kexB Gene Correlates With Aspergillus flavus Keratitis Severity: A Whole-Genome Analysis
Jiamin Liu1, Min Kang1, Yuan Wei1
1Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing, China.
Purpose:
Fungal keratitis caused by Aspergillus flavus (A. flavus) can result in severe inflammation and corneal stromal melting, leading to visual impairment. This study aimed to identify virulent genes correlated with the severity of A. flavus keratitis using whole-genome sequencing.
Methods:
Whole-genome sequencing of 21 clinical A. flavus strains from cornea was performed to elucidate the pathogenesis of A. flavus in infectious keratitis, followed by pan-genome analysis and virulence analysis. To further understand the results from the previous analyses, growth phenotypes and virulence effect of mutant strains were validated experimentally, including the spore counting, growth pattern under different conditions, and clinical and pathological evaluation of A. flavus keratitis in mice models.
Results:
The A. flavus pan-genome was composed of 17,326 gene clusters with a core genome of 5378 (31.0% of the pan-genome) orthogroups in all 21 isolates. Virulence gene analysis revealed 183 genes contributing to A. flavus pathogenesis and mutation of the kexB gene was associated with the severity of keratitis. The kexB mutant (ΔkexB) strains showed significantly reduced conidia formation and lower growth rates in the presence of the cell-wall perturbing agents. Further, the mice models validated that clinical score, and corneal perforation rates significantly decreased in the group infected by ΔkexB strains. Infiltration of immune cells, gene expression of cytokines, and matrix metalloproteinase (MMP) were also decreased in the mutant group.
Conclusions:
The role of kexB gene in A. flavus keratitis was identified through whole-genome sequencing. Its mutation impairs conidia formation, cell wall integrity, and invasion, leading to milder clinical symptoms.
Insights
Whole-genome sequencing identified the kexB gene as crucial for Aspergillus flavus virulence in fungal keratitis. Mutations in kexB significantly reduced disease severity and corneal damage in mouse models.
Area of Science:
- Ophthalmology
- Mycology
- Genomics
Background:
- Fungal keratitis, particularly from Aspergillus flavus, causes severe inflammation and corneal melting, leading to vision loss.
- Understanding the genetic basis of Aspergillus flavus pathogenicity is crucial for developing targeted therapies.
Purpose of the Study:
- To identify genes associated with the severity of Aspergillus flavus keratitis using whole-genome sequencing.
- To elucidate the role of specific genes in the pathogenesis of fungal keratitis.
Main Methods:
- Whole-genome sequencing of 21 clinical Aspergillus flavus isolates from corneal infections.
- Pan-genome and virulence gene analysis.
- Experimental validation of mutant strains' phenotypes and virulence in mouse models of keratitis.
Main Results:
- The Aspergillus flavus pan-genome comprises 17,326 gene clusters, with 5,378 core orthogroups.
- 183 virulence genes were identified; mutation of the kexB gene significantly reduced conidia formation and growth.
- Mice infected with kexB mutant strains showed decreased clinical scores, corneal perforation rates, immune cell infiltration, and matrix metalloproteinase expression.
Conclusions:
- Whole-genome sequencing identified the kexB gene's critical role in Aspergillus flavus virulence.
- kexB mutation impairs conidia formation, cell wall integrity, and invasion, resulting in attenuated keratitis.
- Targeting kexB may offer a therapeutic strategy for Aspergillus flavus fungal keratitis.
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