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.
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.
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