Corneal infections caused by the Gram positive bacterial Staphylococcus aureus (Staph) and Streptococcus pneumoniae (Strep) occur in the USA and worldwide, causing painful, sight-threatening disease. Further, methicillin resistant S. aureus (MRSA) are becoming more common, as MRSA are more difficult to treat and are more virulent than methicillin sensitive strains.
The Aims of this proposal will focus on the role of IL1 in S. aureus and S. pneumoniae keratitis because our preliminary data show that this cytokine has a critical role in regulating corneal infection by either bacteria. IL-1 secretion requires tw signals - Signal 1 for transcription, and Signal 2 for enzymatic processing; therefore, Aim 1 will examine the role of bacterial cell wall in inducing NOD2/RIP2 signaling in IL-1-/- transcription, and Aim 2 will examine the role of Staph aureus ?-hemolysin and Strep pneumoniae pneumolysin induction of the NLRP3/ASC inflammasome in caspase-1 mediated IL-1 cleavage.
Aim 3 will examine the role of ATP and purinergic receptors in amplifying inflammasome activity and IL-1 production. Results of these studies will identify novel pathways that can be targeted for anti-inflammatory therapies.

Public Health Relevance

Bacterial infections of the cornea are a cause of painful, sight-threatening disease in the USA and worldwide. Further, methicillin resistant Staphylococcus aureus (MRSA) are becoming more common and are more difficult to treat. In addition, Streptococcus pneumoniae is a major cause of keratitis in developing countries. The Aims of this proposal will focus on the role of an inflammatory cytokine - IL-1 - which has an important role in regulating corneal disease due to either bacteria. Experiments described in the proposed study will examine the role of virulence factors (toxins) from these bacteria in host cell signalin and IL-1 production in the cornea with the goal of identifying novel, targeted anti-inflammatory therapy that can be used for treatment during corneal infection.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014362-15
Application #
9428446
Study Section
Diseases and Pathophysiology of the Visual System Study Section (DPVS)
Program Officer
Mckie, George Ann
Project Start
2003-04-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Irvine
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92617
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