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      Animal Models of Bacterial Keratitis

      review-article
      Author(s): *
      Publication date (Electronic):
      Journal: Journal of Biomedicine and Biotechnology
      Publisher: Hindawi Publishing Corporation

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          Abstract

          Bacterial keratitis is a disease of the cornea characterized by pain, redness, inflammation, and opacity. Common causes of this disease are Pseudomonas aeruginosa and Staphylococcus aureus. Animal models of keratitis have been used to elucidate both the bacterial factors and the host inflammatory response involved in the disease. Reviewed herein are animal models of bacterial keratitis and some of the key findings in the last several decades.

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          TLR4 and TLR5 on corneal macrophages regulate Pseudomonas aeruginosa keratitis by signaling through MyD88-dependent and -independent pathways.

          Yan-Song Sun, Yiping Han, Sanhita Roy … (2010)
          Pseudomonas aeruginosa is a major cause of blindness and visual impairment in the United States and worldwide. Using a murine model of keratitis in which abraded corneas are infected with P. aeruginosa parent and ΔfliC (aflagellar) strains 19660 and PAO1, we found that F4/80(+) macrophages were the predominant cell type in the cornea expressing TLR2, TLR4, and TLR5. Depletion of macrophages and dendritic cells using transgenic Mafia mice, in which Fas ligand is selectively activated in these cells, resulted in diminished cytokine production and cellular infiltration to the corneal stroma and unimpaired bacterial growth. TLR4(-/-) mice showed a similar phenotype postinfection with ΔfliC strains, whereas TLR4/5(-/-) mice were susceptible to corneal infection with parent strains. Bone marrow-derived macrophages stimulated with ΔfliC bacteria induced Toll/IL-1R intracellular domain (TIR)-containing adaptor inducing IFN-β (TRIF)-dependent phosphorylation of IFN regulatory factor 3 in addition to TIR-containing adaptor protein/MyD88-dependent phosphorylation of IκB and nuclear translocation of the p65 subunit of NFκB. Furthermore, TRIF(-/-) mice showed a similar phenotype as TLR4(-/-) mice in regulating only ΔfliC bacteria, whereas MyD88(-/-) mice were unable to clear parent or ΔfliC bacteria. Finally, IL-1R1(-/-) and IL-1α/β(-/-) mice were highly susceptible to infection. Taken together, these findings indicate that P. aeruginosa activates TLR4/5 on resident corneal macrophages, which signal through TRIF and TIR-containing adaptor protein/MyD88 pathways, leading to NF-κB translocation to the nucleus, transcription of CXCL1 and other CXC chemokines, recruitment of neutrophils to the corneal stroma, and subsequent bacterial killing and tissue damage. IL-1α and IL-1β are also produced, which activate an IL-1R1/MyD88-positive feedback loop in macrophages and IL-1R on other resident cells in the cornea.
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            Dimensions and morphology of the cornea in three strains of mice.

            Patrik Henriksson, Lee McDermott, Jan P G Bergmanson (2009)
            To use a histologic approach to obtain dimensional and morphologic information on the cornea in three commonly used strains of mice. Adult mice (three each of 129/SVJ, C57BL/6, and BALB/c) were euthanatized, and the eyes were enucleated, immersed in 2% glutaraldehyde fixative, and prepared for light and transmission electron microscopy. The full corneal, epithelial, stromal, and posterior limiting lamina (PLL) with endothelium thicknesses were measured at the same location centrally and peripherally. All three strains showed a statistically significant (P < 0.001) decrease in overall thickness in the peripheral compared with the central cornea. The decrease was due to a reduced thickness of both the epithelium and the stroma. The stroma and epithelium contributed to approximately two thirds and one third of the total corneal thickness, respectively. The epithelium had the classic stratified layout and consisted of 13.00 +/- 1.41 layers centrally versus 10.33 +/- 1.37 peripherally. Some adaptation of stromal tissue was found immediately adjacent to the epithelial basement membrane, but a clearly defined anterior limiting lamina did not exist. The stroma was organized into lamellae but lacked the anterior branching and interweaving reported in humans and had unmyelinated nerve fibers within micrometers of the endothelium. The PLL was 2.17 +/- 0.3 microm thick and was divided into pre- and postnatal layers, with striated bodies in the postnatal portion. This study demonstrated that in the three strains of mice examined, the cornea becomes significantly thinner toward the periphery. Dimensionally, proportionally, and anatomically the three strains used appeared to be similar. However, morphologic differences were observed compared with other mammals, and awareness of these differences is important when using the mouse as an animal model applicable to the human.
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              Contribution of proteases and LasR to the virulence of Pseudomonas aeruginosa during corneal infections.

              M P Seed, Ira Goldberg, D S Toder … (1997)
              The roles of the Pseudomonas aeruginosa proteases LasB (elastase) and LasA and the transcriptional activator LasR, which regulates the expression of these proteases, were evaluated in a murine model of P. aeruginosa corneal infection. In scarified corneas, P. aeruginosa PAO-A1 (LasA negative) or PAO-B1A1 (LasB and LasA negative) at a dose of 10(8) CFU per eye caused very mild or no disease following infection; however, the defect in PAO-A1 could not be complemented by supplying a functional copy of lasA either on a plasmid or inserted into the chromosome. In contrast, PAO-B1 (LasB negative) colonized the cornea and caused disease equal in severity to disease caused by the parental strain, PAO1-I. Although LasR is a known regulator of lasA expression, PAO-R1, a lasR-negative derivative of PAO1-I, was as virulent as the parental strain during corneal infection. When transcriptional fusion plasmids were used to quantify the expression of the lasB and lasA genes in P. aeruginosa PAO1-I and PAO-R1, the lasB::lacZ fusion in PAO-R1 showed only 3.5% as much activity as it did in PAO1-I, while the activity of the lasA::lacZ fusion in PAO-R1 was 27.8% of that in PAO1-I. Coadministration of 5 microg of purified LasA protease with PAO-A1 did not reconstitute a wild-type infection. This treatment produced an acute toxic reaction leading to prolonged eyelid closure without inflammatory destruction of the cornea that was similar to that observed when LasA was administered alone. These results indicate that insertional inactivation of lasA renders P. aeruginosa avirulent in a murine model of keratitis and that neither LasR nor elastase production is required for the establishment and maintenance of corneal infection. However, the lack of virulence of the LasA-deficient strains cannot be ascribed with certainty to the deficiency of LasA from the available data.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Biomed Biotechnol
                Journal ID (publisher-id): JBB
                Title: Journal of Biomedicine and Biotechnology
                Publisher: Hindawi Publishing Corporation
                ISSN (Print): 1110-7243
                ISSN (Electronic): 1110-7251
                Publication date (Print): 2011
                Publication date (Electronic): 4 January 2011
                Volume: 2011
                Electronic Location Identifier: 680642
                Affiliations
                Department of Microbiology, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA
                Author notes
                *Mary E. Marquart: mmarquart@ 123456umc.edu

                Academic Editor: Oreste Gualillo

                Article
                DOI: 10.1155/2011/680642
                PMC ID: 3022227
                PubMed ID: 21274270
                SO-VID: 6a1b9cc3-1df2-40af-b776-fab05091072d
                Copyright © Copyright © 2011 Mary E. Marquart.
                License:

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 16 October 2010
                Date revision received : 29 November 2010
                Date accepted : 9 December 2010
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Molecular medicine
                Data availability:
                ScienceOpen disciplines: Molecular medicine

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