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Meredith S. Gregory-Ksander, Michelle Crane, William J. Vincent; TLR2, But Not NOD2, Is Required For Clearance Of Bacteria During S. Aureus Induced Endophthalmitis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5864.
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Endophthalmitis is an infection of the posterior segment of the eye. Staphylococcus aureus (S. aureus) is a leading cause of destructive endophthalmitis associated with severe inflammation and loss of retinal function. The innate immune response is the first line of defense against pathogens. Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD) proteins are signaling receptors of the innate immune system that recognize S. aureus and respond to pathogenic microorganisms via: secretion of antimicrobial factors, phagocytosis of pathogens, and release of pro-inflammatory cytokines. Using a murine model of endophthalmitis we determined whether successful clearance of S. aureus is mediated by NOD2 and/or TLR2.
NOD2-KO (B6.129S1-Nod2tm1Flv/J), TLR2-KO (B6.129-Tlr2tm1Kir/J), and C57BL/6 WT mice received intravitreal injections of 500 CFU S. aureus (RN6390). Clinical examinations and bacterial quantification were performed at 24, 48, 72, and 96 hours post injection. H&E retinal sections were used to assess retinal damage. Neutrophil infiltration was assessed quantitatively using a myeloperoxidase (MPO) assay.
C57BL/6 WT and NOD2-KO mice injected with 500 CFU S. aureus successfully cleared the infection as demonstrated by (i) clinical scores, (ii) bacterial quantification, and (iii) histology. By contrast, TLR2-KO mice were unable to clear an identical inoculation resulting in extensive retinal damage. While previous studies demonstrate a correlation between neutrophil infiltration and successful bacterial clearance, MPO analysis revealed no delay nor decrease in the numbers of neutrophils infiltrating the eyes of TLR2-KO mice as compared to WT mice. At 24 hours post infection, the average MPO units per eye were 5.11±1.3 in WT mice as compared to 13.7 ±1.4 in TLR2-KO mice. Moreover, the neutrophil infiltrate increased significantly in TLR2-KO mice by 72 hours to 54.7±13.3 as compared to 18.9±7 in WT mice (p<.01).
Together these data demonstrate that TLR2, but not NOD2, is required for clearance of bacteria from the posterior segment. However, the susceptibility to infection in TLR2-KO mice is not due to a decreased or delayed neutrophil infiltration. These results suggest that resistance to S. aureus is mediated via another TLR2 mediated protective mechanism, possibly the release of antimicrobial peptides.
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