Sunday, October 27, 2024
10/27/2024
Project Summary Invasive fungal infections are a serious public health threat and are associated with high mortality rates, demonstrating that current antifungal therapies are inadequate. While innate immunity is known to be critical for host defense against fungi, these complex host-pathogen interactions remain poorly elucidated. Recently, a novel behavior of neutrophils, a key innate immune cell for antifungal defense, has been characterized, that of neutrophil swarming. Swarming is thought to play a role in the containment of pathogenic microbes, but its role in antifungal defense is poorly characterized, representing a significant gap in knowledge in neutrophil function. The hypothesis driving this research application is that the early events in swarming are critical determinants of if the pathogen will be successfully contained and that characterization of these pathways will highlight novel therapeutic options for optimizing neutrophil function during infection and inflammation. Unfortunately, detailed study of these host-pathogen swarming interactions has been hindered by the shortcomings of current experimental assays. To address this, we have developed and optimized a novel microscale device to allow us to characterize human neutrophil swarming to live fungal pathogens. This microspotting assay allows us to pattern live microorganisms in large arrays, with direct access both visually and to supernatants for molecular analysis. The objective of this application is therefore to leverage novel microscale tools to allow rigorous investigation of the dynamic interactions between host immunity and live fungi during swarming to expand our understanding of swarming biology. We will do this by via the pursuit of two specific aims (1) Identify the molecular mechanisms by which neutrophils decide to initiate swarming behavior and (2) Elucidate the molecular pathways that enhance swarming mediated fungal killing. In the short term, this research is expected to generate critical knowledge on the role of neutrophil swarming in antifungal defense. Leveraging these tools and the knowledge they generate, the long term goal is the development of improved and novel therapeutic options for patients with invasive fungal infections. The work will also provide a strong foundation which the candidate can use to achieve his immediate career goals of attaining an independent, tenure-track faculty position and to progress towards his long term career goals of a tenured research faculty position with a unique academic research program studying innate host- pathogen interactions during fungal infection. In order to attain these career goals, the candidate will also assemble an effective mentoring and consulting team to promote the successful completion of research and the continuing improvement of grantsmanship and lab management skills. These career goals and the proposed research are therefore fulfil NIAID’s mission to pursue and identify novel therapeutic strategies to combat infection and to support the transition of junior scientists into independent faculty positions via the K22.
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).
