Targets of immunomodulation in bacterial endophthalmitis

Miller, Frederick C.; Coburn, Phillip S.; Huzzatul, Mursalin Md; LaGrow, Austin L.; Livingston, Erin; Callegan, Michelle C.

doi:10.1016/j.preteyeres.2019.05.004

Cited by 55 publications

(60 citation statements)

References 124 publications

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“…Among bacterial pathogens, Staphylococci remain the leading cause of bacterial endophthalmitis, with S. aureus infection resulting in severe disease outcomes and often leading to visual disability and blindness [27]. In clinical settings, most bacterial endophthalmitis arises due to postsurgical complications (e.g., cataract surgery), where pathogens from the ocular surface gain access to the eye and cause ocular tissue damage [28,29]. To mimic this situation, studies from our [7,26,30] and other laboratories [31,32] have developed murine models where bacteria are directly inoculated in the vitreous cavity.…”

Section: Discussionmentioning

confidence: 99%

“…Our data showed a significantly increased expression of Il-1β and Il-6, and no changes were observed in the levels of Tnf-α in the control versus the S. aureus-infected eyes. While the production of inflammatory mediators is a protective host response during infection, their excessive levels could lead to collateral tissue damage [29]. Among the various inflammatory mediators produced, Tnf-α has been shown to cause retinal tissue damage in several ocular diseases [37] and has been reported to exert a protective role in Bacillus endophthalmitis [38].…”

Section: Discussionmentioning

confidence: 99%

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Zebrafish are Resistant to Staphylococcus aureus Endophthalmitis

et al. 2019

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Gram-positive bacteria remain the leading cause of endophthalmitis, a blinding infectious disease of the eye. Murine models have been widely used for understanding the pathogenesis of bacterial endophthalmitis. In this study, we sought to develop an alternative zebrafish (Danio rerio) model for Staphylococcus aureus and compare the disease pathobiology to a murine model. Endophthalmitis was induced in zebrafish and C57BL/6 mice through the intravitreal injection of S. aureus. Disease progression was monitored by assessing corneal haze, opacity, bacterial burden, and retinal histology. Our results demonstrated that, unlike the murine models, zebrafish maintained ocular integrity, corneal transparency, and retinal architecture. We found that the zebrafish was capable of clearing S. aureus from the eye via transport through retinal vessels and the optic nerve and by mounting a monocyte/macrophage response beginning at 8 hour post-infection (hpi). The bacterial burden increased up to 8 hpi and significantly decreased thereafter. An assessment of the innate retinal response revealed the induced expression of Il-1β and Il-6 transcripts. Collectively, our study shows that unlike the murine model, zebrafish do not develop endophthalmitis and rapidly clear the pathogen. Hence, a better understanding of the zebrafish protective ocular innate response may provide new insights into the pathobiology of bacterial endophthalmitis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Zebrafish are Resistant to Staphylococcus aureus Endophthalmitis

et al. 2019

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“…Our findings suggest that the InhAs may facilitate intraocular bacterial growth by producing an environment more conducive to persistence. Current therapeutics are relatively ineffective in treating Bacillus endophthalmitis [1,[9][10][11][59][60][61][62][63], and due to its rapidly blinding course, Bacillus endophthalmitis requires early and precise treatment [62,63]. Treatment strategies for Bacillus and other types of endophthalmitis should be based on knowledge of the virulence factors that contribute to disease pathogenesis.…”

Section: Retained Retinal Function In Eyes Infected With Bacillus Lacmentioning

confidence: 99%

Immune Inhibitor A Metalloproteases Contribute to Virulence inBacillusEndophthalmitis

Livingston

Mursalin

Coburn

et al. 2020

Preprint

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AbstractBacterial endophthalmitis is a devastating infection that can cause blindness following the introduction of organisms into the posterior segment of the eye. Over half of Bacillus endophthalmitis cases result in significant loss of useful vision. Often, these eyes have to be enucleated. Bacillus produces many virulence factors in the eye that may contribute to retinal damage and robust inflammation. This study analyzed Bacillus immune inhibitor A (InhA) metalloproteases, which digest extracellular matrix, tight junction proteins, and antimicrobial proteins. We hypothesized that InhAs contribute to Bacillus intraocular virulence and inflammation. We analyzed phenotypes and infectivity of wild type (WT), InhA1-deficient (ΔinhA1), InhA2-deficient (ΔinhA2), or InhA1, A2, and A3-deficient (ΔinhA1-3) Bacillus thuringiensis. In vitro analysis of growth, proteolysis, and cytotoxicity were compared between B. thuringiensis strains. WT and InhA mutants were similarly cytotoxic to retinal cells. Mutant ΔinhA1 and ΔinhA2 entered log phase growth earlier than WT. Proteolysis of the ΔinhA1-3 mutant was decreased, but this strain grew similar to WT in vitro. Experimental endophthalmitis was initiated by intravitreally infecting C57BL/6J mice with 200 CFU of B. thuringiensis WT or InhA mutants. Intraocular Bacillus and retinal function loss were quantified. Intraocular myeloperoxidase concentrations were quantified and histology was analyzed. Eyes infected with ΔinhA1 or ΔinhA2 strains contained greater numbers of bacteria than eyes infected with WT throughout the course of infection. Eyes infected with single mutants had inflammation and retinal function loss similar to eyes infected with WT strain. Eyes infected with ΔinhA1-3 cleared the infection, with less retinal function loss and inflammation compared to eyes infected with the WT strain. RT-PCR results suggested that single InhA mutant results may be explained by compensatory expression of the other InhAs in these mutants. These results indicate that together, the InhA metalloproteases contribute to the severity of infection and inflammation in Bacillus endophthalmitis.Author summaryBacterial endophthalmitis is an infection of the eye, which can follow accidental contamination of the posterior segment following ocular surgery (postoperative), a penetrating wound (post-traumatic), or during spread of bacteria into the eye from the bloodstream (endogenous). During bacterial endophthalmitis, virulent pathogens such as Bacillus cause ocular damage via the activities of an array of virulence factors, including proteases. A class of proteases that are expressed by Bacillus during ocular infection are the immune inhibitor A metalloproteases. Here, we used a mouse model of endophthalmitis to test mutant Bacillus that lack single or multiple InhAs to determine if these metalloproteases contributed to the virulence during the disease. In the absence of the production of all InhAs, Bacillus could not cause severe infection. Our study provides new insights into the virulence of Bacillus in the eye, and the contribution of its InhA metalloproteases to establishing infection.

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“…4 Mostly, ocular trauma or surgical procedures predispose the eye to develop bacterial endophthalmitis. 5,6 Visual prognosis mainly depends on the virulence properties of the causative organism, visual ingenuity, and the efficacy of the antimicrobial treatment regime. 7 Eye being an immunoprivileged organ, the retina is highly susceptible to host-induced inflammatory damage along with the injury caused by pathogens virulence factors.…”

Section: Introductionmentioning

confidence: 99%

Toll‐like receptor 2 (TLR2) engages endoplasmic reticulum stress sensor IRE1α to regulate retinal innate responses in Staphylococcus aureus endophthalmitis

2020

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Endoplasmic reticulum (ER) stress response has been implicated in a variety of pathophysiological conditions, including infectious and inflammatory diseases. However, its contribution in ocular bacterial infections, such as endophthalmitis, which often cause blindness is not known. Here, using a mouse model of Staphylococcus (S.) aureus endophthalmitis, our study demonstrates the induction of inositol‐requiring enzyme 1α (IRE1α) and splicing of X‐box binding protein‐1 (Xbp1) branch of the ER‐stress pathway, but not the other classical ER stress sensors. Interestingly, S aureus‐induced ER stress response was found to be dependent on Toll‐like receptor 2 (TLR2), as evident by reduced expression of IRE1α and Xbp1 mRNA splicing in TLR2 knockout mouse retina. Pharmacological inhibition of IRE1α using 4µ8C or experiments utilizing IRE1α−/− macrophages revealed that IRE1α positively regulates S aureus‐induced inflammatory responses. Moreover, IRE1α inhibition attenuated S aureus‐triggered NF‐κB, p38, and ERK pathways activation and cells treated with these pathway‐specific inhibitors reduced Xbp1 splicing, suggesting a positive feedback inhibition. In vivo, inhibition of IRE1α diminished the intraocular inflammation and reduced PMN infiltration in mouse eyes, but, increased the bacterial burden and caused more retinal tissue damage. These results revealed a critical role of the IRE1α/XBP1 pathway as a regulator of TLR2‐mediated protective innate immune responses in S aureus‐induced endophthalmitis.

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Targets of immunomodulation in bacterial endophthalmitis

Cited by 55 publications

References 124 publications

Zebrafish are Resistant to Staphylococcus aureus Endophthalmitis

Zebrafish are Resistant to Staphylococcus aureus Endophthalmitis

Immune Inhibitor A Metalloproteases Contribute to Virulence inBacillusEndophthalmitis

Toll‐like receptor 2 (TLR2) engages endoplasmic reticulum stress sensor IRE1α to regulate retinal innate responses in Staphylococcus aureus endophthalmitis

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