The broad, long term goals of this grant application are to understand the molecular and cellular host responses to bacterial pathogens that are significant causes of corneal infection. Specifically, this application will focus on infections caused by Pseudomonas aeruginosa and Staphylococcus aureus. These two pathogens are among the most common causes of serious corneal infections. Strains of both pathogens have acquired significant means to resist antimicrobial therapies and elaborate a large armamentarium of virulence factors that contribute to corneal damage and loss of visual acuity. Therapies for these infections need to both reduce bacterial numbers and allow the host to have an adequate and helpful inflammatory response to clear pathogens without causing damage to the cornea. For P. aeruginosa, most of the bacteria infecting scratch-injured mouse eyes are found inside of cells, and entry requires binding to the cystic fibrosis transmembrane conductance regulator (CFTR). This leads to initiation of inflammation, including activation of transcription factors for pro-inflammatory genes, synthesis of the pro-inflammatory molecules, and initiation of the cellular influx, primarily composed of PMNs, that will both clear the pathogen but can also cause damage to the cornea. PMN influx is also controlled by the TH17 regulatory T cell network, which will also be investigated in these studies. To determine how CFTR coordinates inflammation, we will analyze the specific effectors produced by cells with wild-type CFTR that are infected with P. aeruginosa, compare these with cells lacking CFTR, and validate in animal models of corneal infection the role of the CFTR-dependent factors in bacterial clearance and corneal pathology. For S. aureus, the recent dramatic increase in methicillin-resistant S. aureus (MRSA), particularly strains elaborating the Pantone-Valentine leukocidin (PVL), makes this pathogen a significant concern as a cause of serious eye disease. The role of PVL, and antibody to PVL which is found commonly in normal human sera, will be examined in tissue culture and murine models of infection using isogenic S. aureus strains positive or negative for PVL expression, as well as immunizing mice with the PVL components to analyze how antibody modulates the course of infection. These studies should also be informative about the general role leukocidins have in the pathogenesis of S. aureus corneal infections. Further studies on MRSA strains will extend to the potential of a candidate vaccine for S. aureus infections, utilizing the poly-N-acetyl glucosamine (PNAG) surface polysaccharide as the active component of a conjugate vaccine, to ameliorate the consequences of infection. Active vaccination, as well as passive transfer studies using both polyclonal antibodies and a fully human monoclonal antibody, will be evaluated in the murine model of corneal injury to determine if PNAG is a rationale target for immunotherapy of S. aureus corneal infection. The proposed studies should ex- tend our insights into the mechanisms of bacterial virulence and effective host defense for corneal infections and provide pre-clinical data for vaccine approaches to S. aureus that could be highly effective.

Public Health Relevance

Infections of the eye surface (cornea) are the most significant cause of loss of vision and visual acuity in the world. Bacterial pathogens are very important causes of these infections, and among the most common are Pseudomonas aeruginosa and Staphylococcus aureus. This application will study how these microbes cause damage to the cornea that can result in vision loss and evaluate interventions, including vaccines, that could be used to prevent or treat these infections and minimize damage to the cornea and thus to an individual's eyesight.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
Program Officer
Mckie, George Ann
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Brigham and Women's Hospital
United States
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Zaidi, Tanweer; Zaidi, Tauqeer; Cywes-Bentley, Colette et al. (2014) Microbiota-driven immune cellular maturation is essential for antibody-mediated adaptive immunity to Staphylococcus aureus infection in the eye. Infect Immun 82:3483-91
Zaidi, Tanweer; Zaidi, Tauqeer; Yoong, Pauline et al. (2013) Staphylococcus aureus corneal infections: effect of the Panton-Valentine leukocidin (PVL) and antibody to PVL on virulence and pathology. Invest Ophthalmol Vis Sci 54:4430-8
Reidy, Thomas; Rittenberg, Alexander; Dwyer, Markryan et al. (2013) Homotrimeric macrophage migration inhibitory factor (MIF) drives inflammatory responses in the corneal epithelium by promoting caveolin-rich platform assembly in response to infection. J Biol Chem 288:8269-78
Zaidi, Tanweer S; Zaidi, Tauqeer; Pier, Gerald B (2010) Role of neutrophils, MyD88-mediated neutrophil recruitment, and complement in antibody-mediated defense against Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 51:2085-93
Gadjeva, Mihaela; Nagashima, Jill; Zaidi, Tanweer et al. (2010) Inhibition of macrophage migration inhibitory factor ameliorates ocular Pseudomonas aeruginosa-induced keratitis. PLoS Pathog 6:e1000826
Zaidi, Tanweer; Pier, Gerald B (2008) Prophylactic and therapeutic efficacy of a fully human immunoglobulin G1 monoclonal antibody to Pseudomonas aeruginosa alginate in murine keratitis infection. Infect Immun 76:4720-5
Zaidi, Tanweer; Bajmoczi, Milan; Zaidi, Tauqeer et al. (2008) Disruption of CFTR-dependent lipid rafts reduces bacterial levels and corneal disease in a murine model of Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 49:1000-9
DiGiandomenico, Antonio; Rao, Jayasimha; Harcher, Katie et al. (2007) Intranasal immunization with heterologously expressed polysaccharide protects against multiple Pseudomonas aeruginosa infections. Proc Natl Acad Sci U S A 104:4624-9
Zaidi, Tanweer; Mowrey-McKee, Mary; Pier, Gerald B (2004) Hypoxia increases corneal cell expression of CFTR leading to increased Pseudomonas aeruginosa binding, internalization, and initiation of inflammation. Invest Ophthalmol Vis Sci 45:4066-74