Biology, immunology and therapy of Acanthamoeba keratitis

Summary

Principal Investigator: Hassan Alizadeh
Affiliation: University of Texas Southwestern Medical Center
Country: USA
Abstract: Acanthamoeba keratitis is a sight-threatening corneal disease caused by pathogenic free-living amoebae. The pathogenic cascade of Acanthamoeba keratitis involves a series of processes that include: (1) binding of the trophozoites to the corneal epithelial cells via lectin-glycoprotein interactions, (2) generation of cytopathic factors that destroy the corneal epithelium and stromal cells, (3) production of proteolytic enzymes that facilitate the invasion and penetration of trophozoites through the basement membrane and stroma, (4) elaboration of collagenolytic enzymes that degrade types I and IV collagens, which constitute the corneal matrix, (5) activation of corneal membrane metalloproteinases and, (6) induction of perineuritis. Stromal dissolution is a major blinding complication of Acanthamoeba keratitis. It will be important to determine what factors are involved in pathogenesis of stromal disease. In the present application, we are using different strategies to attack crucial steps in the pathogenic cascade in an effort to mitigate ongoing keratitis and preserve corneal tissues. Accordingly, therapeutic modalities are designed to inhibit invasion and destruction of corneal tissues after the organisms have invaded corneal matrix. The specific aims for this project are: 1) determine the role of Acanthamoeba plasminogen activator (aPA) in the pathogenesis of Acanthamoeba keratitis, 2) analyze the collagenolytic activity of the mannose-induced Acanthamoeba protein (133 -kDa), 3 ) determine if the mannose-induced Acanthamoeba protein (133-kDa) activate matrix metalloproteinases 4) determine feasibility of using the mannose-induced protein (133-kDa) and Acanthamoeba plasminogen activator (aPA) as immunogens for inducing immunity and mitigating the pathogenesis of Acanthamoeba infections. 5) Clone the 133-kDa protein and analyze the fragment that might be suitable for use as a subunit vaccine to induce better protection against Acanthamoeba infections. These studies utilize the Chinese hamster model of Acanthamoeba keratitis, that is similar to the human counterpart. Continued presence of Acanthamoeba keratitis and emergence of the drug resistant strains is underscoring the significance of this endeavor. The long-range goal of this project is to develop an anti-disease vaccine as a therapeutic adjunct for the management of Acanthamoeba keratitis.
Funding Period: 1995-08-01 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. pmc Pathogenic strains of Acanthamoeba are recognized by TLR4 and initiated inflammatory responses in the cornea
    Hassan Alizadeh
    Department of Cell Biology and Immunology, University of North Texas Health Science Center, and North Texas Eye Research Institute, Fort Worth, Texas, United States of America
    PLoS ONE 9:e92375. 2014
  2. pmc Role of phospholipase A₂ (PLA₂) inhibitors in attenuating apoptosis of the corneal epithelial cells and mitigation of Acanthamoeba keratitis
    Trivendra Tripathi
    Department of Cell Biology and Anatomy, University of North Texas Health Science Center, North Texas Eye Research Institute, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
    Exp Eye Res 113:182-91. 2013
  3. pmc Acanthamoeba-cytopathic protein induces apoptosis and proinflammatory cytokines in human corneal epithelial cells by cPLA2α activation
    Trivendra Tripathi
    Department of Cell Biology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Invest Ophthalmol Vis Sci 53:7973-82. 2012
  4. doi Amoebicidal activities of alexidine against 3 pathogenic strains of acanthamoeba
    Hassan Alizadeh
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9057, USA
    Eye Contact Lens 35:1-5. 2009
  5. pmc Modulation of corneal and stromal matrix metalloproteinase by the mannose-induced Acanthamoeba cytolytic protein
    Hassan Alizadeh
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9057, USA
    Exp Eye Res 87:286-91. 2008
  6. doi Role of activated macrophages in Acanthamoeba keratitis
    Hassan Alizadeh
    Department of Ophthalmology and Microbiology, University of Texas Southwestern Medical Center, Dallas 75390 9057, USA
    J Parasitol 93:1114-20. 2007
  7. ncbi Effect of immunization with the mannose-induced Acanthamoeba protein and Acanthamoeba plasminogen activator in mitigating Acanthamoeba keratitis
    Hassan Alizadeh
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9057, USA
    Invest Ophthalmol Vis Sci 48:5597-604. 2007
  8. ncbi Intracorneal instillation of latex beads induces macrophage-dependent protection against Acanthamoeba keratitis
    Daniel W Clarke
    Department of Ophthalmology and Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Invest Ophthalmol Vis Sci 47:4917-25. 2006
  9. pmc Oral immunization with Acanthamoeba castellanii mannose-binding protein ameliorates amoebic keratitis
    M Garate
    Department of Ophthalmology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
    Infect Immun 74:7032-4. 2006
  10. ncbi The immunobiology of Acanthamoeba keratitis
    Daniel W Clarke
    Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 9057, USA
    Microbes Infect 8:1400-5. 2006

Scientific Experts

  • Hassan Alizadeh
  • Daniel W Clarke
  • Trivendra Tripathi
  • Jerry Y Niederkorn
  • Mahshid Abdi
  • M Garate
  • Haochuan Li
  • Ashley Dawn Smith
  • S Neelam
  • J Y Niederkorn
  • N Panjwani
  • James P McCulley
  • Sudha Neelam
  • R Ann Word
  • Elizabeth Mayhew

Detail Information

Publications14

  1. pmc Pathogenic strains of Acanthamoeba are recognized by TLR4 and initiated inflammatory responses in the cornea
    Hassan Alizadeh
    Department of Cell Biology and Immunology, University of North Texas Health Science Center, and North Texas Eye Research Institute, Fort Worth, Texas, United States of America
    PLoS ONE 9:e92375. 2014
    ..TLR4 may be a potential target in the development of novel treatment strategies in Acanthamoeba and other microbial infections that activate TLR4 in corneal cells. ..
  2. pmc Role of phospholipase A₂ (PLA₂) inhibitors in attenuating apoptosis of the corneal epithelial cells and mitigation of Acanthamoeba keratitis
    Trivendra Tripathi
    Department of Cell Biology and Anatomy, University of North Texas Health Science Center, North Texas Eye Research Institute, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA
    Exp Eye Res 113:182-91. 2013
    ..Moreover, cPLA2α inhibitors can be used as a therapeutic target in Acanthamoeba keratitis...
  3. pmc Acanthamoeba-cytopathic protein induces apoptosis and proinflammatory cytokines in human corneal epithelial cells by cPLA2α activation
    Trivendra Tripathi
    Department of Cell Biology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
    Invest Ophthalmol Vis Sci 53:7973-82. 2012
    ..The aim of this study was to determine if MIP-133 induces apoptosis and proinflammatory cytokines/chemokines in human corneal epithelial (HCE) cells via the cytosolic phospholipase A(2α) (cPLA(2α)) pathway...
  4. doi Amoebicidal activities of alexidine against 3 pathogenic strains of acanthamoeba
    Hassan Alizadeh
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9057, USA
    Eye Contact Lens 35:1-5. 2009
    ....
  5. pmc Modulation of corneal and stromal matrix metalloproteinase by the mannose-induced Acanthamoeba cytolytic protein
    Hassan Alizadeh
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390 9057, USA
    Exp Eye Res 87:286-91. 2008
    ..The results indicate that the MIP-133 protein modulates MMP-2 and -3 expression differently in human corneal epithelial and stromal cells...
  6. doi Role of activated macrophages in Acanthamoeba keratitis
    Hassan Alizadeh
    Department of Ophthalmology and Microbiology, University of Texas Southwestern Medical Center, Dallas 75390 9057, USA
    J Parasitol 93:1114-20. 2007
    ..05). Killing was inhibited by cytochalasin D, but not by L-N6-1-iminoethyl-L-lysine dihydrochloride (L-NIL), which is a selective inhibitor of inducible NO synthase (INOS)...
  7. ncbi Effect of immunization with the mannose-induced Acanthamoeba protein and Acanthamoeba plasminogen activator in mitigating Acanthamoeba keratitis
    Hassan Alizadeh
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9057, USA
    Invest Ophthalmol Vis Sci 48:5597-604. 2007
    ..The goal of the present study was to gain insight into the pathogenicity of Acanthamoeba infection as well as to determine whether oral immunization with aPA and MIP-133 produce an additive protection against Acanthamoeba keratitis...
  8. ncbi Intracorneal instillation of latex beads induces macrophage-dependent protection against Acanthamoeba keratitis
    Daniel W Clarke
    Department of Ophthalmology and Microbiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
    Invest Ophthalmol Vis Sci 47:4917-25. 2006
    ..castellanii antigens fails to protect against Acanthamoeba keratitis. This study was undertaken to examine the mechanisms that mediate latex bead-induced resistance to Acanthamoeba keratitis...
  9. pmc Oral immunization with Acanthamoeba castellanii mannose-binding protein ameliorates amoebic keratitis
    M Garate
    Department of Ophthalmology, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA
    Infect Immun 74:7032-4. 2006
    ....
  10. ncbi The immunobiology of Acanthamoeba keratitis
    Daniel W Clarke
    Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 9057, USA
    Microbes Infect 8:1400-5. 2006
    ..The innate immune apparatus is crucial for the resolution of the disease. With the exception of mucosal antibody, elements of the adaptive immune system fail to prevent infection or contribute to its resolution in experimental animals...
  11. ncbi The pathophysiology of Acanthamoeba keratitis
    Daniel W Clarke
    Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390 9057, USA
    Trends Parasitol 22:175-80. 2006
    ..Targeting such proteases could lead to the development of vaccines that target the disease process rather than the pathogen itself...
  12. ncbi Failure of Acanthamoeba castellanii to produce intraocular infections
    Daniel W Clarke
    Department of Ophthalmology and Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 9057, USA
    Invest Ophthalmol Vis Sci 46:2472-8. 2005
    ..The second hypothesis proposed that the trophozoites can enter the AC; however, the aqueous humor (AH) contains factors that either induce encystment or kill the amoebae...
  13. ncbi Immunosuppressive factors secreted by human amniotic epithelial cells
    Haochuan Li
    Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Invest Ophthalmol Vis Sci 46:900-7. 2005
    ....
  14. pmc Role of contact lens wear, bacterial flora, and mannose-induced pathogenic protease in the pathogenesis of amoebic keratitis
    Hassan Alizadeh
    Department of Ophthalmology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 9057, USA
    Infect Immun 73:1061-8. 2005
    ..Oral immunization with MIP133 mitigates Acanthamoeba keratitis and demonstrates the feasibility of antidisease vaccines for pathogens that resist immune elimination...