The cereus matter of Bacillus endophthalmitis

Summary The eye is highly susceptible to inflammation-mediated tissue damage evoked during bacterial infection. However, mechanisms regulating inflammation to protect the eye remain elusive. Here, we used integrated metabolomics and transcriptomics to show that the immunomodulatory metabolite itaconate and immune-responsive gene 1 (Irg1) are induced in bacterial (Staphylococcus aureus)-infected mouse eyes, bone-marrow-derived macrophages (BMDMs), and Muller glia. Itaconate levels are also elevated in the vitreous of patients with bacterial endophthalmitis. Irg1 deficiency in mice led to increased ocular pathology. Conversely, intraocular administration of itaconate protects both Irg1−/− and wild-type mice from bacterial endophthalmitis by reducing inflammation, bacterial burden, and preserving retinal architecture and visual function. Notably, itaconate exerts synergistic effects with antibiotics. The protective, anti-inflammatory effects of itaconate are mediated via activation of NRF2/HO-1 signaling and inhibition of NLRP3 inflammasome. Collectively, our study demonstrates the Irg1/itaconate axis is a regulator of intraocular inflammation and provides evidence for using itaconate, along with antibiotics, to treat bacterial infections.

Integrative metabolomics and transcriptomics identifies itaconate as an adjunct therapy to treat ocular bacterial infection.

Bacterial endophthalmitis (BE) is an acute eye infection and potentially irreversible blinding ocular disease. The empirical intravitreous injection of antibiotic is the primary treatment once diagnosed as BE. However, the overuse of antibiotic contributes to the drug resistance of pathogens and the retinal toxicity of antibiotic limits its application in clinic. Herein, a cationic aggregation-induced emission luminogens named with triphenylamine thiophen pyridinium (TTPy) is reported for photodynamic treatment of BE. TTPy can selectively discriminate and kill bacteria efficiently over normal ocular cells. More importantly, TTPy shows excellent antibacterial ability in BE rat models infected by Staphylococcus aureus. Meanwhile, the bacterial killing behavior triggered by TTPy induces innate immune response at an early stage of infection, limiting subsequent robust inflammation and protecting retina from bacterial toxins and inflammation-induced bystander damage. In addition, TTPy performs better antibacterial ability than commercially used Rose Bengal, suggesting its excellent capability of vision salvage in acute BE. This study exhibits an efficient photodynamic antibacterial treatment to BE, which induces an early intraocular immune response and saves useful vision, endowing TTPy a promising potential for clinical application of ocular infections. 

Vision Defense: Efficient Antibacterial AIEgens Induced Early Immune Response for Bacterial Endophthalmitis

Bacillus endophthalmitis is a severe intraocular infection. Hallmarks of Bacillus endophthalmitis include robust inflammation and rapid loss of vision. We reported that the absence of Bacillus surface layer protein (SLP) significantly blunted endophthalmitis severity. Here, we further investigated SLP in the context of Bacillus-retinal cell interactions and innate immune pathways to explore the mechanisms by which SLP contributes to intraocular inflammation. We compared phenotypes of Wild-type (WT) and SLP deficient (ΔslpA) Bacillus thuringiensis by analyzing bacterial adherence to and phagocytosis by human retinal Muller cells and phagocytosis by mouse neutrophils. Innate immune receptor activation by the Bacillus envelope and purified SLP was analyzed using TLR2/4 reporter cell lines. A synthetic TLR2/4 inhibitor was used as a control for this receptor activation. To induce endophthalmitis, mouse eyes were injected intravitreally with 100 CFU WT or ΔslpA B. thuringiensis. A group of WT infected mice was treated intravitreally with a TLR2/4 inhibitor at 4 h postinfection. At 10 h postinfection, infected eyes were analyzed for viable bacteria, inflammation, and retinal function. We observed that B. thuringiensis SLPs contributed to retinal Muller cell adherence, and protected this pathogen from Muller cell- and neutrophil-mediated phagocytosis. We found that B. thuringiensis envelope activated TLR2 and, surprisingly, TLR4, suggesting the presence of a surface-associated TLR4 agonist in Bacillus. Further investigation showed that purified SLP from B. thuringiensis activated TLR4, as well as TLR2 in vitro. Growth of WT B. thuringiensis was significantly higher and caused greater inflammation in untreated eyes than in eyes treated with the TLR2/4 inhibitor. Retinal function analysis also showed greater retention of A-wave and B-wave function in infected eyes treated with the TLR2/4 inhibitor. The TLR2/4 inhibitor was not antibacterial in vitro, and did not cause inflammation when injected into uninfected eyes. Taken together, these results suggest a potential role for Bacillus SLP in host-bacterial interactions, as well as in endophthalmitis pathogenesis via TLR2- and TLR4-mediated pathways.

/pdf/bacillus-s-layer-mediated-innate-interactions-during-529k79krs6.pdf

Bacillus S-Layer-Mediated Innate Interactions During Endophthalmitis.

Development of a dual delivery of levofloxacin and prednisolone acetate via PLGA nanoparticles/ thermosensitive chitosan-based hydrogel for postoperative management: An in-vitro and ex-vivo study.

Targets of immunomodulation in bacterial endophthalmitis.

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Targets of immunomodulation in bacterial endophthalmitis.