Friday, November 22, 2024
11/22/2024
ABSTRACT Aspergillus fumigatus is the main etiological agent of invasive aspergillosis (IA). IA primarily affects immunocompromised patients and carries a mortality rate as high as 60%. Due to the significant increase in the immunocompromised patient population and the emergence of azole-resistant A. fumigatus, a critical understanding of A. fumigatus biology is needed to improve patient outcomes. Septins are a conserved family of GTP-binding proteins. Septins interact with each other to form higher-order structures and recruit other proteins. Septins play roles in recognizing micron-scale plasma membrane curvature, cytokinesis, cell cycle progression, and response to cell wall stress. Septins can also regulate A. fumigatus spore surface organization. Since the spore cell surface is key for host-pathogen interaction, the septin cytoskeleton also contributes to immune recognition avoidance by organizing the spore cell surface. The overall aim of our R15 application is to determine the role of the septin cytoskeleton in spore surface organization and how that dictates spore-host immune interactions. We hypothesize that septins AspA, AspB, and AspC mediate the organization of the spore cell wall, and this regulation contributes to spores’ ability to evade immune recognition by the host. Our hypothesis is supported by the 1) disorganized spore cell wall and the cell surface in the ∆aspB strain, 2) the increased increase in binding of wheat germ agglutin, indicating increased exposed chitin in the spores from septin deletion strains, and 3) our preliminary macrophage co-culture experiments, in which the ∆aspA, ∆aspB, and ∆aspC deletion strains induce a higher TNF-a production. We will test our central hypothesis with three aims: Aim 1. Elucidate the role of septin in the rodlet layer assembly and masking the spore PAMPs, Aim 2. Define spore-macrophage interactions, and Aim 3. Determine the role of the septin cytoskeleton in the early stages of infection. Completing this grant with close a critical gap in our understanding of how fungal septin contributes to immune evasion. With this knowledge, novel therapeutic approaches can be designed that will ultimately prevent and/or improve the outcome of invasive aspergillosis treatment. This proposal will also expose undergraduate and graduate students to cell biology, immunology, and biomedical research.
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).
