Horizontal gene transfer introduces foreign DNA that can disrupt cellular processes and is therefore subject to xenogeneic silencing by nucleoid-associated proteins such as H-NS and Hha. In Enterohaemorrhagic Escherichia coli (EHEC), prophages make up a large fraction of the accessory genome and encode many virulence factors, yet their expression must overcome this silencing. We identify a prophage-encoded small RNA (sRNA), HnrS, that functions as an anti-silencing factor by targeting the H-NS paralogue Hha. HnrS is a short (66-nt) sRNA that is enriched in the locus of enterocyte effacement (LEE⁺) E. coli strains and present in up to nine copies in EHEC and Enteropathogenic Escherichia coli (EPEC) genomes. HnrS base-pairs with the hha ribosome-binding site to inhibit translation, thereby modulating Hha–H-NS repression of virulence loci including the LEE type III secretion system. Loss of HnrS alters motility, T3SS expression, and a subset of Hha-regulated genes. These findings reveal an RNA-based counter-silencing strategy encoded by prophage to relieve xenogenic silencing.
Pranita Poudyal, Brandon M. Sy, Daniel G. Mediati et al.· PLoS Pathogens· 0 citations
ABSTRACT Cystic fibrosis (CF) has shifted from a fatal paediatric lung disease to a multi‐organ, lifespan‐spanning disorder in which gastrointestinal (GI) complications and malignancies are increasingly prominent. With improved survival into mid‐ and late adulthood, aided by newborn screening, optimised nutrition and the advent of highly effective CF transmembrane conductance regulator (CFTR) modulators, implementation of colonoscopic surveillance has highlighted a several‐fold increase in early‐onset colorectal cancer (CRC) and a broader spectrum of intestinal pathology. In parallel, work in mouse models, human tissue and patient‐derived intestinal organoids now places the CFTR at the centre of a complex epithelial compartment that integrates ion and pH homeostasis, mucus biology, microbiota, redox balance and immune/stromal function. In this review, we advance the hypothesis that CF may be conceptualised as a niche‐centric hereditary CRC predisposition syndrome, in which germline CFTR dysfunction chronically destabilises epithelial identity in addition to increasing mutational burden. We synthesise evidence that CFTR loss remodels stem cell regulation, promotes hypoxia and oxidative stress, perturbs microbial ecosystems, drives chronic immune activation and stromal remodelling, and induces epithelial–mesenchymal plasticity (EMP) and DNA‐damage vulnerability, collectively creating a pre‐neoplastic intestinal ecosystem. We situate this model within contemporary CRC frameworks that emphasise cell‐state transitions, hybrid epithelial–mesenchymal (E/M) states and specialised stromal niches, and we distinguish it from oncofoetal reprogramming, an APC‐driven programme that CF does not clearly recapitulate. We propose that CF may provide a naturally occurring human context in which chronic epithelial stress sustains EMP‐like pressure, a concept that requires direct validation in human CF intestinal tissue. Finally, we consider how CFTR modulators, microbiome‐directed therapies and redox‐targeted interventions might re‐programme the CF intestinal niche and outline experimental and clinical strategies needed to determine whether early, ecosystem‐level correction can prevent GI cancers in this high‐risk population.
Bala Umashankar, Ines Pankonien, Margarida D. Amaral et al.· Cell Proliferation· 0 citations
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