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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (DPVS)
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Mckie, George Ann
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Case Western Reserve University
Schools of Medicine
United States
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Sun, Yan; Abbondante, Serena; Karmakar, Mausita et al. (2018) Neutrophil Caspase-11 Is Required for Cleavage of Caspase-1 and Secretion of IL-1? in Aspergillus fumigatus Infection. J Immunol 201:2767-2775
Clark, Heather L; Minns, Martin S; Sun, Yan et al. (2018) Atovaquone Impairs Growth of Aspergillus and Fusarium Keratitis Isolates by Modulating Mitochondrial Function and Zinc Homeostasis. Invest Ophthalmol Vis Sci 59:1589-1598
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