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

Talreja, Deepa; Singh, Pawan Kumar; Kumar, Ashok

doi:10.1167/iovs.14-16087

Cited by 50 publications

(83 citation statements)

References 48 publications

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“…Our MyD88 data agree with those of Talreja et al, who recently reported on the importance of MyD88 in experimental S. aureus endophthalmitis (41). There was a significant reduction of inflammatory cell influx in MyD88 Ϫ/Ϫ and TRIF Ϫ/Ϫ eyes, likely due to significantly decreased concentrations of proinflammatory mediators in these eyes compared to those in C57BL/6J controls.…”

Section: C57bl/6j and Tlr4supporting

confidence: 92%

“…*, P Յ 0.036. ular environment in TRIF Ϫ/Ϫ mice. Talreja et al (41) recently reported that a deficiency in cathelicidin-related antimicrobial peptide (CRAMP) led to an increased S. aureus burden in mouse eyes with endophthalmitis, so it would be reasonable to speculate that increased levels of AMP would lead to a lower bacterial burden. However, Stockinger et al (42) reported that TRIF Ϫ/Ϫ mice had low AMP expression levels but in the intestine.…”

Section: Fig 9 Proinflammatory Mediator Expression In Tlr4mentioning

confidence: 99%

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Unexpected Roles for Toll-Like Receptor 4 and TRIF in Intraocular Infection with Gram-Positive Bacteria

et al. 2015

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Inflammation caused by infection with Gram-positive bacteria is typically initiated by interactions with Toll-like receptor 2 (TLR2). Endophthalmitis, an infection and inflammation of the posterior segment of the eye, can lead to vision loss when initiated by a virulent microbial pathogen. Endophthalmitis caused by Bacillus cereus develops as acute inflammation with infiltrating neutrophils, and vision loss is potentially catastrophic. Residual inflammation observed during B. cereus endophthalmitis in TLR2 ؊/؊ mice led us to investigate additional innate pathways that may trigger intraocular inflammation. We first hypothesized that intraocular inflammation during B. cereus endophthalmitis would be controlled by MyD88-and TRIF-mediated signaling, since MyD88 and TRIF are the major adaptor molecules for all bacterial TLRs. In MyD88 ؊/؊ and TRIF ؊/؊ mice, we observed significantly less intraocular inflammation than in eyes from infected C57BL/6J mice, suggesting an important role for these TLR adaptors in B. cereus endophthalmitis. These results led to a second hypothesis, that TLR4, the only TLR that signals through both MyD88 and TRIF signaling pathways, contributed to inflammation during B. cereus endophthalmitis. Surprisingly, B. cereus-infected TLR4 ؊/؊ eyes also had significantly less intraocular inflammation than infected C57BL/6J eyes, indicating an important role for TLR4 in B. cereus endophthalmitis. Taken together, our results suggest that TLR4, TRIF, and MyD88 are important components of the intraocular inflammatory response observed in experimental B. cereus endophthalmitis, identifying a novel innate immune interaction for B. cereus and for this disease. Bacillus cereus is a Gram-positive, spore-forming, and beta-hemolytic soil bacterium (1). Commonly identified as a causative agent of foodborne illnesses, B. cereus is also associated with a multitude of clinical conditions, such as central nervous system infections (2), pneumonia (3), endocarditis (4), and gas-gangrene-like cutaneous infections (5). B. cereus also causes a virulent form of endophthalmitis, an intraocular inflammatory condition resulting from the introduction of microorganisms into the posterior segment of the eye following surgery or injury or from a distant site of infection. This infection causes irreversible damage to the retina, often leading to vision loss within 1 or 2 days (6). Typically, B. cereus endophthalmitis occurs following a penetrating eye injury (posttraumatic) with retained intraocular foreign bodies (7, 8) but has also been reported in postoperative patients (9-11). Fewer than 30% of posttraumatic B. cereus endophthalmitis patients retained useful vision, and out of these, only 9% retained 20/70 vision or better (7, 12). Moreover, 48% of B. cereus and other Bacillus species infections required evisceration or enucleation of the eye despite therapeutic intervention (7, 12). Intraocular inflammation that occurs during B. cereus endophthalmitis interferes with the clarity of the visual axis, contributing to disruption...

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Section: C57bl/6j and Tlr4supporting

confidence: 92%

Section: Fig 9 Proinflammatory Mediator Expression In Tlr4mentioning

confidence: 99%

Unexpected Roles for Toll-Like Receptor 4 and TRIF in Intraocular Infection with Gram-Positive Bacteria

et al. 2015

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“…Parkunan et al (2015) reported that mice deficient in MyD88, the intracellular adapter molecule for several TLRs, had significantly delayed intraocular inflammation than wild type mouse eyes infected with B. cereus . Similar findings were reported for S. aureus in MyD88-deficient mice (Talreja et al, 2015). Surprisingly, deficiencies in Toll/IL-1 receptor domain-containing adapter-inducing interferon β (TRIF, the intracellular adaptor molecule for TLR4) and in TLR4 itself also resulted in significantly less intraocular inflammation during experimental B. cereus endophthalmitis, suggesting that MyD88-independent pathways were involved in the intraocular response to B. cereus and that B. cereus may harbor ligands for TLR4 which instigate intraocular inflammation (Parkunan et al, 2015).…”

Section: Experimental Models: Therapeutics and Virulencesupporting

confidence: 90%

Modeling intraocular bacterial infections

Astley

Coburn

Parkunan

et al. 2016

Progress in Retinal and Eye Research

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Bacterial endophthalmitis is an infection and inflammation of the posterior segment of the eye which can result in significant loss of visual acuity. Even with prompt antibiotic, anti-inflammatory and surgical intervention, vision and even the eye itself may be lost. For the past century, experimental animal models have been used to examine various aspects of the pathogenesis and pathophysiology of bacterial endophthalmitis, to further the development of anti-inflammatory treatment strategies, and to evaluate the pharmacokinetics and efficacies of antibiotics. Experimental models allow independent control of many parameters of infection and facilitate systematic examination of infection outcomes. While no single animal model perfectly reproduces the human pathology of bacterial endophthalmitis, investigators have successfully used these models to understand the infectious process and the host response, and have provided new information regarding therapeutic options for the treatment of bacterial endophthalmitis. This review highlights experimental animal models of endophthalmitis and correlates this information with the clinical setting. The goal is to identify knowledge gaps that may be addressed in future experimental and clinical studies focused on improvements in the therapeutic preservation of vision during and after this disease.

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“…TLR2 is also important in mediating inflammation in Staphylococcus aureus endophthalmitis (Kochan et al, 2012 and Talreja et al, 2015). We do not know whether the pili of Bacillus interact with these innate immune receptors and are, in fact, TLR ligands.…”

Section: Discussionmentioning

confidence: 99%

The role of pili in Bacillus cereus intraocular infection

Callegan

Parkunan

Randall

et al. 2017

Experimental Eye Research

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Bacterial endophthalmitis is a potentially blinding intraocular infection. The bacterium Bacillus cereus causes a devastating form of this disease which progresses rapidly, resulting in significant inflammation and loss of vision within a few days. The outer surface of B. cereus incites the intraocular inflammatory response, likely through interactions with innate immune receptors such as TLRs. This study analyzed the role of B. cereus pili, adhesion appendages located on the bacterial surface, in experimental endophthalmitis. To test the hypothesis that the presence of pili contributed to intraocular inflammation and virulence, we analyzed the progress of experimental endophthalmitis in mouse eyes infected with wild type B. cereus (ATCC 14579) or its isogenic pilus-deficient mutant (ΔbcpA-srtD-bcpB or ΔPil). One hundred CFU were injected into the mid-vitreous of one eye of each mouse. Infections were analyzed by quantifying intraocular bacilli and retinal function loss, and by histology from 0 to 12 h postinfection. In vitro growth and hemolytic phenotypes of the infecting strains were also compared. There was no difference in hemolytic activity (1:8 titer), motility, or in vitro growth (p>0.05, every 2 h, 0-18 h) between wild type B. cereus and the ΔPil mutant. However, infected eyes contained greater numbers of wild type B. cereus than ΔPil during the infection course (p≤0.05, 3-12 h). Eyes infected with wild type B. cereus experienced greater losses in retinal function than eyes infected with the ΔPil mutant, but the differences were not always significant. Eyes infected with ΔPil or wild type B. cereus achieved similar degrees of severe inflammation. The results indicated that the intraocular growth of pilus-deficient B. cereus may have been better controlled, leading to a trend of greater retinal function in eyes infected with the pilus-deficient strain. Although this difference was not enough to significantly alter the severity of the inflammatory response, these results suggest a potential role for pili in protecting B. cereus from clearance during the early stages of endophthalmitis, which is a newly described virulence mechanism for this organism and this infection.

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

Abstract: TLR2 and MyD88 signaling plays an important role in protecting the retina from staphylococcal endophthalmitis by production of the antimicrobial peptide CRAMP.

Cited by 50 publications

References 48 publications

Unexpected Roles for Toll-Like Receptor 4 and TRIF in Intraocular Infection with Gram-Positive Bacteria

Unexpected Roles for Toll-Like Receptor 4 and TRIF in Intraocular Infection with Gram-Positive Bacteria

Modeling intraocular bacterial infections

The role of pili in Bacillus cereus intraocular infection

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