Oxidative Stress Initiates Receptor-Interacting Protein Kinase-3/Mixed Lineage Kinase Domain-Like–Mediated Corneal Epithelial Necroptosis and Nucleotide-Binding Oligomerization Domain–Like Receptor Protein 3 Inflammasome Signaling during Fungal Keratitis

Wang, Bowen; Yang, Xue; Zuo, Xi‐Nian; Zeng, Hanmin; Wang, Xiaoran; Huang, Huaxing; He, Dalian; Wang, Li; Ouyang, Hong; Yuan, Jingjie

doi:10.1016/j.ajpath.2023.04.004

Cited by 3 publications

(2 citation statements)

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“…In our topical model, for example, we observed that the epithelial ulcer fails to reform in infected corneas, whereas it does so by 24 h in sham-inoculated controls ( Figure 1 and data not shown). While direct fungal-mediated damage to the epithelial cells cannot be ruled out as a primary cause of this phenomenon, previous studies have shown that hypoxia decreases the proliferation rate of the basal epithelial cell layer and causes delay in epithelial wound healing 54,55 . Several mechanisms may account for this, including the hypoxia-mediated activation of the polo-like-kinase 3 (Plk3) leading to cell-cycle arrest, as well as a disruption of Ca 2+ signaling from corneal nerves to epithelial cells 38,39 .…”

Section: Discussionmentioning

confidence: 99%

Aspergillus fumigatushypoxia adaptation is critical for the establishment of fungal keratitis

Lightfoot,

Adams,

Kamath

et al. 2023

Preprint

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Purpose: The poor visual outcomes associated with fungal keratitis (FK) underscore a need to identify fungal pathways that can serve as novel antifungal targets. In this report, we investigated whether hypoxia develops in the FK cornea and, by extension, if fungal hypoxia adaptation is essential for virulence in this setting. Methods: C57BL/6j mice were inoculated withAspergillus fumigatusandFusarium solanivarpetroliphilumvia topical overlay or instrastromal injection. At various time points post-inoculation (p.i.), animals we were injected with pimonidazole for the detection of tissue hypoxia through immunofluorescence imaging. TheA. fumigatus srbAgene was deleted through Cas9-mediated homologous recombination and its virulence was assessed in the topical infection model using slit-lamp microscopy and optical coherence tomography (OCT). Results: Topical inoculation withA. fumigatusresulted in diffuse pimonidazole staining across the epithelial and endothelial layers within 6 h. Stromal hypoxia was evident by 48 h p.i., which corresponded to leukocytic infiltration. Instrastromal inoculation with eitherA. fumigatusorF. solanisimilarly led to diffuse staining patterns across all corneal cell layers. TheA. fumigatus srbAdeletion mutant was unable to grow at oxygen levels below 3%in vitro,and corneas inoculated with the mutant failed to develop signs of corneal opacification, inflammation or fungal burden. Conclusions: These results suggest that fungal antigen rapidly drives the development of corneal hypoxia, thus rendering fungal SrbA or related pathways essential for the establishment of infection. Such pathways may therefore serve as targets for novel antifungal intervention.

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Section: Discussionmentioning

confidence: 99%

Aspergillus fumigatushypoxia adaptation is critical for the establishment of fungal keratitis

Lightfoot,

Adams,

Kamath

et al. 2023

Preprint

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show abstract

“…Although direct fungal-mediated damage to the epithelial cells cannot be ruled out as a primary cause of this phenomenon, previous studies have shown that hypoxia decreases the proliferation rate of the basal epithelial cell layer and causes delay in epithelial wound healing. 66 , 67 Several mechanisms may account for this, including the hypoxia-mediated activation of the polo-like-kinase 3 (Plk3) leading to cell-cycle arrest, as well as a disruption of Ca 2+ signaling from corneal nerves to epithelial cells. 52 , 53 As epithelial ulcers also develop in later stages of our intrastromal model as well as in patients with FK, we suggest this may be initiated or exacerbated by the influence of hypoxia on epithelial cell biology.…”

Section: Discussionmentioning

confidence: 99%

Aspergillus fumigatus Hypoxia Adaptation Is Critical for the Establishment of Fungal Keratitis

Lightfoot,

Adams,

Kamath

et al. 2024

Invest. Ophthalmol. Vis. Sci.

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Purpose The poor visual outcomes associated with fungal keratitis (FK) underscore a need to identify fungal pathways that can serve as novel antifungal targets. In this report, we investigated whether hypoxia develops in the FK cornea and, by extension, if fungal hypoxia adaptation is essential for virulence in this setting. Methods C57BL/6J mice were inoculated with Aspergillus fumigatus and Fusarium solani var. petroliphilum via topical overlay or intrastromal injection. At various time points post-inoculation (p.i.), animals were injected with pimonidazole for the detection of tissue hypoxia through immunofluorescence imaging. The A. fumigatus srbA gene was deleted through Cas9-mediated homologous recombination and its virulence was assessed in the topical infection model using slit-lamp microscopy and optical coherence tomography (OCT). Results Topical inoculation with A. fumigatus resulted in diffuse pimonidazole staining across the epithelial and endothelial layers within 6 hours. Stromal hypoxia was evident by 48 hours p.i., which corresponded to leukocytic infiltration. Intrastromal inoculation with either A. fumigatus or F. solani similarly led to diffuse staining patterns across all corneal cell layers. The A. fumigatus srbA deletion mutant was unable to grow at oxygen levels below 3% in vitro, and corneas inoculated with the mutant failed to develop signs of corneal opacification, inflammation, or fungal burden. Conclusions These results suggest that fungal antigen rapidly drives the development of corneal hypoxia, thus rendering fungal SrbA or related pathways essential for the establishment of infection. Such pathways may therefore serve as targets for novel antifungal intervention.

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Hydrogen sulfide regulates macrophage polarization and necroptosis to accelerate diabetic skin wound healing

He,

Zhu,

et al. 2024

International Immunopharmacology

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Oxidative Stress Initiates Receptor-Interacting Protein Kinase-3/Mixed Lineage Kinase Domain-Like–Mediated Corneal Epithelial Necroptosis and Nucleotide-Binding Oligomerization Domain–Like Receptor Protein 3 Inflammasome Signaling during Fungal Keratitis

Cited by 3 publications

References 54 publications

Aspergillus fumigatushypoxia adaptation is critical for the establishment of fungal keratitis

Aspergillus fumigatushypoxia adaptation is critical for the establishment of fungal keratitis

Aspergillus fumigatus Hypoxia Adaptation Is Critical for the Establishment of Fungal Keratitis

Hydrogen sulfide regulates macrophage polarization and necroptosis to accelerate diabetic skin wound healing

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