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Published on: January 13, 2016
Time-Course Transcriptomic Analysis Reveals the Crucial Roles of PANoptosis in Fungal Keratitis
Xizhan Xu1, Yuan Wei1, Jinding Pang1
1Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
Purpose:
Fungal keratitis (FK) is a serious corneal infection with high morbidity. Host immune responses function as a double-edged sword by eradicating fungal pathogens while also causing corneal damage, dictating the severity, progression, and outcome of FK. However, the underlying immunopathogenesis remains elusive.
Methods:
Time-course transcriptome was performed to illustrate the dynamic immune landscape in a mouse model of FK. Integrated bioinformatic analyses included identification of differentially expressed genes, time series clustering, Gene Ontology enrichment, and inference of infiltrating immune cells. Gene expression was verified by quantitative polymerase chain reaction (qPCR), Western blot, or immunohistochemistry.
Results:
FK mice exhibited dynamic immune responses with concerted trends with clinical score, transcriptional alteration, and immune cell infiltration score peaking at 3 days post infection (dpi). Disrupted substrate metabolism, broad immune activation, and corneal wound healing occurred sequentially in early, middle, and late stages of FK. Meanwhile, dynamics of infiltrating innate and adaptive immune cells displayed distinct characteristics. Proportions of dendritic cells showed overall decreasing trend with fungal infection, whereas that of macrophages, monocytes, and neutrophils rose sharply in early stage and then gradually decreased as inflammation resolved. Activation of adaptive immune cells was also observed in late stage of infection. Furthermore, shared immune responses and activation of AIM2-, pyrin-, and ZBP1-mediated PANoptosis were revealed across different time points.
Conclusions:
Our study profiles the dynamic immune landscape and highlights the crucial roles of PANoptosis in FK pathogenesis. These findings provide novel insights into host responses to fungi and contribute to the development of PANoptosis-targeted therapeutics for patients with FK.
Insights
This study reveals dynamic immune responses in fungal keratitis (FK), highlighting PANoptosis as key to disease development. These findings offer new therapeutic targets for FK patients.
Area of Science:
- Ophthalmology
- Immunology
- Microbiology
Background:
- Fungal keratitis (FK) is a severe corneal infection with significant morbidity.
- Host immune responses are critical in FK pathogenesis but can also cause corneal damage.
- The precise immunopathogenesis of FK remains incompletely understood.
Purpose of the Study:
- To elucidate the dynamic immune landscape during fungal keratitis (FK) progression.
- To identify key immune pathways and cell types involved in FK pathogenesis.
- To explore the role of PANoptosis in FK.
Main Methods:
- Time-course transcriptome analysis in a mouse model of FK.
- Integrated bioinformatic analyses including gene expression, clustering, and pathway enrichment.
- Validation of gene expression using qPCR, Western blot, and immunohistochemistry.
Main Results:
- Dynamic immune responses in FK correlated with clinical scores and immune cell infiltration, peaking at 3 days post-infection.
- Sequential changes in metabolism, immune activation, and wound healing were observed.
- Distinct dynamics of innate and adaptive immune cells, including macrophages, monocytes, neutrophils, and dendritic cells, were identified.
- Shared immune responses and activation of AIM2-, pyrin-, and ZBP1-mediated PANoptosis were revealed.
Conclusions:
- This study provides a comprehensive profile of the dynamic immune landscape in FK.
- PANoptosis plays a crucial role in the pathogenesis of fungal keratitis.
- Findings offer novel insights into host-pathogen interactions and potential therapeutic strategies targeting PANoptosis for FK.
