Secreted Compounds of the Probiotic Bacillus clausii Strain O/C Inhibit the Cytotoxic Effects Induced by Clostridium difficile and Bacillus cereus Toxins

Although the use of probiotics based onBacillusstrains to fight off intestinal pathogens and antibiotic-associated diarrhea is widespread, the mechanisms involved in producing their beneficial effects remain unclear. Here, we studied the ability of compounds secreted by the probioticBacillus clausiistrain O/C to counteract the cytotoxic effects induced by toxins of two pathogens,Clostridium difficileandBacillus cereus, by evaluating eukaryotic cell viability and expression of selected genes. Coincubation ofC. difficileandB. cereustoxic culture supernatants with theB. clausiisupernatant completely prevented the damage induced by toxins in Vero and Caco-2 cells. The hemolytic effect ofB. cereuswas also avoided by the probiotic supernatant. Moreover, in these cells, the expression ofrhoB, encoding a Rho GTPase target forC. difficiletoxins, was normalized whenC. difficilesupernatant was pretreated using theB. clausiisupernatant. All of the beneficial effects observed with the probiotic were abolished by the serine protease inhibitor phenylmethylsulfonyl fluoride (PMSF). Suspecting the involvement of a secreted protease in this protective effect, a protease was purified from theB. clausiisupernatant and identified as a serine protease (M-protease; GenBank accession numberQ99405). Experiments on Vero cells demonstrated the antitoxic activity of the purified protease against pathogen supernatants. This is the first report showing the capacity of a protease secreted by probiotic bacteria to inhibit the cytotoxic effects of toxinogenicC. difficileandB. cereusstrains. This extracellular compound could be responsible, at least in part, for the protective effects observed for this human probiotic in antibiotic-associated diarrhea.

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Novel Effective Bacillus cereus Group Species “Bacillus clarus” Is Represented by Antibiotic-Producing Strain ATCC 21929 Isolated from Soil

mSphere ◽

10.1128/msphere.00882-20 ◽

2020 ◽

Vol 5 (6) ◽

Author(s):

Marysabel Méndez Acevedo ◽

Laura M. Carroll ◽

Manjari Mukherjee ◽

Emma Mills ◽

Lingzi Xiaoli ◽

...

Keyword(s):

Bacillus Cereus ◽

Hela Cells ◽

Species Complex ◽

Taxonomic Classification ◽

Phenotypic Characterization ◽

Pathogenic Potential ◽

Cytotoxic Effects ◽

Content Type ◽

Group Species

ABSTRACT Gram-positive, spore-forming members of the Bacillus cereus group species complex are widespread in natural environments and display various degrees of pathogenicity. Recently, B. cereus group strain Bacillus mycoides Flugge ATCC 21929 was found to represent a novel lineage within the species complex, sharing a relatively low degree of genomic similarity with all B. cereus group genomes (average nucleotide identity [ANI] < 88). ATCC 21929 has been previously associated with the production of a patented antibiotic, antibiotic 60-6 (i.e., cerexin A); however, the virulence potential and growth characteristics of this lineage have never been assessed. Here, we provide an extensive genomic and phenotypic characterization of ATCC 21929, and we assess its pathogenic potential in vitro. ATCC 21929 most closely resembles Bacillus paramycoides NH24A2T (ANI and in silico DNA-DNA hybridization values of 86.70 and 34.10%, respectively). Phenotypically, ATCC 21929 does not possess cytochrome c oxidase activity and is able to grow at a range of temperatures between 15 and 43°C and a range of pH between 6 and 9. At 32°C, ATCC 21929 shows weak production of diarrheal enterotoxin hemolysin BL (Hbl) but no production of nonhemolytic enterotoxin (Nhe); at 37°C, neither Hbl nor Nhe is produced. Additionally, at 37°C, ATCC 21929 does not exhibit cytotoxic effects toward HeLa cells. With regard to fatty acid composition, ATCC 21929 has iso-C17:0 present in highest abundance. Based on the characterization provided here, ATCC 21929T (= PS00077AT = PS00077BT = PSU-0922T = BHPT) represents a novel effective B. cereus group species, which we propose as effective species “Bacillus clarus.” IMPORTANCE The B. cereus group comprises numerous closely related lineages with various degrees of pathogenic potential and industrial relevance. Species-level taxonomic classification of B. cereus group strains is important for risk evaluation and communication but remains challenging. Biochemical and phenotypic assays are often used to assign B. cereus group strains to species but are insufficient for accurate taxonomic classification on a genomic scale. Here, we show that antibiotic-producing ATCC 21929 represents a novel lineage within the B. cereus group that, by all metrics used to delineate prokaryotic species, exemplifies a novel effective species. Furthermore, we show that ATCC 21929 is incapable of producing enterotoxins Hbl and Nhe or exhibiting cytotoxic effects on HeLa cells at human body temperature in vitro. These results provide greater insight into the genomic and phenotypic diversity of the B. cereus group and may be leveraged to inform future public health and food safety efforts.

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Clostridium difficileLipoprotein GerS Is Required for Cortex Modification and Thus Spore Germination

mSphere ◽

10.1128/msphere.00205-18 ◽

2018 ◽

Vol 3 (3) ◽

Cited By ~ 8

Author(s):

Oscar R. Diaz ◽

Cameron V. Sayer ◽

David L. Popham ◽

Aimee Shen

Keyword(s):

Clostridium Difficile ◽

Spore Germination ◽

Protective Layer ◽

Thick Layer ◽

Lytic Enzyme ◽

Gram Positive ◽

Content Type ◽

Clostridioides Difficile ◽

Antibiotic Associated Diarrhea ◽

Biochemical Analyses

ABSTRACTClostridium difficile, also known asClostridioides difficile, is a Gram-positive, spore-forming bacterium that is a leading cause of antibiotic-associated diarrhea.C. difficileinfections begin when its metabolically dormant spores germinate to form toxin-producing vegetative cells. Successful spore germination depends on the degradation of the cortex, a thick layer of modified peptidoglycan that maintains dormancy. Cortex degradation is mediated by the SleC cortex lytic enzyme, which is thought to recognize the cortex-specific modification muramic-δ-lactam.C. difficilecortex degradation also depends on thePeptostreptococcaceae-specific lipoprotein GerS for unknown reasons. In this study, we tested whether GerS regulates production of muramic-δ-lactam and thus controls the ability of SleC to recognize its cortex substrate. By comparing the muropeptide profiles of ΔgerSspores to those of spores lacking either CwlD or PdaA, both of which mediate cortex modification inBacillus subtilis, we determined thatC. difficileGerS, CwlD, and PdaA are all required to generate muramic-δ-lactam. Both GerS and CwlD were needed to cleave the peptide side chains from N-acetylmuramic acid, suggesting that these two factors act in concert. Consistent with this hypothesis, biochemical analyses revealed that GerS and CwlD directly interact and that CwlD modulates GerS incorporation into mature spores. Since ΔgerS, ΔcwlD, and ΔpdaAspores exhibited equivalent germination defects, our results indicate thatC. difficilespore germination depends on cortex-specific modifications, reveal GerS as a novel regulator of these processes, and highlight additional differences in the regulation of spore germination inC. difficilerelative toB. subtilisand other spore-forming organisms.IMPORTANCEThe Gram-positive, spore-forming bacteriumClostridium difficileis a leading cause of antibiotic-associated diarrhea. BecauseC. difficileis an obligate anaerobe, its aerotolerant spores are essential for transmitting disease, and their germination into toxin-producing cells is necessary for causing disease. Spore germination requires the removal of the cortex, a thick layer of modified peptidoglycan that maintains spore dormancy. Cortex degradation is mediated by the SleC hydrolase, which is thought to recognize cortex-specific modifications. Cortex degradation also requires the GerS lipoprotein for unknown reasons. In our study, we tested whether GerS is required to generate cortex-specific modifications by comparing the cortex composition of ΔgerSspores to the cortex composition of spores lacking two putative cortex-modifying enzymes, CwlD and PdaA. These analyses revealed that GerS, CwlD, and PdaA are all required to generate cortex-specific modifications. Since loss of these modifications in ΔgerS, ΔcwlD, and ΔpdaAmutants resulted in spore germination and heat resistance defects, the SleC cortex lytic enzyme depends on cortex-specific modifications to efficiently degrade this protective layer. Our results further indicate that GerS and CwlD are mutually required for removing peptide chains from spore peptidoglycan and revealed a novel interaction between these proteins. Thus, our findings provide new mechanistic insight intoC. difficilespore germination.

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Clostridium difficile Toxins TcdA and TcdB Cause Colonic Tissue Damage by Distinct Mechanisms

Infection and Immunity ◽

10.1128/iai.00583-16 ◽

2016 ◽

Vol 84 (10) ◽

pp. 2871-2877 ◽

Cited By ~ 24

Author(s):

Nicole M. Chumbler ◽

Melissa A. Farrow ◽

Lynne A. Lapierre ◽

Jeffrey L. Franklin ◽

D. Borden Lacy

Keyword(s):

Clostridium Difficile ◽

Apoptotic Cell ◽

Large Body ◽

Health Care Facilities ◽

Dependent Manner ◽

Content Type ◽

Culture Model ◽

Care Facilities ◽

Antibiotic Associated Diarrhea ◽

A Cell

As the major cause of antibiotic-associated diarrhea,Clostridium difficileis a serious problem in health care facilities worldwide.C. difficileproduces two large toxins, TcdA and TcdB, which are the primary virulence factors in disease. The respective functions of these toxins have been difficult to discern, in part because the cytotoxicity profiles for these toxins differ with concentration and cell type. The goal of this study was to develop a cell culture model that would allow a side-by-side mechanistic comparison of the toxins. Conditionally immortalized, young adult mouse colonic (YAMC) epithelial cells demonstrate an exquisite sensitivity to both toxins with phenotypes that agree with observations in tissue explants. TcdA intoxication results in an apoptotic cell death that is dependent on the glucosyltransferase activity of the toxin. In contrast, TcdB has a bimodal mechanism; it induces apoptosis in a glucosyltransferase-dependent manner at lower concentrations and glucosyltransferase-independent necrotic death at higher concentrations. The direct comparison of the responses to TcdA and TcdB in cells and colonic explants provides the opportunity to unify a large body of observations made by many independent investigators.

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Observations on the Role of TcdE Isoforms in Clostridium difficile Toxin Secretion

Journal of Bacteriology ◽

10.1128/jb.00224-15 ◽

2015 ◽

Vol 197 (15) ◽

pp. 2600-2609 ◽

Cited By ~ 20

Author(s):

Revathi Govind ◽

Leah Fitzwater ◽

Rebekah Nichols

Keyword(s):

Amino Acids ◽

Clostridium Difficile ◽

Cell Viability ◽

Virulence Factors ◽

Start Codon ◽

Nosocomial Pathogen ◽

Content Type ◽

Antibiotic Associated Diarrhea ◽

Toxin Secretion

ABSTRACTClostridium difficileis a major nosocomial pathogen and the principal causative agent of antibiotic-associated diarrhea. The toxigenicC. difficilestrains that cause disease secrete virulence factors, toxin A and toxin B, that cause colonic injury and inflammation.C. difficiletoxins have no export signature and are secreted by an unusual mechanism that involves TcdE, a holin-like protein. We isolated a TcdE mutant of the epidemic R20291 strain with impaired toxin secretion, which was restored by complementation with functional TcdE. In the TcdE open reading frame (ORF), we identified three possible translation start sites; each translated isoform may play a specific role in TcdE-controlled toxin release. We created plasmid constructs that express only one of the three TcdE isoforms and complemented the TcdE mutant with these isoforms. Western blot analysis of the complemented strains demonstrated that TcdE is translated efficiently from the start codon at the 25th and 27th positions in the predicted ORF, producing proteins with 142 amino acids (TcdE142) and 140 amino acids (TcdE140), respectively. TcdE166was not detected when expressed from its own ribosomal binding site (RBS). The effects of all three TcdE isoforms onC. difficilecell viability and toxin release were determined. Among the three isoforms, overexpression of TcdE166and TcdE142had a profound effect on cell viability compared to the TcdE140isoform. Similarly, TcdE166and TcdE142facilitated toxin release more efficiently than did TcdE140. The importance of these variations among TcdE isoforms and their role in toxin release are discussed.IMPORTANCEC. difficileis a nosocomial pathogen that has become the most prevalent cause of antibiotic-associated diarrhea in North America and in several countries in Europe. Most strains ofC. difficileproduce two high-molecular-weight toxins that are regarded as the primary virulence factors. The mechanism by which these large toxins are secreted from bacterial cells is not yet clear but involves TcdE, a holin-like protein. In this work, we show that TcdE could be translated from three different start codons, resulting in the production of three TcdE isoforms. Furthermore, we investigated the role of these isoforms in toxin release and cell lysis inC. difficile. An understanding of TcdE-dependent toxin secretion may be helpful for the development of strategies for preventing and treatingC. difficileinfections.

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Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections

mBio ◽

10.1128/mbio.00551-15 ◽

2015 ◽

Vol 6 (3) ◽

Cited By ~ 129

Author(s):

Glen P. Carter ◽

Anjana Chakravorty ◽

Tu Anh Pham Nguyen ◽

Steven Mileto ◽

Fernanda Schreiber ◽

...

Keyword(s):

Clostridium Difficile ◽

Animal Models ◽

Virulence Factors ◽

Host Response ◽

Organ Damage ◽

Intestinal Damage ◽

Content Type ◽

Animal Infection ◽

Antibiotic Associated Diarrhea ◽

First Time

ABSTRACTClostridium difficileis a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease-causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA+TcdB−mutants are attenuated in virulence in comparison to the wild-type (TcdA+TcdB+) strain, whereas TcdA−TcdB+mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication ofC. difficileinfection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing thein vivohost innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor ofC. difficileand provide new insights into the host response toC. difficileduring infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms.IMPORTANCEClostridium difficileis a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms ofC. difficileinfections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response toC. difficileduring infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI.

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Mouse Relapse Model of Clostridium difficile Infection

Infection and Immunity ◽

10.1128/iai.01336-10 ◽

2011 ◽

Vol 79 (7) ◽

pp. 2856-2864 ◽

Cited By ~ 61

Author(s):

Xingmin Sun ◽

Haiying Wang ◽

Yongrong Zhang ◽

Kevin Chen ◽

Barbara Davis ◽

...

Keyword(s):

Clostridium Difficile ◽

Primary Infection ◽

Recurrent Disease ◽

Immunosuppressive Agents ◽

Disease Recurrence ◽

First Episode ◽

Full Spectrum ◽

Content Type ◽

Antibiotic Associated Diarrhea

ABSTRACTClostridium difficileis the causative agent of primary and recurrent antibiotic-associated diarrhea and colitis in hospitalized patients. The disease is caused mainly by two exotoxins, TcdA and TcdB, produced by the bacteria. RecurrentC. difficileinfection (CDI) constitutes one of the most significant clinical issues of this disease, occurs in more than 20% of patients after the first episode, and may be increasing in frequency. However, there is no well-established animal model of CDI relapse currently available for studying disease pathogenesis, prevention, and therapy. Here we report the establishment of a conventional mouse model of recurrence/relapse CDI. We found that the primary episode of CDI induced little or no protective antibody response againstC. difficiletoxins and mice continued sheddingC. difficilespores. Antibiotic treatment of surviving mice induced a second episode of diarrhea, while a simultaneous reexposure of animals toC. difficilebacteria or spores elicited a full spectrum of CDI similar to that of the primary infection. Moreover, mice treated with immunosuppressive agents were prone to more severe and fulminant recurrent disease. Finally, utilizing this model, we demonstrated that vancomycin only delayed disease recurrence, whereas neutralizing polysera against both TcdA and TcdB completely protected mice against CDI relapse. In conclusion, we have established a mouse relapse CDI model that allows for future investigations of the role of the host immune response in the disease's pathogenesis and permits critical testing of new therapeutics targeting recurrent disease.

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Biocide Resistance and Transmission of Clostridium difficile Spores Spiked onto Clinical Surfaces from an American Health Care Facility

Applied and Environmental Microbiology ◽

10.1128/aem.01090-19 ◽

2019 ◽

Vol 85 (17) ◽

Cited By ~ 4

Author(s):

Calie Dyer ◽

Lee P. Hutt ◽

Robert Burky ◽

Lovleen Tina Joshi

Keyword(s):

Health Care ◽

Clostridium Difficile ◽

High Strength ◽

Control Measures ◽

Content Type ◽

Infection Control Measures ◽

Biocide Resistance ◽

Antibiotic Associated Diarrhea ◽

Sodium Dichloroisocyanurate ◽

Spore Transmission

ABSTRACT Clostridium difficile is the primary cause of antibiotic-associated diarrhea globally. In unfavorable environments, the organism produces highly resistant spores which can survive microbicidal insult. Our previous research determined the ability of C. difficile spores to adhere to clinical surfaces, finding that spores had markedly different hydrophobic properties and adherence abilities. Investigation into the effect of the microbicide sodium dichloroisocyanurate on C. difficile spore transmission revealed that sublethal concentrations increased spore adherence without reducing viability. The present study examined the ability of spores to transmit across clinical surfaces and their response to an in-use disinfection concentration of 1,000 ppm of chlorine-releasing agent sodium dichloroisocyanurate. In an effort to understand if these surfaces contribute to nosocomial spore transmission, surgical isolation gowns, hospital-grade stainless steel, and floor vinyl were spiked with 1 × 106 spores/ml of two types of C. difficile spore preparations: crude spores and purified spores. The hydrophobicity of each spore type versus clinical surface was examined via plate transfer assay and scanning electron microscopy. The experiment was repeated, and spiked clinical surfaces were exposed to 1,000 ppm sodium dichloroisocyanurate at the recommended 10-min contact time. Results revealed that the hydrophobicity and structure of clinical surfaces can influence spore transmission and that outer spore surface structures may play a part in spore adhesion. Spores remained viable on clinical surfaces after microbicide exposure at the recommended disinfection concentration, demonstrating ineffectual sporicidal action. This study showed that C. difficile spores can transmit and survive between various clinical surfaces despite appropriate use of microbicides. IMPORTANCE Clostridium difficile is a health care-acquired organism and the causative agent of antibiotic-associated diarrhea. Its spores are implicated in fecal to oral transmission from contaminated surfaces in the health care environment due to their adherent nature. Contaminated surfaces are cleaned using high-strength chemicals to remove and kill the spores; however, despite appropriate infection control measures, there is still high incidence of C. difficile infection in patients in the United States. Our research examined the effect of a high-strength biocide on spores of C. difficile which had been spiked onto a range of clinically relevant surfaces, including isolation gowns, stainless steel, and floor vinyl. This study found that C. difficile spores were able to survive exposure to appropriate concentrations of biocide, highlighting the need to examine the effectiveness of infection control measures to prevent spore transmission and to consider the prevalence of biocide resistance when decontaminating health care surfaces.

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Clostridium difficileToxoid Vaccine Candidate Confers Broad Protection against a Range of Prevalent Circulating Strains in a Nonclinical Setting

Infection and Immunity ◽

10.1128/iai.00742-17 ◽

2018 ◽

Vol 86 (6) ◽

pp. e00742-17 ◽

Cited By ~ 5

Author(s):

Laurence Quemeneur ◽

Nadine Petiot ◽

Nadège Arnaud-Barbe ◽

Catherine Hessler ◽

Patricia J. Pietrobon ◽

...

Keyword(s):

Clostridium Difficile ◽

Cytotoxic Activity ◽

Vaccine Candidate ◽

Cross Protection ◽

Clinical Isolates ◽

Disease Symptoms ◽

Content Type ◽

Antibiotic Associated Diarrhea ◽

Cross Neutralization ◽

Culture Supernatants

ABSTRACTClostridium difficileinfection (CDI) is a leading cause of nosocomial and antibiotic-associated diarrhea. A vaccine, based on formalin-inactivated toxins A and B purified from anaerobic cultures ofC. difficilestrain VPI 10463 (toxinotype 0), has been in development for the prevention of symptomatic CDI. We evaluated the breadth of protection conferred by thisC. difficiletoxoid vaccine in cross-neutralization assessments using sera from vaccinated hamsters against a collection of 165 clinical isolates. Hamster antisera raised against theC. difficiletoxoid vaccine neutralized the cytotoxic activity of culture supernatants from several toxinotype 0 strains and heterologous strains from 10 different toxinotypes. Further assessments performed with purified toxins confirmed that vaccine-elicited antibodies can neutralize both A and B toxins from a variety of toxinotypes. In the hamster challenge model, the vaccine conferred significant cross-protection against disease symptoms and death caused by heterologousC. difficilestrains from the most common phylogenetic clades, including the most prevalent toxinotypes.

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Activity of a Novel Cyclic Lipopeptide, CB-183,315, against Resistant Clostridium difficile and Other Gram-Positive Aerobic and Anaerobic Intestinal Pathogens

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.06257-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 3448-3452 ◽

Cited By ~ 43

Author(s):

D. R. Snydman ◽

N. V. Jacobus ◽

L. A. McDermott

Keyword(s):

Staphylococcus Aureus ◽

Clostridium Difficile ◽

Vancomycin Resistant Enterococcus ◽

Gram Positive ◽

Content Type ◽

Cyclic Lipopeptide ◽

Excellent Activity ◽

Intestinal Pathogens ◽

Vancomycin Resistant ◽

Aerobic And Anaerobic

ABSTRACTWe evaluated the activity of CB-183,315 againstClostridium difficile, including strains that are resistant to fluoroquinolones and metronidazole and with elevated MICs to vancomycin as well as other Gram-positive intestinal pathogens. The MICs of CB-183,315 against allC. difficileisolates were ≤1 μg/ml. CB-183,315 had greater activity than vancomycin and metronidazole againstC. difficileisolates and was more active than the comparators against vancomycin-resistant enterococcus (VRE). CB-183,315 also had excellent activity against methicillin-resistantStaphylococcus aureus(MRSA), otherClostridiumspp., andPeptostreptococcusspp.

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TheClostridium difficile spo0AGene Is a Persistence and Transmission Factor

Infection and Immunity ◽

10.1128/iai.00147-12 ◽

2012 ◽

Vol 80 (8) ◽

pp. 2704-2711 ◽

Cited By ~ 207

Author(s):

Laura J. Deakin ◽

Simon Clare ◽

Robert P. Fagan ◽

Lisa F. Dawson ◽

Derek J. Pickard ◽

...

Keyword(s):

Health Care ◽

Clostridium Difficile ◽

Murine Model ◽

Persistent Infection ◽

Transcriptional Regulator ◽

Transmission Factor ◽

Content Type ◽

Antibiotic Associated Diarrhea ◽

Significant Health

ABSTRACTClostridium difficileis a major cause of chronic antibiotic-associated diarrhea and a significant health care-associated pathogen that forms highly resistant and infectious spores. Spo0A is a highly conserved transcriptional regulator that plays a key role in initiating sporulation inBacillusandClostridiumspecies. Here, we use a murine model to study the role of theC. difficile spo0Agene during infection and transmission. We demonstrate thatC. difficile spo0Amutant derivatives can cause intestinal disease but are unable to persist within and effectively transmit between mice. Thus, theC. difficileSpo0A protein plays a key role in persistent infection, including recurrence and host-to-host transmission in mice.

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