Antimicrobial peptides (AMPs) such as defensins and cathelicidin are multifunctional molecules that kill invading pathogens and modulate mammalian cell activities including proliferation, migration and cytokine production thus helping to regulate immune responses and wound healing. Recent studies have established roles for AMPs in defending the ocular surface from bacterial infection (keratitis). A logical progression to this to further our understanding of AMP actions at the ocular surface is to address the role of AMPs in keratitis caused by fungal pathogens. Fungal keratitis is a vision threatening disease, which is increasing in incidence (including a world-wide epidemic in 2004-2006), current treatments are only moderately effective and outcomes are typically more devastating than with bacterial corneal disease. Many AMPs have potent antifungal activity in vitro so likely act in innate defense against fungal pathogens and have potential as therapeutics. There have been few reports on the role for AMPs in defense against fungal keratitis thus more in depth study encompassing multiple fungal pathogens is needed to delineate their involvement and identify ways this can be exploited to prevent/treat infection. The following hypothesis will be tested: AMPs are required for ocular surface innate defense against fungal infection. This will be addressed by three specific aims.
In specific aim 1, modulation of human corneal epithelial AMP expression in response to common ocular fungi will be investigated in vitro and participation of specific pattern recognition receptors elucidated.
In specific aim 2, the antimicrobial activity of AMPs in solution and tethered to surfaces against common ocular fungi will be determined, and the influence of tear components on this activity investigated. These two aims will be informative regarding which endogenously expressed AMPs are active at the human ocular surface in vivo.
The final aim will utilize mice deficient in specific AMPs (either genetic knockouts or siRNA knockdown) to establish a role for AMPs in vivo in a model of experimental fungal keratitis. Also in specific aim 3, the potential of AMP-tethered liposomes as novel topical antifungal agents will be addressed. These studies will provide important information regarding normal host defense mechanisms against fungal pathogens and may identify novel antifungal agents for preventing and treating fungal keratitis.

Public Health Relevance

Fungal keratitis is a vision threatening disease, which is increasing in incidence (including a world-wide epidemic in 2004-2006), current treatments are only moderately effective and outcomes are typically worse than with bacterial corneal disease. This proposal addresses the role of antimicrobial peptides in defending the ocular surface against fungal pathogens and their potential as novel, topical antifungal agents.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY013175-08A1S1
Application #
8536032
Study Section
Special Emphasis Panel (ZRG1-BDCN-C (02))
Program Officer
Mckie, George Ann
Project Start
2000-07-01
Project End
2017-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$311,381
Indirect Cost
$90,224
Name
University of Houston
Department
Type
Schools of Optometry/Ophthalmol
DUNS #
036837920
City
Houston
State
TX
Country
United States
Zip Code
77204
Mangoni, Maria Luisa; McDermott, Alison M; Zasloff, Michael (2016) Antimicrobial peptides and wound healing: biological and therapeutic considerations. Exp Dermatol 25:167-73
Reins, Rose Y; Hanlon, Samuel D; Magadi, Sri et al. (2016) Effects of Topically Applied Vitamin D during Corneal Wound Healing. PLoS One 11:e0152889
Reins, Rose Yvonne; Baidouri, Hasna; McDermott, Alison Marie (2015) Vitamin D Activation and Function in Human Corneal Epithelial Cells During TLR-Induced Inflammation. Invest Ophthalmol Vis Sci 56:7715-27
Kolar, Satya Sree N; Luca, Vincenzo; Baidouri, Hasna et al. (2015) Esculentin-1a(1-21)NH2: a frog skin-derived peptide for microbial keratitis. Cell Mol Life Sci 72:617-27
Qin, G T; Lopez, A; Santos, C et al. (2015) Antimicrobial peptide LL-37 on surfaces presenting carboxylate anions. Biomater Sci 3:771-8
Redfern, Rachel L; Barabino, Stefano; Baxter, Jessica et al. (2015) Dry eye modulates the expression of toll-like receptors on the ocular surface. Exp Eye Res 134:80-9
Reins, Rose Y; McDermott, Alison M (2015) Vitamin D: Implications for ocular disease and therapeutic potential. Exp Eye Res 134:101-10
Wang, Lin; Zhao, Meirong; Li, Siheng et al. (2014) ""Click"" immobilization of a VEGF-mimetic peptide on decellularized endothelial extracellular matrix to enhance angiogenesis. ACS Appl Mater Interfaces 6:8401-6
Boochoon, Kieran S; Manarang, Joseph C; Davis, Joshua T et al. (2014) The influence of substrate elastic modulus on retinal pigment epithelial cell phagocytosis. J Biomech 47:3237-40
Santos, Catherine M; Kumar, Amit; Kolar, Satya S et al. (2013) Immobilization of antimicrobial peptide IG-25 onto fluoropolymers via fluorous interactions and click chemistry. ACS Appl Mater Interfaces 5:12789-93

Showing the most recent 10 out of 37 publications