Increased Resistance to Staphylococcus aureus Endophthalmitis in BALB/c Mice: Fas Ligand Is Required for Resolution of Inflammation but Not for Bacterial Clearance

Abstract

FasL was recently shown be required for bacterial clearance in C57BL/6 mice that express the FasL.1 allotype. The FasL.2 allotype is expressed in BALB/c mice and exhibits increased binding affinity to and increased cytotoxic activity against Fas ؉ target cells. Therefore, we hypothesized that BALB/c mice would be more resistant to Staphylococcus aureus-induced endophthalmitis. To test this hypothesis, C57BL/6, BALB/c, and BALB(gld) mice received intravitreal injections of 2,500 CFU of S. aureus (RN6390). Clinical examinations, electroretinography (ERG), histology, and bacterial quantification were performed at 24, 48, 72, and 96 h postinjection. The myeloperoxidase (MPO) assay was used to quantitate neutrophil infiltration. At 96 h postinfection, 86% of C57BL/6 mice presented with complete destruction of the eye, compared to only 29% of BALB/c mice with complete destruction. To our surprise, in the absence of Fas ligand, BALB(gld) mice showed no difference in bacterial clearance compared to BALB/c mice. However, histology and ERG analysis revealed increased retinal damage and significant loss of retinal function. MPO analysis revealed equal numbers of neutrophils in BALB(gld) and BALB/c mice at 24 h postinfection. However, at 48 h, the neutrophil numbers remained significantly elevated in BALB(gld) mice, correlating with the increased retinal damage observed in BALB(gld) mice. We conclude that the increased resistance to S. aureus induced endophthalmitis in BALB/c mice is not dependent upon the FasL. However, in contrast to C57BL/6 mice, FasL is required for resolution of inflammation and protecting host tissue from nonspecific damage in BALB/c mice.

In Vivo Role of TLR2 and MyD88 Signaling in Eliciting Innate Immune Responses in Staphylococcal Endophthalmitis

“…To determine the in vivo roles of TLR2 and MyD88 signaling in the pathogenesis of bacterial endophthalmitis, the eyes of WT (C57BL/6), TLR2 À/À , and MyD88 À/À mice were challenged by inoculation of S. aureus as described previously. 2,17,28 Disease severity, as measured by clinical score, showed a time-dependent progression. The average clinical score of TLR2 À/À mice did not differ significantly from that of WT mice, whereas MyD88 À/À mice had higher clinical scores at 1 day post infection (DPI).…”

“…A Lower Dose of S. aureus Causes Endophthalmitis in TLR2 À/À and MyD88 À/À Mice Previous studies have shown that intravitreal injection of 500 CFU of S. aureus causes transient inflammation in WT mice; however, the bacteria are cleared by 3 DPI, and inflammation is resolved. 4,17,28 Having shown the increased susceptibility of TLR2 À/À and MyD88 À/À mice by using a dose of 5000 CFU/eye, we sought to determine whether 500 CFU/eye, a 10-fold lower dose could cause endophthalmitis in these KO mice. To this FIGURE 7.…”

“…16 Much of the pathology observed in endophthalmitis appears to result from deleterious host responses to the bacteria. 4,17 Consequently, the administration of heat-killed S. aureus and its cell wall sacculi has been shown to result in inflammatory responses nearly identical to that seen with live bacteria. 18 Although much is known about the cause of infectious endophthalmitis, the induction of retinal immunity, particularly as it relates to protective responses is not well understood.…”

Modeling intraocular bacterial infections

“…However, S. aureus endophthalmitis in FasL-deficient knockout mice followed a much more aggressive course than infection in wild type background mice which were able to clear the infection (Engelbert and Gilmore, 2005). Sugi et al (2013) also reported that FasL was required for resolution of inflammation during experimental S. aureus endophthalmitis, but not for clearance of the bacteria.…”

Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans

“…aureus remains largely unknown. We [6–8] and others [9, 10] have reported the different susceptibility to S . aureus in various inbred mouse strains.…”