Parasitic filarial nematodes infect over 200 million individuals worldwide, causing debilitating inflammatory diseases such as river blindness and lymphatic filariasis. Rickettsia - like Wolbachia bacteria are essential symbionts of the major pathogenic filarial nematode parasites of humans, including the Onchocerca volvulus, which causes river blindness. Using a murine model, we reported that Wolbachia play an essential role in the pathogenesis of Onchocerca keratitis, primarily by mediating neutrophil recruitment to the corneal stroma [Science 2002.295:1892]. In the current proposal, we will use microfilaria larvae (Mf) which harbor Wolbachia to examine the interaction between Wolbachia and the neutrophils that lead to stromal disease, focusing on mediators of neutrophil migration through the extracellular matrix (ECM) of the corneal stroma which include CXC chemokine receptors, beta 2 integrins, and matrix metalloproteinases. The experimental plan is a logical progression from studies conducted in the previous funding period, which focused on the role of vascular endothelial cells in recruitment of neutrophils from limbal vessels to the cornea. In addition to furthering our understanding of the role of Wolbachia in the pathogenesis of river blindness, results of proposed studies represent a novel approach to define the early molecular events underlying the interaction of neutrophils with ECM that lead to development of corneal haze. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY010320-12
Application #
6840787
Study Section
Special Emphasis Panel (ZRG1-VISA (02))
Program Officer
Shen, Grace L
Project Start
1993-12-01
Project End
2008-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
12
Fiscal Year
2005
Total Cost
$382,500
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Carlson, Eric C; Sun, Yan; Auletta, Jeffery et al. (2010) Regulation of corneal inflammation by neutrophil-dependent cleavage of keratan sulfate proteoglycans as a model for breakdown of the chemokine gradient. J Leukoc Biol 88:517-22
Gentil, Katrin; Pearlman, Eric (2009) Gamma interferon and interleukin-1 receptor 1 regulate neutrophil recruitment to the corneal stroma in a murine model of Onchocerca volvulus keratitis. Infect Immun 77:1606-12
Turner, Joseph D; Langley, R Stuart; Johnston, Kelly L et al. (2009) Wolbachia lipoprotein stimulates innate and adaptive immunity through Toll-like receptors 2 and 6 to induce disease manifestations of filariasis. J Biol Chem 284:22364-78
Du, Yiqin; Carlson, Eric C; Funderburgh, Martha L et al. (2009) Stem cell therapy restores transparency to defective murine corneas. Stem Cells 27:1635-42
Lin, Michelle; Jackson, Patricia; Tester, Angus M et al. (2008) Matrix metalloproteinase-8 facilitates neutrophil migration through the corneal stromal matrix by collagen degradation and production of the chemotactic peptide Pro-Gly-Pro. Am J Pathol 173:144-53
Gillette-Ferguson, Illona; Daehnel, Katrin; Hise, Amy G et al. (2007) Toll-like receptor 2 regulates CXC chemokine production and neutrophil recruitment to the cornea in Onchocerca volvulus/Wolbachia-induced keratitis. Infect Immun 75:5908-15
Hise, Amy G; Daehnel, Katrin; Gillette-Ferguson, Illona et al. (2007) Innate immune responses to endosymbiotic Wolbachia bacteria in Brugia malayi and Onchocerca volvulus are dependent on TLR2, TLR6, MyD88, and Mal, but not TLR4, TRIF, or TRAM. J Immunol 178:1068-76
Daehnel, K; Gillette-Ferguson, I; Hise, A G et al. (2007) Filaria/Wolbachia activation of dendritic cells and development of Th1-associated responses is dependent on Toll-like receptor 2 in a mouse model of ocular onchocerciasis (river blindness). Parasite Immunol 29:455-65
Lin, Michelle; Carlson, Eric; Diaconu, Eugenia et al. (2007) CXCL1/KC and CXCL5/LIX are selectively produced by corneal fibroblasts and mediate neutrophil infiltration to the corneal stroma in LPS keratitis. J Leukoc Biol 81:786-92
Pearlman, Eric; Gillette-Ferguson, Illona (2007) Onchocerca volvulus, Wolbachia and river blindness. Chem Immunol Allergy 92:254-65

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