Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY014362-10A1
Application #
8652690
Study Section
Special Emphasis Panel (DPVS)
Program Officer
Mckie, George Ann
Project Start
2003-04-01
Project End
2018-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
10
Fiscal Year
2014
Total Cost
$396,250
Indirect Cost
$146,250

  Institution

Name
Case Western Reserve University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

Rathkey, Joseph K; Zhao, Junjie; Liu, Zhonghua et al. (2018) Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci Immunol 3:
Vareechon, Chairut; Zmina, Stephanie Elizabeth; Karmakar, Mausita et al. (2017) Pseudomonas aeruginosa Effector ExoS Inhibits ROS Production in Human Neutrophils. Cell Host Microbe 21:611-618.e5
Boyd-Tressler, Andrea M; Lane, Graham S; Dubyak, George R (2017) Up-regulated Ectonucleotidases in Fas-Associated Death Domain Protein- and Receptor-Interacting Protein Kinase 1-Deficient Jurkat Leukemia Cells Counteract Extracellular ATP/AMP Accumulation via Pannexin-1 Channels during Chemotherapeutic Drug-Induced Apo Mol Pharmacol 92:30-47
Russo, Hana M; Rathkey, Joseph; Boyd-Tressler, Andrea et al. (2016) Active Caspase-1 Induces Plasma Membrane Pores That Precede Pyroptotic Lysis and Are Blocked by Lanthanides. J Immunol 197:1353-67
Karmakar, Mausita; Katsnelson, Michael A; Dubyak, George R et al. (2016) Neutrophil P2X7 receptors mediate NLRP3 inflammasome-dependent IL-1? secretion in response to ATP. Nat Commun 7:10555
Karmakar, Mausita; Katsnelson, Michael; Malak, Hesham A et al. (2015) Neutrophil IL-1? processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K+ efflux. J Immunol 194:1763-75
Lee, Ji-Eun; Sun, Yan; Gjorstrup, Per et al. (2015) Inhibition of Corneal Inflammation by the Resolvin E1. Invest Ophthalmol Vis Sci 56:2728-36
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

Showing the most recent 10 out of 35 publications