Three Orphan Histidine Kinases Inhibit Clostridioides difficile Sporulation

Edwards, Adrianne N.; Wetzel, Daniela; DiCandia, Michael A; McBride, Shonna M.

doi:10.1128/jb.00106-22

Cited by 19 publications

(37 citation statements)

References 67 publications

(93 reference statements)

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“…Unlike B. subtilis, C. difficile does not encode an apparent intermediate phosphorelay system 8 . Although three putative sensor histidine kinases (PtpA-C) have been described to directly influence Spo0A phosphorylation, the overall process of Spo0A activation remains barely understood and points towards additional unknown mechanisms regulating Spo0A activity in C. difficile 8,52,53 .…”

Section: Discussionmentioning

confidence: 99%

A network of small RNAs regulates sporulation initiation inC. difficile

Fuchs

Lamm‐Schmidt

Lenče

et al. 2022

Preprint

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The obligate anaerobic, enteric pathogenClostridioides difficilepersists in the intestinal tract by forming antibiotic resistant endospores that contribute to relapsing and recurrent infections. Despite the importance of sporulation forC. difficilepathogenesis, environmental cues, and molecular mechanisms regulating sporulation initiation remain ill defined. Here, using RIL-seq to capture the Hfq-dependent RNA-RNA interactome, we discovered a network of small RNAs that bind to mRNAs encoding sporulation-related genes. We show that two of these small RNAs, SpoX and SpoY, regulate translation of the master regulator of sporulation, Spo0A, in an opposing manner, which ultimately leads to altered sporulation rates. Infection of antibiotic-treated mice with SpoX and SpoY deletion mutants revealed a global effect on gut colonization and intestinal sporulation. Our work uncovers an elaborate RNA-RNA interactome controlling the physiology and virulence ofC. difficileand identifies a complex post-transcriptional layer in the regulation of spore formation in this important human pathogen.

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Section: Discussionmentioning

confidence: 99%

A network of small RNAs regulates sporulation initiation inC. difficile

Fuchs

Lamm‐Schmidt

Lenče

et al. 2022

Preprint

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“…The master regulator Spo0A and the subsequent sigma factor cascade is largely conserved, although with some difference in temporal regulation and mechanisms of sigma factor activation [ 42 ]. The signaling events upstream of Spo0A are not conserved and, despite the identification of several regulators that feed into C. difficile Spo0A expression, it is not yet clear how its activation is controlled [ 43–45 ]. Regulation of sporulation involves integration of multiple environmental and nutritional cues.…”

Section: Life Cycle and Disease Transmissionmentioning

confidence: 99%

Pathogenicity and virulence of Clostridioides difficile

Buddle

Fagan

2023

Virulence

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Clostridioides difficile is the most common cause of nosocomial antibiotic-associated diarrhea, and is responsible for a spectrum of diseases characterized by high levels of recurrence, morbidity, and mortality. Treatment is complex, since antibiotics constitute both the main treatment and the major risk factor for infection. Worryingly, resistance to multiple antibiotics is becoming increasingly widespread, leading to the classification of this pathogen as an urgent threat to global health. As a consummate opportunist, C. difficile is well equipped for promoting disease, owing to its arsenal of virulence factors: transmission of this anaerobe is highly efficient due to the formation of robust endospores, and an array of adhesins promote gut colonization. C. difficile produces multiple toxins acting upon gut epithelia, resulting in manifestations typical of diarrheal disease, and severe inflammation in a subset of patients. This review focuses on such virulence factors, as well as the importance of antimicrobial resistance and genome plasticity in enabling pathogenesis and persistence of this important pathogen.

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“…While Spo0A also regulates biofilm formation, flagella production, expression of cell-wall proteins [178] and indirect regulation with the sin locus [176,181,182], modulators like RstA control sporulation and toxin production through the phosphorylation of Spo0A [183]. Three of five orphan kinases (PtpA, PtpB and PtpC) have been reported to negatively regulate sporulation [184,185]. Both carbon catabolite protein A (CcpA) and CodY are global regulators associated with metabolic activity and repress sporulation.…”

Section: Sporulationmentioning

confidence: 99%

Clostridioides difficile infection: traversing host–pathogen interactions in the gut

Cheng

Unnikrishnan

2023

Microbiology

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C. difficile is the primary cause for nosocomial infective diarrhoea. For a successful infection, C. difficile must navigate between resident gut bacteria and the harsh host environment. The perturbation of the intestinal microbiota by broad-spectrum antibiotics alters the composition and the geography of the gut microbiota, deterring colonization resistance, and enabling C. difficile to colonize. This review will discuss how C. difficile interacts with and exploits the microbiota and the host epithelium to infect and persist. We provide an overview of C. difficile virulence factors and their interactions with the gut to aid adhesion, cause epithelial damage and mediate persistence. Finally, we document the host responses to C. difficile , describing the immune cells and host pathways that are associated and triggered during C. difficile infection.

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Three Orphan Histidine Kinases Inhibit Clostridioides difficile Sporulation

Abstract: The formation of inactive spores is critical for the long-term survival of the gastrointestinal pathogen Clostridioides difficile . The onset of sporulation is controlled by the master regulator of sporulation, Spo0A, which is activated by phosphorylation.

Cited by 19 publications

References 67 publications

A network of small RNAs regulates sporulation initiation inC. difficile

A network of small RNAs regulates sporulation initiation inC. difficile

Pathogenicity and virulence of Clostridioides difficile

Clostridioides difficile infection: traversing host–pathogen interactions in the gut

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