Shigella species are human-adapted bacterial pathogens that evade innate and adaptive immunity to invade the colonic mucosa. We analyzed colonic biopsies, stool, and blood from Shigella-infected patients during acute disease and 60 days post-infection using tissue transcriptomics, spatial proteomics, spectral flow cytometry, and serologic profiling.
Acute infection was characterized by elevated inflammatory biomarkers, including plasma myeloperoxidase and fecal calprotectin. Circulating RORγt⁺ myeloid subsets were expanded during acute disease, consistent with type-17 polarization and activation of barrier defense. Colonic transcriptional profiling reflected broad induction of IL-17–responsive genes mediating neutrophil recruitment (CXCL8, CXCL1, CXCL2, CXCL5, CSF3), antimicrobial defense (REG1A, REG1B, REG3A, LCN2, S100A8/A9, DEFB4A, DUOX2, DUOXA2), and matrix remodeling (MMP1, MMP3, MMP9, COL4A1, COL7A1, TIMP1). Cytokine signaling pathways (IL11, IL33, IL23A, PTGS2, ICAM1) were also enriched, defining a robust mucosal type-17 response. Gene-set enrichment further identified strong enrichment of E2F and MYC target pathways, and a coordinated shift from metabolic and oxidative functions to DNA synthesis and proliferation.
Spatial proteomics localized these processes to distinct tissue compartments: the lamina propria showed increased antigen presentation and apoptosis (HLA-A, HLA-F, Caspase-3/10, p53), while epithelial cells induced canonical E2F-regulated proteins involved in DNA-damage responses (ATM, MDM2, SIRT1), cell-cycle and translational control (CDK1/2/3, RPS6, UBE2C, HDAC1/2), and tissue remodeling (Fibronectin, Caveolin-1).Together, these findings define a spatially resolved axis linking IL-17-mediated barrier responses to proliferative regeneration and DNA repair driven by E2F. This integrative multi-omic framework provides new insight into Shigella pathogenesis and identifies host pathways linking immune activation, epithelial damage, mucosal remodeling, and tissue repair in human shigellosis.