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.
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.
|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|
|Clark, Heather L; Abbondante, Serena; Minns, Martin S et al. (2018) Protein Deiminase 4 and CR3 Regulate Aspergillus fumigatus and ?-Glucan-Induced Neutrophil Extracellular Trap Formation, but Hyphal Killing Is Dependent Only on CR3. Front Immunol 9:1182|
|Dietl, Anna-Maria; Amich, Jorge; Leal, Sixto et al. (2016) Histidine biosynthesis plays a crucial role in metal homeostasis and virulence of Aspergillus fumigatus. Virulence 7:465-76|
|Clark, Heather L; Jhingran, Anupam; Sun, Yan et al. (2016) Zinc and Manganese Chelation by Neutrophil S100A8/A9 (Calprotectin) Limits Extracellular Aspergillus fumigatus Hyphal Growth and Corneal Infection. J Immunol 196:336-44|
|Taylor, Patricia R; Roy, Sanhita; Meszaros, Evan C et al. (2016) JAK/STAT regulation of Aspergillus fumigatus corneal infections and IL-6/23-stimulated neutrophil, IL-17, elastase, and MMP9 activity. J Leukoc Biol 100:213-22|
|Deng, Zihou; Ma, Shixin; Zhou, Hao et al. (2015) Tyrosine phosphatase SHP-2 mediates C-type lectin receptor-induced activation of the kinase Syk and anti-fungal TH17 responses. Nat Immunol 16:642-52|
|Underhill, David M; Pearlman, Eric (2015) Immune Interactions with Pathogenic and Commensal Fungi: A Two-Way Street. Immunity 43:845-58|
|Karthikeyan, Rajapandian Sivaganesa; Vareechon, Chairut; Prajna, Namperumalsamy Venkatesh et al. (2015) Interleukin 17 expression in peripheral blood neutrophils from fungal keratitis patients and healthy cohorts in southern India. J Infect Dis 211:130-4|
|Muszkieta, Laetitia; Carrion, Steven de Jesus; Robinet, Pauline et al. (2014) The protein phosphatase PhzA of A. fumigatus is involved in oxidative stress tolerance and fungal virulence. Fungal Genet Biol 66:79-85|
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