Abstract: TH-OR07
Spatial Multi-Omic Atlas of Pyelonephritis
Session Information
- AKI Mechanisms: Cellular and Organ Cross-Talk
November 02, 2023 | Location: Room 118, Pennsylvania Convention Center
Abstract Time: 05:24 PM - 05:33 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Wang, Xin, Nationwide Children's Hospital, Columbus, Ohio, United States
- Cotzomi Ortega, Israel, Nationwide Children's Hospital, Columbus, Ohio, United States
- Sanchez-Zamora, Yuriko I., Nationwide Children's Hospital, Columbus, Ohio, United States
- Patel, Rishil H., Nationwide Children's Hospital, Columbus, Ohio, United States
- Kercsmar, Macie M., Nationwide Children's Hospital, Columbus, Ohio, United States
- Jackson, Ashley R., Nationwide Children's Hospital, Columbus, Ohio, United States
- Spencer, John David, Nationwide Children's Hospital, Columbus, Ohio, United States
- Becknell, Brian, Nationwide Children's Hospital, Columbus, Ohio, United States
- Ruiz-Rosado, Juan de Dios, Nationwide Children's Hospital, Columbus, Ohio, United States
Background
Pyelonephritis (PN) causes renal injury, inflammation, and scarring. Over 80% of PN episodes are due to uropathogenic Escherichia coli (UPEC). The molecular mechanisms of acute kidney injury and renal fibrosis in PN patients are poorly understood, hindering the development of effective therapies.
Methods
We infected female C3H/HeOuJ mice via transurethral inoculation with UPEC. Spatial transcriptomics (ST, Visium 10x genomics) and PIPseqTM single-cell RNA-seq were performed on kidney samples at multiple time points (0, 1, 3, 5, 7, and 28 days post infection). The integrative analysis encompassed pathological evaluation, cell type annotation, spatial deconvolution, differential gene expression, cell-cell communication, pseudotime inference, and signaling pathway exploration, aiming to unravel the dynamic structural and molecular changes during PN.
Results
We characterized 20,831 spatial spots with deconvoluted cell-type compositions at six timepoints. We profiled 40,224 single cells representing 18 major cell types and identified infected proximal tubule cells with distinct cell-cycle and key signaling states. Integration of these multi-modal datasets revealed two distinct clustering structures of tissue abscesses that were specific to the infection and associated with fibrotic injury, repair, and remodeling. These abscess structures exhibited increased levels of colocalization between leukocytes, fibroblasts, and endothelial cells after infection, along with activations in leukocyte migration and proliferation, T cell activation, TNF-α signaling, and cell-cell adhesion. Signaling analyses unveiled unique spatial dependencies in hypoxia, apoptosis, proinflammatory responses, profibrotic and proliferative processes. The marginal regions of the renal abscess displayed dramatically increased activation in NF-κB, TNF-α, EGFR, and P53 signaling pathways, but decreased Stat1 and Wnt pathway activity.
Conclusion
Our study provides an integrative map of the spatial gene expression and gene-regulation networks involved in maintaining kidney homeostasis and immune responses during PN. We believe our findings will contribute to the advancement of mechanistic insights and potential therapeutic strategies to treat PN.
Funding
- NIDDK Support