Acanthamoeba keratitis is a sight-threatening corneal disease caused by pathogenic free-living amoebae. The rationale for this research project is based on the following observations: 1) The innate immune system plays an important role in Acanthamoeba keratitis and polymorphonuclear neutrophils (PMN) are the prominent inflammatory cells in Acanthamoeba keratitis lesions;2) neutrophils are important in initial resolution of Acanthamoeba infection;3) pathogenesis of Acanthamoeba keratitis is exacerbated by the protease elaborated by infiltrating neutrophils;4 ) Toll-like receptors (TLRs) on the corneal epithelium initiate the inflammatory responses to Acanthamoeba infections. This may be achieved by immobilizing PMN at the site of infection;5) keratitis is the consequence of tissue damage mediated by factors (preliminary proteases) elaborated by Acanthamoeba trophozoites;6) parasite- derived pathogenic molecules persist even after trophozoites encyst or die;7) parasite-borne pathogenic molecules react with several molecules on the surface of the cornea and induce the release of chemokines and cytokines by the epithelial cells;8) parasite-derived molecules are immunogenic and can be used to elicit the production of mucosal antibodies that will neutralize the pathogenic molecules and thus, mitigate tissue damage and reduce neutrophil infiltration. Thus, the protective and destructive roles of PMNs influence the outcome of Acanthamoeba infection and disease processes respectively. The first specific aim will test the hypothesis that Toll-like receptors (TLRs) on the corneal epithelium initiate the inflammatory responses to ocular Acanthamoeba infections. This may be achieved by immobilizing PMNs that either initially kill Acanthamoeba or contribute to the pathogenesis of the disease. The second specific aim will test the hypothesis that the mannose induced- Acanthamoeba cytopathic protein (MIP-133) interacts with phospholipids on the corneal epithelial cells and induces both apoptosis and arachidonic acid release through a novel pathway involving phospholipase A2 (PLA2) activation. The Third specific aim will test the hypothesis that Acanthamoeba trophozoites constitutively express PLA2 that either directly induces cytopathic effects on the corneal epithelial cells or activates phospholipids and induces arachidonic acid release. The forth specific aim will test the hypothesis that treatment with PLA2 inhibitors and immunization with MIP-133 will mitigate the pathogenesis of Acanthamoeba keratitis. The long-range goal of this project is to evaluate the pathogenic mechanisms of Acanthamoeba keratitis that could have an enormous impact on designing improved therapies for Acanthamoeba patients that represent the most serious therapeutic dilemmas.

Public Health Relevance

The long-range goal of this project is to evaluate the pathogenic mechanisms of Acanthamoeba keratitis that could have an enormous impact for designing improved therapies for Acanthamoeba patients that represent the most serious therapeutic dilemmas.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY009756-15
Application #
8327243
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
Project Start
1995-08-01
Project End
2014-09-29
Budget Start
2012-09-30
Budget End
2013-09-29
Support Year
15
Fiscal Year
2012
Total Cost
$344,520
Indirect Cost
$106,920
Name
University of North Texas
Department
Anatomy/Cell Biology
Type
Other Domestic Higher Education
DUNS #
110091808
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Tripathi, Trivendra; Abdi, Mahshid; Alizadeh, Hassan (2014) Protease-activated receptor 2 (PAR2) is upregulated by Acanthamoeba plasminogen activator (aPA) and induces proinflammatory cytokine in human corneal epithelial cells. Invest Ophthalmol Vis Sci 55:3912-21
Alizadeh, Hassan; Tripathi, Trivendra; Abdi, Mahshid et al. (2014) Pathogenic strains of Acanthamoeba are recognized by TLR4 and initiated inflammatory responses in the cornea. PLoS One 9:e92375
Tripathi, Trivendra; Abdi, Mahshid; Alizadeh, Hassan (2013) Role of phospholipase Aýýý (PLAýýý) inhibitors in attenuating apoptosis of the corneal epithelial cells and mitigation of Acanthamoeba keratitis. Exp Eye Res 113:182-91
Alizadeh, Hassan; Neelam, Sudha; Cavanagh, H Dwight (2009) Amoebicidal activities of alexidine against 3 pathogenic strains of acanthamoeba. Eye Contact Lens 35:1-5
Alizadeh, Hassan; Li, Haochuan; Neelam, Sudha et al. (2008) Modulation of corneal and stromal matrix metalloproteinase by the mannose-induced Acanthamoeba cytolytic protein. Exp Eye Res 87:286-91
Alizadeh, Hassan; Neelam, Sudha; Niederkorn, Jerry Y (2007) Role of activated macrophages in Acanthamoeba keratitis. J Parasitol 93:1114-20
Alizadeh, Hassan; Neelam, Sudha; Niederkorn, Jerry Y (2007) Effect of immunization with the mannose-induced Acanthamoeba protein and Acanthamoeba plasminogen activator in mitigating Acanthamoeba keratitis. Invest Ophthalmol Vis Sci 48:5597-604
Garate, M; Alizadeh, H; Neelam, S et al. (2006) Oral immunization with Acanthamoeba castellanii mannose-binding protein ameliorates amoebic keratitis. Infect Immun 74:7032-4
Clarke, Daniel W; Niederkorn, Jerry Y (2006) The pathophysiology of Acanthamoeba keratitis. Trends Parasitol 22:175-80
Clarke, Daniel W; Niederkorn, Jerry Y (2006) The immunobiology of Acanthamoeba keratitis. Microbes Infect 8:1400-5

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