Characterization of Neutrophil Decision making during Swarming to Fungal Pathogens - 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.
