The incidence of human fungal infections has steadily increased over the past few decades. Though associated with an increased immunosuppressed population size, not all fungal infections necessitate an immunocompromised hosts. This is especially true for filamentous fungal infections of the cornea (i.e keratitis), in which the majority of patients are fully immunocompetent. Indeed, in such cases the etiology of corneal pathology is due to an excessive inflammatory response to the invading organism, not the infection itself. During Aspergillus keratitis, the inflammation can be so severe that 42-60% of infections end with corneal transplantation. Before such bleak clinical outcomes improve, we must invest in research to better understand the mediators of host-fungai interactions. This proposal will utilize a murine corneal infection model (i.e Aspergillus keratitis) to address gaps in our current understanding of in vivo host-mycelia interactions. Using this model, we will address the hypothesis that specific pathogen recognition receptors on resident macrophages mediate neutrophil recruitment into the cornea during Aspergillus keratitis (AIM 1).
In AIM 2 we will address the hypothesis that similar receptors on infiltrating neutrophils mediate A. fumigatus hyphal killing. Lastly, in AIM 3 we will address the hypothesis that the fungal secondary metabolite, gliotoxin, mediates fungal survival and enhanced corneal pathology during Aspergillus keratitis through inhibition of reactive oxygen species formation by infiltrating neutrophils. The studies proposed herein will greatly expand our understanding of host-mycelial interactions in the cornea, while identifying anti-inflammatory and anti-fungal targets for therapeutic intervention during Aspergillus keratitis. Lay Language: The goal of this proposal is to identify potential anti-inflammatory and anti-fungal therapeutic targets during Aspergillus fumigatus infection in the cornea. We propose to do this by using mouse models of A. fumigatus corneal infection to study the innate immune receptors required for recognition and killing of this fungus, as well as the mechanism by which A.fumigatus evades fungal killing during corneal infection.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31EY019841-04
Application #
8326714
Study Section
Special Emphasis Panel (ZRG1-DKUS-D (29))
Program Officer
Agarwal, Neeraj
Project Start
2009-09-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$55,473
Indirect Cost
Name
Case Western Reserve University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Ryan, Sean O; Leal Jr, Sixto M; Abbott, Derek W et al. (2014) Mgat2 ablation in the myeloid lineage leads to defective glycoantigen T cell responses. Glycobiology 24:262-71
Taylor, Patricia R; Roy, Sanhita; Leal Jr, Sixto M et al. (2014) Activation of neutrophils by autocrine IL-17A-IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORýýt and dectin-2. Nat Immunol 15:143-51
Taylor, Patricia R; Leal Jr, Sixto M; Sun, Yan et al. (2014) Aspergillus and Fusarium corneal infections are regulated by Th17 cells and IL-17-producing neutrophils. J Immunol 192:3319-27
Leal Jr, Sixto M; Roy, Sanhita; Vareechon, Chairut et al. (2013) Targeting iron acquisition blocks infection with the fungal pathogens Aspergillus fumigatus and Fusarium oxysporum. PLoS Pathog 9:e1003436
Leal Jr, Sixto M; Pearlman, Eric (2012) The role of cytokines and pathogen recognition molecules in fungal keratitis - Insights from human disease and animal models. Cytokine 58:107-11
Karthikeyan, Rajapandian Sivaganesa; Leal Jr, Sixto M; Prajna, Namperumalsamy Venkatesh et al. (2011) Expression of innate and adaptive immune mediators in human corneal tissue infected with Aspergillus or fusarium. J Infect Dis 204:942-50
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