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 IL-1? 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 two 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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Toska, Jonida; Sun, Yan; Carbonell, Dalina Alvarez et al. (2014) Diversity of virulence phenotypes among type III secretion negative Pseudomonas aeruginosa clinical isolates. PLoS One 9:e86829
Roy, Sanhita; Karmakar, Mausita; Pearlman, Eric (2014) CD14 mediates Toll-like receptor 4 (TLR4) endocytosis and spleen tyrosine kinase (Syk) and interferon regulatory transcription factor 3 (IRF3) activation in epithelial cells and impairs neutrophil infiltration and Pseudomonas aeruginosa killing in vivo. J Biol Chem 289:1174-82
Sun, Yan; Zhang, Rui; Gadek, Thomas R et al. (2013) Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocul Pharmacol Ther 29:395-402
Karthikeyan, Rajapandian SivaGanesa; Priya, Jeganathan Lakshmi; Leal Jr, Sixto M et al. (2013) Host response and bacterial virulence factor expression in Pseudomonas aeruginosa and Streptococcus pneumoniae corneal ulcers. PLoS One 8:e64867
Pearlman, Eric; Sun, Yan; Roy, Sanhita et al. (2013) Host defense at the ocular surface. Int Rev Immunol 32:4-18
Sun, Yan; Karmakar, Mausita; Taylor, Patricia R et al. (2012) ExoS and ExoT ADP ribosyltransferase activities mediate Pseudomonas aeruginosa keratitis by promoting neutrophil apoptosis and bacterial survival. J Immunol 188:1884-95
Chinnery, Holly R; McLenachan, Samuel; Binz, Nicolette et al. (2012) TLR9 ligand CpG-ODN applied to the injured mouse cornea elicits retinal inflammation. Am J Pathol 180:209-20
Roy, Sanhita; Sun, Yan; Pearlman, Eric (2011) Interferon-gamma-induced MD-2 protein expression and lipopolysaccharide (LPS) responsiveness in corneal epithelial cells is mediated by Janus tyrosine kinase-2 activation and direct binding of STAT1 protein to the MD-2 promoter. J Biol Chem 286:23753-62
Tu, Zhidan; Portillo, Jose-Andres C; Howell, Scott et al. (2011) Photoreceptor cells constitutively express functional TLR4. J Neuroimmunol 230:183-7
Sun, Yan; Karmakar, Mausita; Roy, Sanhita et al. (2010) TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways. J Immunol 185:4272-83

Showing the most recent 10 out of 21 publications