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Intraocular infections are prevalent after traumatic injuries or after common ocular surgeries. Infections cause inflammation that can damage the retina and architecture of the eye, often resulting in poor visual outcomes. Severe cases may result in blindness or require enucleation of the eye. Treatments for intraocular infections include intravitreal antibiotics and corticosteroids or surgical vitrectomy in serious cases. The increase in multidrug-resistant infections calls for novel treatment options. In the present study, a biomimetic erythrocyte-derived nanosponge was tested for the ability to neutralize pore-forming toxins from the most frequent Gram-positive bacterial causes of intraocular infections (Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae, and Bacillus cereus). Nanosponge pretreatment of supernatants reduced hemolytic activity in vitro. In a murine sterile endophthalmitis model, nanosponge pretreatment of injected supernatants resulted in greater retinal function and less ocular pathology compared to that in eyes injected with untreated supernatants from all pathogens except methicillin-resistant S. aureus In a murine bacterial endophthalmitis model, treatment with gatifloxacin and gatifloxacin-nanosponges reduced intraocular bacterial burdens, except in the case of methicillin-sensitive S. aureus For all pathogens, eyes in both treatment groups showed decreased ocular pathology and inflammation. Overall, reductions in retinal function loss afforded by gatifloxacin-nanosponge treatment were significant for E. faecalis, S. pneumoniae, and methicillin-resistant S. aureus but not for B. cereus and methicillin-sensitive S. aureus These results suggest that clinical improvements in intraocular infections following nanosponge treatment were dependent on the complexity and types of toxins produced. Nanosponges might serve as an adjunctive therapy for the treatment of ocular infections.IMPORTANCE Endophthalmitis is a blinding consequence of bacterial invasion of the interior of the eye. Because of increases in the numbers of ocular surgeries and intraocular injections, the incidence of endophthalmitis is steadily increasing. Staphylococcus aureus, Enterococcus faecalis, Streptococcus pneumoniae, and Bacillus cereus are leading causes of infection following ocular procedures and trauma and are increasingly more difficult to treat due to multidrug resistance. Each of these pathogens produces pore-forming toxins that contribute to the pathogenesis of endophthalmitis. Treatment of these infections with antibiotics alone is insufficient to prevent damage to the retina and vision loss. Therefore, novel therapeutics are needed that include agents that neutralize bacterial pore-forming toxins. Here, we demonstrate that biomimetic nanosponges neutralize pore-forming toxins from these ocular pathogens and aid in preserving retinal function. Nanosponges may represent a new form of adjunct antitoxin therapy for serious potentially blinding intraocular infections.

B. cereus possesses flagella which allow the organism to migrate within the eye during a blinding form of intraocular infection called endophthalmitis. Because flagella is a ligand for Toll-like receptor 5 (TLR5), we hypothesized that TLR5 contributed to endophthalmitis pathogenesis. Endophthalmitis was induced in C57BL/6J and TLR5−/− mice by injecting 100 CFU of B. cereus into the mid-vitreous. Eyes were analyzed for intraocular bacterial growth, retinal function, and inflammation by published methods. Purified B. cereus flagellin was also injected into the mid-vitreous of wild type C57BL/6J mice and inflammation was analyzed. TLR5 activation by B. cereus flagellin was also analyzed in vitro. B. cereus grew rapidly and at similar rates in infected eyes of C57BL/6J and TLR5−/− mice. A significant loss in retinal function in both groups of mice was observed at 8 and 12 hours postinfection. Retinal architecture disruption and acute inflammation (neutrophil infiltration and proinflammatory cytokine concentrations) increased and were significant at 8 and 12 hours postinfection. Acute inflammation was comparable in TLR5−/− and C57BL/6J mice. Physiological concentrations of purified B. cereus flagellin caused significant inflammation in C57BL/6J mouse eyes, but not to the extent of that observed during active infection. Purified B. cereus flagellin was a weak agonist for TLR5 in vitro. These results demonstrated that the absence of TLR5 did not have a significant effect on the evolution of B. cereus endophthalmitis. This disparity may be due to sequence differences in important TLR5 binding domains in B. cereus flagellin or the lack of flagellin monomers in the eye to activate TLR5 during infection. Taken together, these results suggest a limited role for flagellin/TLR5 interactions in B. cereus endophthalmitis. Based on this and previous data, the importance of flagella in this disease lies in its contribution to the motility of the organism within the eye during infection. [ABSTRACT FROM AUTHOR]

Endophthalmitis is an infection and inflammation of the interior of the eye that can result in significant vision loss. This infection occurs as a result of the seeding of organisms into the interior of the eye following surgery (postoperative), trauma (post-traumatic) or an infection in another site in the body (endogenous). The general rate of endophthalmitis has remained steady over the past several years. However, the increased use of intraocular injections to treat various degenerative and inflammatory ocular diseases, in addition to the already large and growing number of invasive ocular surgeries, may increase the opportunities in which organisms can gain access to the eye. In most cases of endophthalmitis, useful vision can be retained if proper treatment is instituted. However, in severe cases of bacterial endophthalmitis, blindness often occurs despite treatment. This article summarizes information on endophthalmitis epidemiology, treatment issues and current regimens, and recent experimental and clinical efforts to improve the outcome of severe and blinding forms of bacterial endophthalmitis. [ABSTRACT FROM AUTHOR]

Abstract: Endophthalmitis is an infection of the posterior segment of the eye that frequently results in loss of vision. This devastating result occurs despite prompt and often aggressive therapeutic and surgical intervention. Over the past decade, research has centered on determining the bacterial and host factors involved in this potentially blinding disease. The initial focus on the bacterial factors responsible for intraocular virulence has recently expanded into analysis the inflammatory response to infection, including the molecular and cellular interactions between the pathogen and host. This review discusses the epidemiology and therapeutic challenges posed by endophthalmitis, as well as recent findings from the analysis of interactions between the host and pathogen. Based on these findings, a model for the pathogenesis of endophthalmitis is presented. A more comprehensive understanding of the molecular and cellular interactions taking place between pathogen and host during endophthalmitis will expose possible therapeutic targets designed to arrest the infection and prevent vision loss. [Copyright &y& Elsevier]

Bacillus cereus produces many factors linked to pathogenesis and is recognized for causing gastrointestinal toxemia and infections. B. cereus also causes a fulminant and often blinding intraocular infection called endophthalmitis. We reported that the PlcR/PapR system regulates intraocular virulence, but the specific factors that contribute to B. cereus virulence in the eye remain elusive. Here, we compared gene expression in ex vivo vitreous humor with expression in Luria Bertani (LB) and Brain Heart Infusion (BHI) broth by RNA-Seq. The expression of several cytolytic toxins in vitreous was less than or similar to levels observed in BHI or LB. Regulators of virulence genes, including PlcR/PapR, were expressed in vitreous. PlcR/PapR was expressed at low levels, though we reported that PlcR-deficient B. cereus was attenuated in the eye. Chemotaxis and motility genes were expressed at similar levels in LB and BHI, but at low to undetectable levels in vitreous, although motility is an important phenotype for B. cereus in the eye. Superoxide dismutase, a potential inhibitor of neutrophil activity in the eye during infection, was the most highly expressed gene in vitreous. Genes previously reported to be important to intraocular virulence were expressed at low levels in vitreous under these conditions, possibly because in vivo cues are required for higher level expression. Genes expressed in vitreous may contribute to the unique virulence of B. cereus endophthalmitis, and future analysis of the B. cereus virulome in the eye will identify those expressed in vivo, which could potentially be targeted to arrest virulence. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus (S. aureus) is a common pathogen of the eye, capable of infecting external tissues such as the tear duct, conjunctiva, and the cornea, as well the inner and more delicate anterior and posterior chambers. S. aureus produces numerous toxins and enzymes capable of causing profound damage to tissues and organs, as well as modulating the immune response to these infections. Unfortunately, in the context of ocular infections, this can mean blindness for the patient. The role of α-toxin in corneal infection (keratitis) and infection of the interior of the eye (endophthalmitis) has been well established by comparing virulence in animal models and α-toxin-deficient isogenic mutants with their wild-type parental strains. The importance of other toxins, such as β-toxin, γ-toxin, and Panton–Valentine leukocidin (PVL), have been analyzed to a lesser degree and their roles in eye infections are less clear. Other toxins such as the phenol-soluble modulins have yet to be examined in any animal models for their contributions to virulence in eye infections. This review discusses the state of current knowledge of the roles of S. aureus toxins in eye infections and the controversies existing as a result of the use of different infection models. The strengths and limitations of these ocular infection models are discussed, as well as the need for physiological relevance in the study of staphylococcal toxins in these models. [ABSTRACT FROM AUTHOR]

Bacillus cereus (B. cereus) endophthalmitis is a vision-threatening bacterial infection. Uncontrolled inflammatory responses are the hallmark of this disease which cause irreversible damage to the retina. We recently reported C-X-C chemokines as a vital modulators which impacted the pathogenesis of this disease. Here, we investigated the impact of two highly upregulated C–C chemokines, CCL2 and CCL3, on intraocular inflammation this disease. B. cereus was injected into the eyes of C57BL/6J (WT), CCL2−/−, and CCL3−/− mice to induce endophthalmitis. Infected eyes were examined for bacterial growth, retinal function, and inflammation. Bacterial growth in CCL2−/− and CCL3−/− mice were similar, but retained retinal function was greater in CCL2−/− and CCL3−/− eyes compared to that of C57BL/6J eyes. The retinal architecture of infected eyes of CCL2−/− mice were conserved for a longer period of time than in infected CCL3−/− eyes. Infected CCL2−/− and CCL3−/− eyes had less inflammation than did infected C57BL/6J eyes. Based on these results, we assessed the efficacies of intravitreal anti-CCL2 or anti-CCL3 with or without the antibiotic gatifloxacin. Compared to infected untreated eyes, there was significantly less inflammation and greater retention of retinal function in eyes treated with anti-CCL2 or anti-CCL3 with gatifloxacin. This study showed that B. cereus endophthalmitis in CCL2−/− mice had a better clinical outcome than in CCL3−/− mice. Intravitreal administration of anti-CCL2 and anti-CCL3 with gatifloxacin significantly reduced inflammation and provided protection of retinal function. These results suggest that CCL2 and CCL3 are prospective anti-inflammatory targets that should be tested along with other antibiotics for treating Bacillus and perhaps other forms of endophthalmitis. • Bacillus endophthalmitis is the most severe form of bacterial eye infection. • Chemokines contribute significantly to the pathogenesis of Bacillus endophthalmitis. • Absence of CCL2 or CCL3 protected the eye from retinal function loss and inflammation during Bacillus endophthalmitis. • Compared to the absence of CCL3, the absence of CCL2 provided prolonged protection during Bacillus endophthalmitis. • CCL2 or anti-CCL3 and an antibiotic resulted in an improved clinical outcome. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]