillset to achieve an independent academic research career studying host-pathogeninteractions in the pathogenesis of bacterial infections. The candidate is currently an Instructor in the Division ofPediatric Infectious Diseases, Department of Pediatrics, at Stanford University. The proposed research drawsupon the candidate?s experience in cellular immunology, bacterial pathogenesis, and clinical infectious diseases.Together with planned didactics and technical training, the experiments outlined will provide the candidate aframework to acquire new domains of expertise including molecular microbiology and bacterial genetics, cutting-edge mammalian genetic manipulation techniques, and computational and systems immunology represented byhis primary mentor, Dr. Denise Monack, and a team of leading physician-scientist advisors.