A Revised Understanding of Clostridioides difficile Spore Germination

Abstract

The dormant resistant spores of Clostridioides difficile are transformed into metabolically active cells through the process of germination. Spore germination in C. difficile is regulated by the detection of bile salt germinants and amino acid cogerminants by pseudoproteases CspC and CspA, respectively. The germinant signal is transduced to the serine protease CspB, which processes the cortex lytic enzyme SleC, leading to degradation of the spore cortex peptidoglycan and subsequent reactivation of the spore. Divergent C. difficile germination models have been proposed to explain interactions between key regulators and transduction of germinant and cogerminant signals. This review summarises advances in understanding C. difficile germination and outlines current models of germination regulation. Clostridioides difficile Infection (CDI)Disruption of the normal intestinal microbiota by broad-spectrum antibiotics is the key risk factor for the development of CDI [1,2]. Susceptibility to CDI increases with age, and the majority of cases occur in those aged N65 years [3,4]. Other risk factors include underlying disease, the duration of hospital stay, and the duration of treatment with broad-spectrum antibiotics [3]. Rates of CDI in the UK have declined dramatically since the introduction of a multicomponent care bundle to prevent healthcare-associated infections (HAIs), but CDI remains a global health burden and a leading source of morbidity and mortality; it is reported to be the most common cause of HAIs in US hospitals [5][6][7]. Symptoms of CDI range from asymptomatic carriage or mild watery diarrhoea to antibiotic-associated colitis and life-threatening pseudomembranous colitis, which is characterised by visible adherent plaques (pseudomembranes) [1,8]. The clinical presentation of CDI results from the mucosal damage, malabsorption, and inflammatory events caused by the production of the C. difficile toxins TcdA (toxin A) and TcdB (toxin B), and in some strains the binary toxin [9,10]. Despite antibiotic treatment, recurrence of CDI, defined as an episode occurring within 8 weeks of a previous episode because of relapse or reinfection, occurs in~25% of cases, although reported rates of recurrence vary considerably (from 4% to N50%) [11][12][13][14].Spore formation by C. difficile is crucial for the survival and dissemination of the bacterium in the environment. The dormant aerotolerant and highly resistant spore facilitates efficient transmission and persistence in the host [9,15,16]. Germination of C. difficile spores is activated by defined environmental signals that trigger the return of metabolic activity and outgrowth of the vegetative cell [4,17]. Despite the clinical significance of CDI, the signalling pathway that leads to the transition from dormant spore to metabolically active vegetative cell has not yet been fully elucidated. This review summarises recent developments in understanding C. difficile germination and the proposed germination signal transduction models. Clostridioides difficile Spore Struct...

Gut Dysbiosis and Clostridioides difficile Infection in Neonates and Adults

“…C. difficile spore germination is regulated by the detection of bile salt and amino acid cogerminants by pseudoproteases CspC and CspA, respectively ( Weingarden et al, 2014 ; Lawler et al, 2020 ). Although some cholate derivatives and the amino acid glycine could act as co-germinant factors, deoxycholate prevents vegetative growth ( Sorg and Sonenshein, 2008 ), while chenodeoxycholate inhibits taurocholate-mediated germination ( Sorg and Sonenshein, 2010 ).…”

Teicoplanin Suppresses Vegetative Clostridioides difficile and Spore Outgrowth

“…At MIC or above, we observed that the outgrowth was inhibited by these antimicrobial agents. This is predictable as spores lose their dormancy upon germination, resume metabolism at the core region and subsequently an outgrowth begins by synthesizing new cell wall peptidoglycan [ 28 , 29 ]. The germinated spores are vulnerable to these glycopeptide antibiotics, which inhibit spore outgrowth.…”

Mechanisms and Applications of Bacterial Sporulation and Germination in the Intestine

“…Importantly, spores of C. difficile and closely related species do not have homologs of IM GRs [ 87 ]. Rather, C. difficile senses bile acids such as taurocholate and cholate, which are released from the gall bladder into the intestinal environment, via the germination-specific pseudoprotease CspC in spores’ outer layers [ 82 , 88 , 89 ].…”