Pathogenic Fusarium and Aspergillus molds are an important cause of vision loss in the USA and worldwide. Proposed studies will focus on the role of IL-17 producing polymorphonuclear leukocytes (PMN-17) in fungal keratitis by promoting reactive oxygen species production, fungal killing and corneal opacification. Preliminary data show that these previously uncharacterized cells have an important role in the early response to fungal infection, and are present in the corneas of infected individuals.
Aim 1 will examine the role of c-type lectins in IL-6 and IL-23 production by macrophages and dendritic cells in response to these pathogens.
Aim 2 will examine IL-17 receptor mediated chemokine production in the cornea leading to recruitment of PMN-17 cells, and Aim 3 will examine IL-17 induced NADPH oxidase and kynurenine mediated ROS production by PMN-17 cells. Results of these studies will further our understanding of the role of PMN-17 cells in fungal keratitis and identify novel targets for anti-inflammatory intervention to limit tissue damage in the cornea.

Public Health Relevance

Aspergillus and Fusarium are very common molds in the environment, especially in hot, humid areas of the USA, and in the developing world. Corneal infection with these organisms, either as a complication of contact lens wear or as a result of trauma results in a painful and sight threatening disease that is extremely difficult to treat. Experiments described in this proposal will examine the role of previously uncharacterized IL-17 producing neutrophils (PMN-17) in the protective immune response to these organisms and their ability to cause tissue damage to the cornea. The long-term goal of proposed studies is to identify novel targets for interventional therapy for this disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY018612-06A1
Application #
8531490
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2008-02-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$540,632
Indirect Cost
$199,003
Name
Case Western Reserve University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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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
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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
Sun, Yan; Chandra, Jyotsna; Mukherjee, Pranab et al. (2010) A murine model of contact lens-associated fusarium keratitis. Invest Ophthalmol Vis Sci 51:1511-6
Leal Jr, Sixto M; Cowden, Susan; Hsia, Yen-Cheng et al. (2010) Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis. PLoS Pathog 6:e1000976

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