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3. Disarming Pore-Forming Toxins with Biomimetic Nanosponges in Intraocular Infections

Author

Coburn, Phillip S, Miller, Frederick C, LaGrow, Austin L, Land, Craig, Mursalin, Huzzatul, Livingston, Erin, Amayem, Omar, Chen, Yijie, Gao, Weiwei, Zhang, Liangfang, and Callegan, Michelle C

Subjects
Antimicrobial Resistance, Eye Disease and Disorders of Vision, Bioengineering, Infectious Diseases, Emerging Infectious Diseases, Nanotechnology, 2.1 Biological and endogenous factors, Aetiology, Eye, Infection, Animals, Bacterial Toxins, Biomimetic Materials, Erythrocytes, Eye Infections, Bacterial, Gatifloxacin, Gram-Positive Bacterial Infections, Methicillin-Resistant Staphylococcus aureus, Mice, Mice, Inbred C57BL, Nanostructures, Polylactic Acid-Polyglycolic Acid Copolymer, Polymers, Rabbits, Staphylococcal Infections, Staphylococcus aureus, antibiotic, endophthalmitis, eye, infection, nanoparticle, Immunology, Microbiology
Abstract

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.

Published
2019

6. Virulence-related genotypic differences among Bacillus cereus ocular and gastrointestinal isolates and the relationship to endophthalmitis pathogenesis.

Author

Coburn, Phillip S., Miller, Frederick C., LaGrow, Austin L., Mursalin, Huzzatul, Gregory, Anna, Parrott, Aaron, Astley, Daniel, and Callegan, Michelle C.

Subjects
BACILLUS cereus, ENDOPHTHALMITIS, GENOTYPES, PATHOGENESIS, ELECTRORETINOGRAPHY
Abstract

Background: Bacillus cereus (Bc) can cause self-limiting gastrointestinal infections, but when infecting the eye, can cause rapid and irreversible blindness. This study investigated whether clinical ocular and gastrointestinal Bc isolates differed in terms of virulence-related genotypes and endophthalmitis virulence. Methods: Twenty-eight Bc ocular, gastrointestinal, and laboratory reference isolates were evaluated. Hemolysis assays were performed to assess potential differences in hemolytic activity. The presence of twenty Bc virulence-related genes was assessed by PCR. A subset of ocular and gastrointestinal isolates differing in PCR positivity for 5 virulence genes was compared to strain ATCC14579 in an experimental murine model of endophthalmitis. At 8 hours post infection, retinal function was evaluated by electroretinography, and intraocular bacterial concentrations were determined by plate counts. Results: Gastrointestinal Bc isolates were more hemolytic than the Bc ocular isolates and ATCC14579 (p < 0.0001). Bc ocular isolates were more frequently PCR-positive for capK, cytK, hblA, hblC, and plcR compared to the gastrointestinal isolates (p ≤ 0.0002). In the endophthalmitis model, mean Awave retention did not differ significantly between eyes infected with ATCC14579 and eyes infected with the selected ocular or gastrointestinal isolates (p ≥ 0.3528). Similar results were observed for mean B-wave retention (p ≥ 0.0640). Only one diarrheal isolate showed significantly greater B-wave retention when compared to ATCC14579 (p = 0.0303). No significant differences in mean A-wave (p ≥ 0.1535) or B-wave (p ≥ 0.0727) retention between the selected ocular and gastrointestinal isolates were observed. Intraocular concentrations of ATCC14579 were significantly higher than the selected ocular isolate and 3 of the gastrointestinal isolates (p ≤ 0.0303). Intraocular concentrations of the selected ocular isolate were not significantly different from the gastrointestinal isolates (p ≥ 0.1923). Conclusions: Among the subset of virulence-related genes assessed, 5 were significantly enriched among the ocular isolates compared to gastrointestinal isolates. While hemolytic activity was higher among gastrointestinal isolates, retinal function retention and intraocular growth was not significantly different between the selected ocular and gastrointestinal isolates. These results suggest that Bc strains causing gastrointestinal infections, while differing from ocular isolates in hemolytic activity and virulence-related gene profile, are similarly virulent in endophthalmitis. [ABSTRACT FROM AUTHOR]

Published
2023
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8. T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

Author

Napier, Ruth J., Lee, Ellen J., Davey, Michael P., Vance, Emily E., Furtado, João M., Snow, Paige E., Samson, Kimberly A., Lashley, Sydney J., Brown, Brieanna R., Horai, Reiko, Mattapallil, Mary J., Xu, Biying, Callegan, Michelle C., Uebelhoer, Luke S., Lancioni, Christina L., Vehe, Richard K., Binstadt, Bryce A., Smith, Justine R., Caspi, Rachel R., and Rosenzweig, Holly L.

Published
2020
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17. The Bacillus virulome in endophthalmitis

Author

Coburn, Phillip S., primary, Miller, Frederick C., additional, Enty, Morgan A., additional, Land, Craig, additional, LaGrow, Austin L., additional, Mursalin, Md Huzzatul, additional, and Callegan, Michelle C., additional

Published
2021
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25. The Bacillus Virulome in Endophthalmitis

Author

Coburn, Phillip S., primary, Miller, Frederick C., additional, Enty, Morgan A., additional, Land, Craig, additional, LaGrow, Austin L., additional, Mursalin, Md Huzzatul, additional, and Callegan, Michelle C., additional

Published
2020
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41. The role of pili in Bacillus cereus intraocular infection

Author

Callegan, Michelle C., primary, Parkunan, Salai Madhumathi, additional, Randall, C. Blake, additional, Coburn, Phillip S., additional, Miller, Frederick C., additional, LaGrow, Austin L., additional, Astley, Roger A., additional, Land, Craig, additional, Oh, So-Young, additional, and Schneewind, Olaf, additional

Published
2017
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46. Endophthalmitis

Author

Coburn, Phillip S. and Callegan, Michelle C.

Subjects
genetic structures, eye diseases
Published
2012

47. Caveolin-1 Increases Proinflammatory Chemoattractants and Blood–Retinal Barrier Breakdown but Decreases Leukocyte Recruitment in Inflammation

Author

Li, Xiaoman, primary, Gu, Xiaowu, additional, Boyce, Timothy M., additional, Zheng, Min, additional, Reagan, Alaina M., additional, Qi, Hui, additional, Mandal, Nawajes, additional, Cohen, Alex W., additional, Callegan, Michelle C., additional, Carr, Daniel J. J., additional, and Elliott, Michael H., additional

Published
2014
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