Thursday, March 13, 2025
3/13/2025
ABSTRACT The major goal of this project is to understand how glypicans protect against bacterial lung infection by coordinating a cellular defense mechanism that promotes bacterial clearance and inhibits bacterial invasion. Pathogens use all tricks available to survive in the hostile host environment. Many pathogens bind to host extracellular matrix (ECM) components and their receptors for their attachment, invasion and immune evasion, suggesting that normal functions of the ECM are exploited for pathogenesis. However, while both host cells and microbes are known to change their phenotypes and adapt to the artificial environment when cultured in vitro, the current paradigm that the host ECM promotes infection as attachment and invasion receptors is based predominately on data from in vitro systems. Furthermore, while the ability of the ECM to promote pathogenesis has received much of the attention, potential beneficial functions of ECM components in infections have been largely ignored. The abundant expression of ECM components and their receptors at sites where pathogens frequently encounter the host, such as at the cell surface and subepithelial compartments, suggests that certain ECM components may actually function in host defense. Glypicans, of which there are 6 members in mammals, comprise a major family of cell surface heparan sulfate proteoglycans, that function as receptors for morphogens, growth factors, cytokines/chemokines, and ECM components, among other heparin/heparan sulfate-binding proteins. We found in preliminary studies that glypican-4 null (Gpc4-/-) mice are significantly hypersusceptible to Staphylococcus aureus lung infection, suggesting that Gpc4 protects against S. aureus pathogenesis. S. aureus is a major human pathogen and it has a unique ability to infect virtually every tissue and organ system, including the lung. Our studies suggested that Gpc4 provides protection against S. aureus lung infection via 2 distinct mechanisms: a neutrophil- dependent and a neutrophil-independent mechanism in which Gpc4 inhibits S. aureus invasion into host cells. This proposal will establish the importance of these previously unknown mechanisms and define their molecular and cellular details in 3 Specific Aims. Aim 1 will determine how glypicans regulate early neutrophil recruitment in bacterial infection. Aim 2 will define how glypicans inhibit bacterial entry of host cells, and Aim 3 will elucidate how bacteria counteract defense mechanisms mediated by glypicans.
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).