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Retinal scRNAseq revelas cell-type-specific responses to bacterial infection

ABSTRACT: Purpose: Endophthalmitis is a serious complication of intraocular surgery due to the risk of irreversible retinal damage. The heterogeneity of retinal cells necessitates analysis at the single-cell level to uncover the detailed mechanisms of infection response. Using a mouse model of bacterial endophthalmitis, we investigated the affected pathways of resident and infiltrating cell types in the retina. Methods: A methicillin-sensitive strain of Staphylococcus aureus was isolated from a patient with endophthalmitis. Adult C57Bl/6J mice received an intravitreal injection of phosphate-buffer solution (PBS) with or without 5000 CFU S. aureus (n=3 per group). 24 hours later, retinas were isolated and single-cell suspensions were sent to the Penn Genomic Core for sequencing with an Illumina NovaSeq 6000. After standard pre-processing of the data, differential genes and pathways were identified for each cell type (adjusted p < 0.01, log2FC > 1 or < -1). Results: Our analysis identified all expected retinal cell types, including a population of infiltrating neutrophils in the infected group. We surveyed genes known to be upregulated at the bulk-retina level in this model (e.g. Tlr2, Nlrp3, Il1b), and found that infiltrating cells mainly drove this expression. A few genes changed across almost all cell types, including upregulation of Hsph1 and Stat3. Muller glia downregulated Gpx4 while upregulating Acsl4 and iron importers Tfrc, Zip14, and Dmt1. Top pathways for macrophages/microglia included chemotaxis, cell-cell adhesion, and wound healing. Vascular cells upregulated angiogenesis-related genes. Cellular respiration was a commonly affected pathway across several neuronal populations, with most genes decreasing. Conclusions: This study sought to advance our understanding of the pathobiology of bacterial endophthalmitis. Muller glia appear to be undergoing ferroptosis, potentially while activating a program to sequester iron away from bacteria. Decreased cellular respiration may indicate hypoxia among neurons. Our results reveal several trends in the retinal response to infection, including iron dysregulation and hypoxia. Understanding these cell-type-specific responses to endophthalmitis may help design therapies to combine with antibiotics.

ORGANISM(S): Mus musculus

PROVIDER: GSE331198 | GEO | 2026/05/21

REPOSITORIES: GEO

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Project description:Unlike mammals, zebrafish possess a remarkable capacity to regenerate ablated retinal neurons. In response to cellular injury and death, Müller glia dedifferentiate into a stem cell state, and each gives rise to a single Müller glia-derived progenitor. Progenitors then proliferate and differentiate into to replace the ablated retinal neurons. This study aimed to determine if the injury context influences the quantity of regenerated neurons and to comprehensively identify the cellular and molecular characteristics and diversity of newly born regenerated neurons during regenerative neurogenesis. To definitely label Muller glia-derived regenerated neurons, we utilized a genetic lineage tracing line, Tg(mmp9:creERt2;Ola.actb2:loxp-dsRed-loxp-eGFP). By integrating this approach with scRNAseq and morphological profiling, we characterize quantity, molecular and morphological identity, and diversity of regenerated neurons across two distinct injury models, an intense light photolytic lesion or an intraocular injection of the excitotoxin, NMDA which procedures selective damage to photoreceptors or inner retinal neurons, respectively. Our data show that while regenerated neurons are biased toward the cell type originally ablated, both lesion modes consistently generate other cell types. This suggests a robust intrinsic neurogenic program present among Muller glia-derived progenitors. Transcriptome analysis demonstrates a high degree of similarity between regenerated and endogenous populations, indicating successful restoration of homeostatic molecular signitures. Finally, subtype analysis of amacrine cells show generation of diverse subtype and successful reestablishment of their neurochemical and morphological identities equivalent to their original counterparts. These findings demonstrate that regenerative neurogenesis in the zebrafish retina can faithfully reconstitute the specialized cellular diversity and molecular and structural complexity of the mature retina.

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Retinal scRNAseq revelas cell-type-specific responses to bacterial infection

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