It is becoming increasingly clear that fungal pathogens pose a significant burden to human health yet currently available chemotherapies are often ineffective in preventing mortality from invasive fungal growth. It has been proposed that the combination of antifungal medications and immune-based interventions may be the key to significantly improve the dire outcomes currently associated with invasive fungal infections. In order to fulfill the promise of immune-based therapeutic interventions, a better understanding of relevant mechanisms of host protection against fungi is needed. Aspergillus fumigatus is a mold fungal pathogen and the most common cause of invasive aspergillosis (IA), a serious infection that develops in patients with compromised immune function. Although a variety of immune cells can help confer protection against IA, the mechanisms that govern immune cell cooperation culminating in the eradication of conidia and IA prevention are unclear. Using selective cell depletion strategies our recent studies have shown that, in addition to neutrophils, CCR2+ inflammatory monocytes (CCR2+Mo) and their derivative monocyte-derived dendritic cells (Mo-DCs) are required for the prevention of IA. Our studies indicate that CCR2+Mo and Mo-DCs are essential for: 1) direct fungal spore eradication; 2) establishment of a protective inflammatory lung milieu; 3) the full activation of neutrophil antifungal activities. In preliminary studies we lso find that IA development in neutrophil-depleted animals is associated with diminished Mo-DC differentiation and lower conidiacidal activity in these cells. The central hypothesis of the studis proposed in this application is that neutrophil and CCR2+Mo functions are interdependent, continuously cross-regulating each other's antifungal activities. Our goal is thus to interrogate the mechanisms of CCR2+Mo and neutrophil cross-regulation and characterize their overall contributions to anti-fungal immunity.
Our first aim i s to determine how CCR2+Mo derived cells regulate neutrophil anti-fungal effector functions. In order to identify relevant upstream regulators of neutrophil conidiacidal activity we thus performed an unbiased transcriptome analysis of neutrophils that responded to a pulmonary Af infection in the presence or absence of CCR2+Mo and Mo-DCs. Our analysis revealed that Af infection induces a strong type I IFN signature profile in antifungal neutrophils and that removal of CCR2+Mo impairs this response.
In aim 1 we will thus define how CCR2+Mo and Mo-DCs control IFN production, the role of myeloid cell intrinsic IFN signaling in the activation of conidiacidal effector functions and determine whether IFN-inducible GTPases are essential effectors of neutrophil conidiacidal function.
In aim 2 we will determine how neutrophils control Mo-DC differentiation and their antifungal effector functions. We will elucidate the role of specific neutrophil-derived factors in the differentiation of Mo-DCs and the role of neutrophil-intrinsic innate receptor deficiencies in the acquisition of neutrophil regulatory pathways. Taken together, these studies will provide novel and significant insights into the mechanisms that mediate innate cell cooperation essential for the development of antifungal immunity.

Public Health Relevance

It is becoming increasingly apparent that fungal pathogens pose a significant burden to human health yet currently available chemotherapies are often ineffective in preventing mortality from invasive fungal growth. In recent studies we have defined a novel essential function for monocyte-derived dendritic cells (Mo-DCs) in defense against invasive aspergillosis (IA). In these studies we seek to determine the mechanisms of Mo-DC- dependent protection from IA with the ultimate goal of identifying potentially novel pathways for therapeutic targeting. Our findings will likely facilitate the development of novel immune-based adjunctive therapies to improve clinical outcomes in patients suffering from invasive fungal disease.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunity and Host Defense (IHD)
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Love, Dona
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Rutgers University
Schools of Medicine
United States
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