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1
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Campidelli C, Bruxelle JF, Collignon A, Péchiné S. Immunization Strategies Against Clostridioides difficile. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1435:117-150. [PMID: 38175474 DOI: 10.1007/978-3-031-42108-2_7] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Clostridioides difficile (C. difficile) infection (CDI) is an important healthcare but also a community-associated disease. CDI is considered a public health threat and an economic burden. A major problem is the high rate of recurrences. Besides classical antibiotic treatments, new therapeutic strategies are needed to prevent infection, to treat patients, and to prevent recurrences. If fecal transplantation has been recommended to treat recurrences, another key approach is to elicit immunity against C. difficile and its virulence factors. Here, after a summary concerning the virulence factors, the host immune response against C. difficile, and its role in the outcome of disease, we review the different approaches of passive immunotherapies and vaccines developed against CDI. Passive immunization strategies are designed in function of the target antigen, the antibody-based product, and its administration route. Similarly, for active immunization strategies, vaccine antigens can target toxins or surface proteins, and immunization can be performed by parenteral or mucosal routes. For passive immunization and vaccination as well, we first present immunization assays performed in animal models and second in humans and associated clinical trials. The different studies are presented according to the mode of administration either parenteral or mucosal and the target antigens and either toxins or colonization factors.
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Affiliation(s)
- Camille Campidelli
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Jean-François Bruxelle
- CIRI-Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm U1111, CNRS UMR5308, ENS Lyon, Lyon, France
| | - Anne Collignon
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Severine Péchiné
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France.
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2
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Heuler J, Chandra H, Sun X. Mucosal Vaccination Strategies against Clostridioides difficile Infection. Vaccines (Basel) 2023; 11:vaccines11050887. [PMID: 37242991 DOI: 10.3390/vaccines11050887] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/16/2023] [Accepted: 04/18/2023] [Indexed: 05/28/2023] Open
Abstract
Clostridioides difficile infection (CDI) presents a major public health threat by causing frequently recurrent, life-threatening cases of diarrhea and intestinal inflammation. The ability of C. difficile to express antibiotic resistance and to form long-lasting spores makes the pathogen particularly challenging to eradicate from healthcare settings, raising the need for preventative measures to curb the spread of CDI. Since C. difficile utilizes the fecal-oral route of transmission, a mucosal vaccine could be a particularly promising strategy by generating strong IgA and IgG responses that prevent colonization and disease. This mini-review summarizes the progress toward mucosal vaccines against C. difficile toxins, cell-surface components, and spore proteins. By assessing the strengths and weaknesses of particular antigens, as well as methods for delivering these antigens to mucosal sites, we hope to guide future research toward an effective mucosal vaccine against CDI.
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Affiliation(s)
- Joshua Heuler
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Harish Chandra
- Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA
| | - Xingmin Sun
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
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3
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Frame NW, Allas MJ, Pequegnat B, Vinogradov E, Liao VCH, Al-Abdul-Wahid S, Arroyo L, Allen-Vercoe E, Lowary TL, Monteiro MA. Structure and synthesis of a vaccine and diagnostic target for Enterocloster bolteae, an autism-associated gut pathogen – Part II. Carbohydr Res 2023; 526:108805. [PMID: 37023666 DOI: 10.1016/j.carres.2023.108805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 03/25/2023] [Accepted: 03/29/2023] [Indexed: 04/03/2023]
Abstract
Enterocloster bolteae (formerly known as Clostridium bolteae) is a gastro-intestinal pathogenic bacterium often detected in the fecal microbiome of children in the autism spectrum. E. bolteae excretes metabolites that are thought to act as neurotoxins. This study is an update of our first E. bolteae investigation that discovered an immunogenic polysaccharide. Through a combination of chemical derivatizations/degradations, spectrometry and spectroscopy techniques, a polysaccharide composed of disaccharide repeating blocks comprised of 3-linked β-d-ribofuranose and 4-linked α-l-rhamnopyranose, [→3)-β-D-Ribf-(1 → 4)-α-L-Rhap-(1→]n, was identified. To confirm the structure, and to provide material for subsequent investigations, the chemical synthesis of a corresponding linker-equipped tetrasaccharide, β-D-Ribf-(1 → 4)-α-L-Rhap-(1 → 3)-β-D-Ribf-(1 → 4)-α-L-Rhap-(1→O(CH2)8N3, is also described. Research tools based on this immunogenic glycan structure can form the foundation for serotype classification, diagnostic/vaccine targets and clinical studies into the hypothesized role of E. bolteae in the onset/augmentation of autism related conditions in children.
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Affiliation(s)
- Nolan W Frame
- Department of Chemistry, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | - Mikel Jason Allas
- Department of Chemistry, University of Alberta, Edmonton, AB, T6G 2G2, Canada; Institute of Biological Chemistry, Academia Sinica, Nangang, Taipei, 11529, Taiwan
| | - Brittany Pequegnat
- Department of Chemistry, University of Guelph, Guelph, ON, N1G 2W1, Canada
| | | | - Victor C-H Liao
- Institute of Biological Chemistry, Academia Sinica, Nangang, Taipei, 11529, Taiwan
| | | | - Luis Arroyo
- Department of Clinical Studies, University of Guelph, N1G 2W1, Guelph, ON, Canada
| | - Emma Allen-Vercoe
- Department of Microbiology, University of Guelph, N1G 2W1, Guelph, ON, Canada
| | - Todd L Lowary
- Institute of Biological Chemistry, Academia Sinica, Nangang, Taipei, 11529, Taiwan; Institute of Biochemical Sciences, National Taiwan University, Taipei, 106, Taiwan.
| | - Mario A Monteiro
- Department of Chemistry, University of Guelph, Guelph, ON, N1G 2W1, Canada.
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Rohokale R, Guo Z. Development in the Concept of Bacterial Polysaccharide Repeating Unit-Based Antibacterial Conjugate Vaccines. ACS Infect Dis 2023; 9:178-212. [PMID: 36706246 PMCID: PMC9930202 DOI: 10.1021/acsinfecdis.2c00559] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The surface of cells is coated with a dense layer of glycans, known as the cell glycocalyx. The complex glycans in the glycocalyx are involved in various biological events, such as bacterial pathogenesis, protection of bacteria from environmental stresses, etc. Polysaccharides on the bacterial cell surface are highly conserved and accessible molecules, and thus they are excellent immunological targets. Consequently, bacterial polysaccharides and their repeating units have been extensively studied as antigens for the development of antibacterial vaccines. This Review surveys the recent developments in the synthetic and immunological investigations of bacterial polysaccharide repeating unit-based conjugate vaccines against several human pathogenic bacteria. The major challenges associated with the development of functional carbohydrate-based antibacterial conjugate vaccines are also considered.
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Affiliation(s)
- Rajendra Rohokale
- Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States of America
| | - Zhongwu Guo
- Department of Chemistry, University of Florida, Gainesville, Florida 32611, United States of America
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Serum IgM antibody response to Clostridioides difficile polysaccharide PS-II vaccination in pony foals. Anaerobe 2022; 77:102635. [PMID: 36064161 DOI: 10.1016/j.anaerobe.2022.102635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 08/16/2022] [Accepted: 08/28/2022] [Indexed: 11/21/2022]
Abstract
OBJECTIVES Clostridioides difficile (formerly Clostridium difficile) is associated with colitis in foals and mature horses. C. difficile exposes specific phosphorylated polysaccharides (PSs), named PS-I, PS-II and PS-III. These cell-surface PSs are potential vaccine targets, especially the hexasaccharide phosphate PS-II, that has been found in all C. difficile ribotypes examined. Since we previously identified anti-PS-II circulating antibodies in horses, we postulated that vaccinating foals with PS-II may prevent colonization by C. difficile. In this study, we aim to evaluate the IgM antibody responses in foals to PS-II. METHODS To evaluate the reactogenicity and immunogenicity of C. difficile PS-II in foals, three-to four-month-old foals were vaccinated intramuscularly three times at intervals of three weeks with 100 μg/dose (3 foals) or 500 μg/dose (3 foals) of purified PS-II antigen with aluminum hydroxide adjuvant, or with a placebo preparation (2 foals) containing adjuvant alone. RESULTS No injection site swelling, pain or fever was observed after vaccination. Two of the three foals receiving 100 μg/dose, and three out of three foals receiving 500 μg/dose of PS-II responded with increases in serum IgM antibodies. No control foals that received the placebo had IgM responses to PS-II. There was a trend towards a higher response rate in foals receiving 500 μg PS-II one week after second vaccination when compared to control foals and towards higher concentrations of serum IgM antibodies in foals receiving 500 μg PS-II. CONCLUSIONS No adverse reactions were observed following vaccination with PS-II in foals; Serum IgM immune responses were induced by vaccination. A polysaccharide-based vaccine for C. difficile in horses deserves further investigation.
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Phanchana M, Harnvoravongchai P, Wongkuna S, Phetruen T, Phothichaisri W, Panturat S, Pipatthana M, Charoensutthivarakul S, Chankhamhaengdecha S, Janvilisri T. Frontiers in antibiotic alternatives for Clostridioides difficile infection. World J Gastroenterol 2021; 27:7210-7232. [PMID: 34876784 PMCID: PMC8611198 DOI: 10.3748/wjg.v27.i42.7210] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/12/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
Clostridioides difficile (C. difficile) is a gram-positive, anaerobic spore-forming bacterium and a major cause of antibiotic-associated diarrhea. Humans are naturally resistant to C. difficile infection (CDI) owing to the protection provided by healthy gut microbiota. When the gut microbiota is disturbed, C. difficile can colonize, produce toxins, and manifest clinical symptoms, ranging from asymptomatic diarrhea and colitis to death. Despite the steady-if not rising-prevalence of CDI, it will certainly become more problematic in a world of antibiotic overuse and the post-antibiotic era. C. difficile is naturally resistant to most of the currently used antibiotics as it uses multiple resistance mechanisms. Therefore, current CDI treatment regimens are extremely limited to only a few antibiotics, which include vancomycin, fidaxomicin, and metronidazole. Therefore, one of the main challenges experienced by the scientific community is the development of alternative approaches to control and treat CDI. In this Frontier article, we collectively summarize recent advances in alternative treatment approaches for CDI. Over the past few years, several studies have reported on natural product-derived compounds, drug repurposing, high-throughput library screening, phage therapy, and fecal microbiota transplantation. We also include an update on vaccine development, pre- and pro-biotics for CDI, and toxin antidote approaches. These measures tackle CDI at every stage of disease pathology via multiple mechanisms. We also discuss the gaps and concerns in these developments. The next epidemic of CDI is not a matter of if but a matter of when. Therefore, being well-equipped with a collection of alternative therapeutics is necessary and should be prioritized.
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Affiliation(s)
- Matthew Phanchana
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand
| | | | - Supapit Wongkuna
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Tanaporn Phetruen
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Wichuda Phothichaisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Supakan Panturat
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Methinee Pipatthana
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | - Sitthivut Charoensutthivarakul
- School of Bioinnovation and Bio-based Product Intelligence, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
| | | | - Tavan Janvilisri
- Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
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α-Galactosylceramide-Reactive NKT Cells Increase IgG1 Class Switch against a Clostridioides difficile Polysaccharide Antigen and Enhance Immunity against a Live Pathogen Challenge. Infect Immun 2021; 89:e0043821. [PMID: 34424751 DOI: 10.1128/iai.00438-21] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
All clinical Clostridioides difficile strains identified to date express a surface capsule-like polysaccharide structure known as polysaccharide II (PSII). The PSII antigen is immunogenic and, when conjugated to a protein carrier, induces a protective antibody response in animal models. Given that CD1d-restricted natural killer T (NKT) cells promote antibody responses, including those against carbohydrates, we tested the hypothesis that immunization with PSII and a CD1d-binding glycolipid adjuvant could lead to enhanced protection against a live C. difficile challenge. We purified PSII from a clinical isolate of C. difficile and immunized B6 mice with PSII alone or PSII plus the CD1d-binding glycolipid α-galactosylceramide (α-GC). PSII-specific IgM and IgG titers were evident in sera from immunized mice. The inclusion of α-GC had a modest influence on isotype switch but increased the IgG1/IgG2c ratio. Enhanced protection against C. difficile disease was achieved by inclusion of the α-GC ligand and was associated with reduced bacterial numbers in fecal pellets. In contrast, NKT-deficient Traj18-/- mice were not protected by the PSII/α-GC immunization modality. Absence of NKT cells similarly had a modest effect on isotype switch, but ratios of IgG1/IgG2c decreased. These results indicate that α-GC-driven NKT cells move the humoral immune response against C. difficile PSII antigen toward Th2-driven IgG1 and may contribute to augmented protection. This study suggests that NKT activation represents a pathway for additional B-cell help that could be used to supplement existing efforts to develop vaccines against polysaccharides derived from C. difficile and other pathogens.
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8
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Seeberger PH. Discovery of Semi- and Fully-Synthetic Carbohydrate Vaccines Against Bacterial Infections Using a Medicinal Chemistry Approach. Chem Rev 2021; 121:3598-3626. [PMID: 33794090 PMCID: PMC8154330 DOI: 10.1021/acs.chemrev.0c01210] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Indexed: 12/13/2022]
Abstract
The glycocalyx, a thick layer of carbohydrates, surrounds the cell wall of most bacterial and parasitic pathogens. Recognition of these unique glycans by the human immune system results in destruction of the invaders. To elicit a protective immune response, polysaccharides either isolated from the bacterial cell surface or conjugated with a carrier protein, for T-cell help, are administered. Conjugate vaccines based on isolated carbohydrates currently protect millions of people against Streptococcus pneumoniae, Haemophilus influenzae type b, and Neisseria meningitides infections. Active pharmaceutical ingredients (APIs) are increasingly discovered by medicinal chemistry and synthetic in origin, rather than isolated from natural sources. Converting vaccines from biologicals to pharmaceuticals requires a fundamental understanding of how the human immune system recognizes carbohydrates and could now be realized. To illustrate the chemistry-based approach to vaccine discovery, I summarize efforts focusing on synthetic glycan-based medicinal chemistry to understand the mammalian antiglycan immune response and define glycan epitopes for novel synthetic glycoconjugate vaccines against Streptococcus pneumoniae, Clostridium difficile, Klebsiella pneumoniae, and other bacteria. The chemical tools described here help us gain fundamental insights into how the human system recognizes carbohydrates and drive the discovery of carbohydrate vaccines.
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9
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Cox AD, St Michael F, Aubry A, Strong PCR, Hayes AC, Logan SM. Comparison of polysaccharide glycoconjugates as candidate vaccines to combat Clostridiodes (Clostridium) difficile. Glycoconj J 2020; 38:493-508. [PMID: 32789783 DOI: 10.1007/s10719-020-09937-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/06/2020] [Accepted: 07/23/2020] [Indexed: 10/23/2022]
Abstract
Two known Clostridiodes (Clostridium) difficile surface antigens, a lipoteichoic acid (LTA) and a polysaccharide (PS-II) were isolated and purified in order to prepare glycoconjugate vaccines to the carrier protein human serum albumin utilising a reductive amination strategy. Mice and rabbits were immunized with a prime and two boost strategy and the resulting sera were examined for their ability to recognise the purified homologous antigens and subsequently killed whole cells of C. difficile strains and other Clostridia species. Immunisation derived antisera from rabbits and mice, recognised all strains of C. difficile vegetative cells examined, with generally similar titers from animals that received the LTA or the PS-II conjugates. Sera raised to the LTA conjugates were able to recognise other Clostridia species C. butyricum, C. bifermentans and C. subterminale whereas sera raised to the PS-II conjugates were not. These LTA and PS-II sera recognised live cells in an immunofluorescence assay and were also able to recognise the spore form of the bacterium. This study has confirmed that the LTA and PS-II polysaccharides are both highly conserved surface polymers of C. difficile that are easily accessible to the immune system and as such may have potential as vaccine antigens or as targets for therapeutics to combat C. difficile infection.
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Affiliation(s)
- A D Cox
- Vaccine Program, Human Health Therapeutics Portfolio, National Research Council, Ottawa, ON, K1A 0R6, Canada.
| | - F St Michael
- Vaccine Program, Human Health Therapeutics Portfolio, National Research Council, Ottawa, ON, K1A 0R6, Canada
| | - A Aubry
- Vaccine Program, Human Health Therapeutics Portfolio, National Research Council, Ottawa, ON, K1A 0R6, Canada
| | - P C R Strong
- Vaccine Program, Human Health Therapeutics Portfolio, National Research Council, Ottawa, ON, K1A 0R6, Canada
| | - A C Hayes
- Vaccine Program, Human Health Therapeutics Portfolio, National Research Council, Ottawa, ON, K1A 0R6, Canada
| | - S M Logan
- Vaccine Program, Human Health Therapeutics Portfolio, National Research Council, Ottawa, ON, K1A 0R6, Canada
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10
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Cairns CM, van Faassen H, St. Michael F, Aubry A, Henry KA, Rossotti MA, Logan SM, Hussack G, Gisch N, Hogendorf WFJ, Pedersen CM, Cox AD. Development and Characterization of Mouse Monoclonal Antibodies Specific for Clostridiodes (Clostridium) difficile Lipoteichoic Acid. ACS Chem Biol 2020; 15:1050-1058. [PMID: 32191024 DOI: 10.1021/acschembio.0c00066] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Clostridiodes (Clostridium) difficile is an anaerobic Gram-positive, spore-forming nosocomial, gastrointestinal pathogen causing C. difficile-associated disease with symptoms ranging from mild cases of antibiotic-associated diarrhea to fatal pseudomembranous colitis. We developed murine monoclonal antibodies (mAbs) specific for a conserved cell surface antigen, lipoteichoic acid (LTA)of C. difficile. The mAbs were characterized in terms of their thermal stability, solubility, and their binding to LTA by surface plasmon resonance and competitive ELISA. Synthetic LTA molecules were prepared in order to better define the minimum epitope required to mimic the natural antigen, and three repeat units of the polymer were required for optimal recognition. One of the murine mAbs was chimerized with human constant region domains and was found to recognize the target antigen identically to the mouse version. These mAbs may be useful as therapeutics (standalone, in conjunction with known antitoxin approaches, or as delivery vehicles for antibody drug conjugates targeting the bacterium), as diagnostic agents, and in infection control applications.
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Affiliation(s)
- Chantelle M. Cairns
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
| | - Henk van Faassen
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
| | - Frank St. Michael
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
| | - Annie Aubry
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
| | - Kevin A. Henry
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
| | - Martin A. Rossotti
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
| | - Susan M. Logan
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
| | - Greg Hussack
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
| | - Nicolas Gisch
- Division of Bioanalytical Chemistry, Priority Research Area Infections, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany
| | | | | | - Andrew D. Cox
- Vaccine and Emerging Infections Research, Human Health Therapeutics Research Centre, National Research Council, Ottawa, Ontario K1A 0R6, Canada
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11
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Ma Z, Zhang GL, Gadi MR, Guo Y, Wang P, Li L. Clostridioides difficile cd2775 Encodes a Unique Mannosyl-1-Phosphotransferase for Polysaccharide II Biosynthesis. ACS Infect Dis 2020; 6:680-686. [PMID: 32073825 DOI: 10.1021/acsinfecdis.9b00494] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Clostridioides difficile (C. difficile) is the leading cause of antibiotic-induced bacterial colitis and life-threatening diarrhea worldwide. The commonly existing anionic polysaccharide II (PSII) is responsible for protein anchoring involved in colonization, and the gene cd2775 located in its biosynthesis gene cluster is essential for bacterial growth. Herein, we demonstrated that cd2775 encodes a novel mannosyl-1-phosphotransferase (ManPT) responsible for the phosphorylation of PSII. Unlike typical mannosyltransferases, CD2775 transfers mannose-α1-phosphate instead of mannose from guanosine 5'-diphospho-d-mannose to disaccharide acceptors, forming a unique mannose-α1-phosphate-6-glucose linkage. The enzyme was overexpressed in E. coli and purified for biochemical characterization and substrate specificity study. It is found that CD2775 possesses a strict acceptor specificity toward Glc-β1,3-GalNAc-diphospho-lipids but extreme promiscuity toward various sugar donors. This is the first report of a ManPT in all living systems. Given its essentiality in C. difficile growth, CD2775 can be a promising target for therapeutics development.
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Affiliation(s)
- Zhongrui Ma
- Department of Chemistry, Georgia State University, 50 Decatur Street SE, Atlanta, Georgia 30303, United States
| | - Gao-Lan Zhang
- Department of Chemistry, Georgia State University, 50 Decatur Street SE, Atlanta, Georgia 30303, United States
| | - Madhusudhan Reddy Gadi
- Department of Chemistry, Georgia State University, 50 Decatur Street SE, Atlanta, Georgia 30303, United States
| | - Yuxi Guo
- Department of Chemistry, Georgia State University, 50 Decatur Street SE, Atlanta, Georgia 30303, United States
| | - Peng Wang
- Department of Chemistry, Georgia State University, 50 Decatur Street SE, Atlanta, Georgia 30303, United States
| | - Lei Li
- Department of Chemistry, Georgia State University, 50 Decatur Street SE, Atlanta, Georgia 30303, United States
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12
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Mettu R, Chen CY, Wu CY. Synthetic carbohydrate-based vaccines: challenges and opportunities. J Biomed Sci 2020; 27:9. [PMID: 31900143 PMCID: PMC6941340 DOI: 10.1186/s12929-019-0591-0] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/18/2019] [Indexed: 01/05/2023] Open
Abstract
Glycoconjugate vaccines based on bacterial capsular polysaccharides (CPS) have been extremely successful in preventing bacterial infections. The glycan antigens for the preparation of CPS based glycoconjugate vaccines are mainly obtained from bacterial fermentation, the quality and length of glycans are always inconsistent. Such kind of situation make the CMC of glycoconjugate vaccines are difficult to well control. Thanks to the advantage of synthetic methods for carbohydrates syntheses. The well controlled glycan antigens are more easily to obtain, and them are conjugated to carrier protein to from the so-call homogeneous fully synthetic glycoconjugate vaccines. Several fully glycoconjugate vaccines are in different phases of clinical trial for bacteria or cancers. The review will introduce the recent development of fully synthetic glycoconjugate vaccine.
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Affiliation(s)
- Ravinder Mettu
- Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nangang District, Taipei, 11529, Taiwan
| | - Chiang-Yun Chen
- Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nangang District, Taipei, 11529, Taiwan.,Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program, Academia Sinica, No. 128 Academia Road, Section 2, Nangang District, Taipei, 11529, Taiwan
| | - Chung-Yi Wu
- Genomics Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nangang District, Taipei, 11529, Taiwan.
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13
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Pequegnat B, Monteiro MA. Carbohydrate Scaffolds for the Study of the Autism-associated Bacterium, Clostridium bolteae. Curr Med Chem 2019; 26:6341-6348. [PMID: 30799780 PMCID: PMC7040508 DOI: 10.2174/0929867326666190225164527] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 10/03/2018] [Accepted: 11/08/2018] [Indexed: 12/23/2022]
Abstract
A large number of children in the autism spectrum disorder suffer from gastrointestinal (GI) conditions, such as constipation and diarrhea. Clostridium bolteae is a part of a set of pathogens being regularly detected in the stool samples of hosts affected by GI and autism symptoms. Accompanying studies have pointed out the possibility that such microbes affect behaviour through the production of neurotoxic metabolites in a so-called, gut-brain connection. As an extension of our Clostridium difficile polysaccharide (PS)-based vaccine research, we engaged in the discovery of C. bolteae surface carbohydrates. So far, studies revealed that C. bolteae produces a specific immunogenic PS capsule comprised of disaccharide repeating blocks of mannose (Manp) and rhamnose (Rhap) units: α-D-Manp-(1→[-4)-β-D-Rhap- (1→3)-α-D-Manp-(1→]n. For vaccinology and further immunogenic experiments, a method to produce C. bolteae PS conjugates has been developed, along with the chemical syntheses of the PS non-reducing end linkage, with D-Rha or L-Rha, α-D-Manp-(1→4)-α-D-Rhap- (1→O(CH2)5NH2 and α-D-Manp-(1→4)-α-L-Rhap-(1→O(CH2)5NH2, equipped with an aminopentyl linker at the reducing end for conjugation purposes. The discovery of C. bolteae PS immunogen opens the door to the creation of non-evasive diagnostic tools to evaluate the frequency and role of this microbe in autistic subjects and to a vaccine to reduce colonization levels in the GI tract, thus impeding the concentration of neurotoxins.
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Affiliation(s)
| | - Mario A Monteiro
- Department of Chemistry, University of Guelph, Guelph, ON, Canada
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14
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Broecker F, Wegner E, Seco BMS, Kaplonek P, Bräutigam M, Ensser A, Pfister F, Daniel C, Martin CE, Mattner J, Seeberger PH. Synthetic Oligosaccharide-Based Vaccines Protect Mice from Clostridioides difficile Infections. ACS Chem Biol 2019; 14:2720-2728. [PMID: 31692324 PMCID: PMC6929054 DOI: 10.1021/acschembio.9b00642] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/06/2019] [Indexed: 12/14/2022]
Abstract
Infections with Clostridioides difficile (formerly Clostridium difficile) have increased in incidence, morbidity, and mortality over the past decade. Preventing infections is becoming increasingly important, as frontline antibiotics become less effective and frequently induce recurrence by disrupting intestinal microbiota. The clinically most advanced vaccine approaches prevent symptoms once C. difficile infection is established by inducing immunity to secreted clostridial cytotoxins. However, they do not inhibit bacterial colonization and thereby favor asymptomatic carriage. Synthetic oligosaccharides resembling the C. difficile surface glycans PS-I, PS-II, and PS-III are immunogenic and serve as basis for colonization-preventing vaccines. Here, we demonstrate that glycoconjugate vaccine candidates based on synthetic oligosaccharides protected mice from infections with two different C. difficile strains. Four synthetic antigens, ranging in size from disaccharides to hexasaccharides, were conjugated to CRM197, which is a carrier protein used in commercial vaccines. The vaccine candidates induced glycan-specific antibodies in mice and substantially limited C. difficile colonization and colitis after experimental infection. The glycoconjugates ameliorated intestinal pathology more substantially than a toxin-targeting vaccine. Colonization of the gut by C. difficile was selectively inhibited while intestinal microbiota remained preserved. Passive transfer experiments with anti-PS-I serum revealed that protection is mediated by specific antiglycan antibodies; however, cell-mediated immunity likely also contributed to protection in vivo. Thus, glycoconjugate vaccines against C. difficile are a complementary approach to toxin-targeting strategies and are advancing through preclinical work.
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Affiliation(s)
- Felix Broecker
- Department
of Biomolecular Systems, Max Planck Institute
of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Institute
of Chemistry and Biochemistry, Freie Universität
Berlin, Arnimallee 22, 14195 Berlin, Germany
| | - Erik Wegner
- Mikrobiologisches
Institut−Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander
Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Bruna M. S. Seco
- Department
of Biomolecular Systems, Max Planck Institute
of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Institute
of Chemistry and Biochemistry, Freie Universität
Berlin, Arnimallee 22, 14195 Berlin, Germany
| | - Paulina Kaplonek
- Department
of Biomolecular Systems, Max Planck Institute
of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Institute
of Chemistry and Biochemistry, Freie Universität
Berlin, Arnimallee 22, 14195 Berlin, Germany
| | - Maria Bräutigam
- Department
of Biomolecular Systems, Max Planck Institute
of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Institute
of Chemistry and Biochemistry, Freie Universität
Berlin, Arnimallee 22, 14195 Berlin, Germany
| | - Armin Ensser
- Virologisches
Institut, Universitätsklinikum Erlangen,
Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Frederick Pfister
- Department
of Nephropathology, Friedrich-Alexander
University of Erlangen-Nürnberg, Erlangen, Germany
| | - Christoph Daniel
- Department
of Nephropathology, Friedrich-Alexander
University of Erlangen-Nürnberg, Erlangen, Germany
| | - Christopher E. Martin
- Department
of Biomolecular Systems, Max Planck Institute
of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Institute
of Chemistry and Biochemistry, Freie Universität
Berlin, Arnimallee 22, 14195 Berlin, Germany
| | - Jochen Mattner
- Mikrobiologisches
Institut−Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen and Friedrich-Alexander
Universität Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Peter H. Seeberger
- Department
of Biomolecular Systems, Max Planck Institute
of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
- Institute
of Chemistry and Biochemistry, Freie Universität
Berlin, Arnimallee 22, 14195 Berlin, Germany
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15
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Pizarro-Guajardo M, Chamorro-Veloso N, Vidal RM, Paredes-Sabja D. New insights for vaccine development against Clostridium difficile infections. Anaerobe 2019; 58:73-79. [DOI: 10.1016/j.anaerobe.2019.04.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 04/17/2019] [Accepted: 04/25/2019] [Indexed: 02/08/2023]
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16
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Zhu D, Sorg JA, Sun X. Clostridioides difficile Biology: Sporulation, Germination, and Corresponding Therapies for C. difficile Infection. Front Cell Infect Microbiol 2018; 8:29. [PMID: 29473021 PMCID: PMC5809512 DOI: 10.3389/fcimb.2018.00029] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 01/23/2018] [Indexed: 12/18/2022] Open
Abstract
Clostridioides difficile is a Gram-positive, spore-forming, toxin-producing anaerobe, and an important nosocomial pathogen. Due to the strictly anaerobic nature of the vegetative form, spores are the main morphotype of infection and transmission of the disease. Spore formation and their subsequent germination play critical roles in C. difficile infection (CDI) progress. Under suitable conditions, C. difficile spores will germinate and outgrow to produce the pathogenic vegetative form. During CDI, C. difficile produces toxins (TcdA and TcdB) that are required to initiate the disease. Meanwhile, it also produces spores that are responsible for the persistence and recurrence of C. difficile in patients. Recent studies have shed light on the regulatory mechanisms of C. difficile sporulation and germination. This review is to summarize recent advances on the regulation of sporulation/germination in C. difficile and the corresponding therapeutic strategies that are aimed at these important processes.
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Affiliation(s)
- Duolong Zhu
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Joseph A Sorg
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Xingmin Sun
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
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17
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Immunization Strategies Against Clostridium difficile. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1050:197-225. [PMID: 29383671 DOI: 10.1007/978-3-319-72799-8_12] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
C. difficile infection (CDI) is an important healthcare- but also community-associated disease. CDI is considered a public health threat and an economic burden. A major problem is the high rate of recurrences. Besides classical antibiotic treatments, new therapeutic strategies are needed to prevent infection, to treat patients and prevent recurrences. If fecal transplantation has been recommended to treat recurrences, another key approach is to restore immunity against C. difficile and its virulence factors. Here, after a summary concerning the virulence factors, the host immune response against C. difficile and its role in the outcome of disease, we review the different approaches of passive immunotherapies and vaccines developed against CDI. Passive immunization strategies are designed in function of the target antigen, the antibody-based product and its administration route. Similarly, for active immunization strategies, vaccine antigens can target toxins or surface proteins and immunization can be performed by parenteral or mucosal routes. For passive immunization and vaccination as well, we first present immunization assays performed in animal models and second in humans and associated clinical trials. The different studies are presented according to the mode of administration either parenteral or mucosal and the target antigens, either toxins or colonization factors.
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18
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Song W, Cai J, Zou X, Wang X, Hu J, Yin J. Applications of controlled inversion strategies in carbohydrate synthesis. CHINESE CHEM LETT 2018. [DOI: 10.1016/j.cclet.2017.09.061] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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19
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Affiliation(s)
- Mark L Lang
- a Department of Microbiology and Immunology , University of Oklahoma Health Sciences Center , Oklahoma City , OK , USA
| | - Binu Shrestha
- a Department of Microbiology and Immunology , University of Oklahoma Health Sciences Center , Oklahoma City , OK , USA
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20
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Henderson M, Bragg A, Fahim G, Shah M, Hermes-DeSantis ER. A Review of the Safety and Efficacy of Vaccines as Prophylaxis for Clostridium difficile Infections. Vaccines (Basel) 2017; 5:E25. [PMID: 28869502 PMCID: PMC5620556 DOI: 10.3390/vaccines5030025] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Revised: 08/24/2017] [Accepted: 08/29/2017] [Indexed: 01/03/2023] Open
Abstract
This review aims to evaluate the literature on the safety and efficacy of novel toxoid vaccines for the prophylaxis of Clostridium difficile infections (CDI) in healthy adults. Literature searches for clinical trials were performed through MEDLINE, ClinicalTrials.gov, and Web of Science using the keywords bacterial vaccines, Clostridium difficile, and vaccine. English-language clinical trials evaluating the efficacy and/or safety of Clostridium difficile toxoid vaccines that were completed and had results posted on ClinicalTrials.gov or in a published journal article were included. Six clinical trials were included. The vaccines were associated with mild self-reported adverse reactions, most commonly injection site reactions and flu-like symptoms, and minimal serious adverse events. Five clinical trials found marked increases in antibody production in vaccinated participants following each dose of the vaccine. Clinical trials evaluating C. difficile toxoid vaccines have shown them to be well tolerated and relatively safe. Surrogate markers of efficacy (seroconversion and geometric mean antibody levels) have shown significant immune responses to a vaccination series in healthy adults, indicating that they have the potential to be used as prophylaxis for CDI. However, more research is needed to determine the clinical benefits of the vaccines.
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Affiliation(s)
- Mackenzie Henderson
- Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
| | - Amanda Bragg
- Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
| | - Germin Fahim
- Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
- Pharmacy Department, Monmouth Medical Center, Long Branch, NJ 07740, USA.
| | - Monica Shah
- Pharmacy Department, Monmouth Medical Center, Long Branch, NJ 07740, USA.
| | - Evelyn R Hermes-DeSantis
- Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
- Pharmacy Department, Robert Wood Johnson University Hospital, New Brunswick, NJ 08901, USA.
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21
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Broecker F, Seeberger PH. Identification and Design of Synthetic B Cell Epitopes for Carbohydrate-Based Vaccines. Methods Enzymol 2017; 597:311-334. [PMID: 28935109 DOI: 10.1016/bs.mie.2017.06.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Synthetic oligosaccharide-based vaccines are promising alternatives to conventional antibacterial carbohydrate vaccines prepared with isolated polysaccharides. Unlike polysaccharides, synthetic glycans are well defined, contaminant-free, and accessible even for pathogens that cannot be fermented or show limited carbohydrate biosynthesis in vitro. However, identifying synthetic glycan B cell epitopes that induce protective immunity has traditionally been a time-consuming trial-and-error process, as predicting the immunogenicity of an oligosaccharide by means of structure alone is not straightforward. We here describe how synthetic oligosaccharide epitopes for candidate vaccines can be rationally identified prior to preclinical immunogenicity studies. Epitopes are selected on the basis of their recognition by antibodies associated with protection from disease in humans or small animals. In addition, we show how murine antibody responses to a large oligosaccharide can inform the identification of a minimal B cell epitope that may help designing easy to synthesize vaccine candidates. The procedures, exemplified with a surface carbohydrate of Clostridium difficile, may serve as a guideline for selecting protective oligosaccharide epitopes for vaccines against infectious and malignant diseases.
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Affiliation(s)
- Felix Broecker
- Max Planck Institute of Colloids and Interfaces, Potsdam, Germany; Freie Universität Berlin, Berlin, Germany
| | - Peter H Seeberger
- Max Planck Institute of Colloids and Interfaces, Potsdam, Germany; Freie Universität Berlin, Berlin, Germany.
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22
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Yu K, Bi N, Xiong C, Cai S, Long Z, Guo Z, Gu G. Synthesis of Defined and Functionalized Glycans of Lipoteichoic Acid: A Cell Surface Polysaccharide from Clostridium difficile. Org Lett 2017; 19:3123-3126. [PMID: 28548838 DOI: 10.1021/acs.orglett.7b01242] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Two structurally defined, functionalized glycans of lipoteichoic acid (LTA, also known as PS-III) from C. difficile, which have one or two repeating units of LTA linked to the core trisaccharide, were efficiently synthesized via a convergent [2 + 3] or [2 + 2 + 3] strategy. The α-linkage of both N-acetylglucosamine residues in the repeating unit were constructed with glycosyl imidates of azidosugars as donors, while the phosphodiester bridges between the oligosaccharides were fashioned using H-phosphonate chemistry. Both synthetic targets contained a 3-aminopropyl group at the core trisaccharide reducing end, facilitating their conjugation to other biomolecules to afford conjugates useful for various biological studies and applications.
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Affiliation(s)
- Kang Yu
- National Glycoengineering Research Center and Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University , 27 Shanda Nan Lu, Jinan 250100, China
| | - Ningning Bi
- National Glycoengineering Research Center and Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University , 27 Shanda Nan Lu, Jinan 250100, China
| | - Chenghe Xiong
- National Glycoengineering Research Center and Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University , 27 Shanda Nan Lu, Jinan 250100, China
| | - Shuihong Cai
- Qidong Dongyue Pharmaceutical Company, 268 Shanghai Road, Qidong, Jiangsu 226200, China
| | - Zhongzhu Long
- Qidong Dongyue Pharmaceutical Company, 268 Shanghai Road, Qidong, Jiangsu 226200, China
| | - Zhongwu Guo
- National Glycoengineering Research Center and Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University , 27 Shanda Nan Lu, Jinan 250100, China.,Department of Chemistry, University of Florida , 214 Leigh Hall, Gainesville, Florida 32611, United States
| | - Guofeng Gu
- National Glycoengineering Research Center and Shandong Provincial Key Laboratory of Carbohydrate Chemistry and Glycobiology, Shandong University , 27 Shanda Nan Lu, Jinan 250100, China
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23
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Chu M, Mallozzi MJG, Roxas BP, Bertolo L, Monteiro MA, Agellon A, Viswanathan VK, Vedantam G. A Clostridium difficile Cell Wall Glycopolymer Locus Influences Bacterial Shape, Polysaccharide Production and Virulence. PLoS Pathog 2016; 12:e1005946. [PMID: 27741317 PMCID: PMC5065235 DOI: 10.1371/journal.ppat.1005946] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023] Open
Abstract
Clostridium difficile is a diarrheagenic pathogen associated with significant mortality and morbidity. While its glucosylating toxins are primary virulence determinants, there is increasing appreciation of important roles for non-toxin factors in C. difficile pathogenesis. Cell wall glycopolymers (CWGs) influence the virulence of various pathogens. Five C. difficile CWGs, including PSII, have been structurally characterized, but their biosynthesis and significance in C. difficile infection is unknown. We explored the contribution of a conserved CWG locus to C. difficile cell-surface integrity and virulence. Attempts at disrupting multiple genes in the locus, including one encoding a predicted CWG exporter mviN, were unsuccessful, suggesting essentiality of the respective gene products. However, antisense RNA-mediated mviN downregulation resulted in slight morphology defects, retarded growth, and decreased surface PSII deposition. Two other genes, lcpA and lcpB, with putative roles in CWG anchoring, could be disrupted by insertional inactivation. lcpA- and lcpB- mutants had distinct phenotypes, implying non-redundant roles for the respective proteins. The lcpB- mutant was defective in surface PSII deposition and shedding, and exhibited a remodeled cell surface characterized by elongated and helical morphology, aberrantly-localized cell septae, and an altered surface-anchored protein profile. Both lcpA- and lcpB- strains also displayed heightened virulence in a hamster model of C. difficile disease. We propose that gene products of the C. difficile CWG locus are essential, that they direct the production/assembly of key antigenic surface polysaccharides, and thereby have complex roles in virulence. Clostridium difficile infection is a leading healthcare-onset bacterial disease, and its management and prevention imposes significant clinical and financial burdens worldwide. While toxins TcdA and TcdB are the primary virulence factors, there is increasing interest in, and appreciation of, non-toxin virulence factors in C. difficile pathogenesis. Cell wall glycopolymers (CWGs) are important virulence determinants in many pathogens, but their role(s) in C. difficile pathogenesis is unclear. We propose a model for C. difficile CWG biosynthesis, and demonstrate that alterations in cell wall assembly profoundly impact bacterial morphology and virulence.
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Affiliation(s)
- Michele Chu
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States of America
| | - Michael J. G. Mallozzi
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States of America
| | - Bryan P. Roxas
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States of America
| | - Lisa Bertolo
- Department of Chemistry, University of Guelph, Guelph, Ontario, Canada
| | - Mario A. Monteiro
- Department of Chemistry, University of Guelph, Guelph, Ontario, Canada
| | - Al Agellon
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States of America
| | - V. K. Viswanathan
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States of America
- Department of Immunobiology, Bio5 Institute for Collaborative Research, University of Arizona, Tucson, Arizona, United States of America
| | - Gayatri Vedantam
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States of America
- Department of Immunobiology, Bio5 Institute for Collaborative Research, University of Arizona, Tucson, Arizona, United States of America
- Southern Arizona VA Healthcare System, Tucson, Arizona, United States of America
- * E-mail:
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24
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Abstract
Clostridium difficile continues to be one of the most prevalent hospital-acquired bacterial infections in the developed world, despite the recent introduction of a novel and effective antibiotic agent (fidaxomicin). Alternative approaches under investigation to combat the anaerobic Gram-positive bacteria include fecal transplantation therapy, vaccines, and antibody-based immunotherapies. In this review, we catalog the recent advances in antibody-based approaches under development and in the clinic for the treatment of C. difficile infection. By and large, inhibitory antibodies that recognize the primary C. difficile virulence factors, toxin A and toxin B, are the most popular passive immunotherapies under investigation. We provide a detailed summary of the toxin epitopes recognized by various antitoxin antibodies and discuss general trends on toxin inhibition efficacy. In addition, antibodies to other C. difficile targets, such as surface-layer proteins, binary toxin, motility factors, and adherence and colonization factors, are introduced in this review.
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Affiliation(s)
- Greg Hussack
- Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa
| | - Jamshid Tanha
- Human Health Therapeutics Portfolio, National Research Council Canada, Ottawa; School of Environmental Sciences, University of Guelph, Guelph; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
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25
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Sheldon E, Kitchin N, Peng Y, Eiden J, Gruber W, Johnson E, Jansen KU, Pride MW, Pedneault L. A phase 1, placebo-controlled, randomized study of the safety, tolerability, and immunogenicity of a Clostridium difficile vaccine administered with or without aluminum hydroxide in healthy adults. Vaccine 2016; 34:2082-91. [DOI: 10.1016/j.vaccine.2016.03.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 03/01/2016] [Accepted: 03/04/2016] [Indexed: 12/21/2022]
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26
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Abstract
Clostridium difficile vaccines composed of surface polysaccharides (PSs) have the potential to simultaneously control infection and colonization levels in humans. Hot water-phenol treatment of C. difficile biomass can extricate water-soluble PS-I and PS-II; and water- and phenol-soluble PS-III. C. difficile vaccines based on PS-II have attracted the most attention due its facile purification and ubiquitous expression by C. difficile ribotypes. Anti PS-II antibodies recognize both C. difficile vegetative cell and sporulating preparations and confer protection against C. difficile infection in a mouse model. The design of such an efficacious C. difficile PS-II conjugate vaccine is described here.
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Affiliation(s)
- Mario A Monteiro
- University of Guelph, 50 Stone Road East, Guelph, ON, Canada, N1G 2W1.
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27
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Zhao S, Ghose-Paul C, Zhang K, Tzipori S, Sun X. Immune-based treatment and prevention of Clostridium difficile infection. Hum Vaccin Immunother 2015; 10:3522-30. [PMID: 25668664 DOI: 10.4161/21645515.2014.980193] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Clostridium difficile (C. difficile) causes over 500,000 infections per year in the US, with an estimated 15,000 deaths and an estimated cost of $1-3 billion. Moreover, a continual rise in the incidence of severe C. difficile infection (CDI) has been observed worldwide. Currently, standard treatment for CDI is the administration of antibiotics. While effective, these treatments do not prevent and may contribute to a disease recurrence rate of 15-35%. Prevention of recurrence is one of the most challenging aspects in the field. A better knowledge of the molecular mechanisms of the disease, the host immune response and identification of key virulence factors of C. difficilenow permits the development of immune-based therapies. Antibodies specific for C. difficile toxins have been shown to effectively treat CDI and prevent disease relapse in animal models and in humans. Vaccination has been recognized as the most cost-effective treatment/prevention for CDI. This review will summarize CDI transmission, epidemiology, major virulent factors and highlights the rational and the development of immune-based approaches against this remerging threat.
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Key Words
- AAD, antibiotic-associated diarrhea
- CDI, Clostridium difficile infection
- CPD, cysteine proteinase domain
- GTD, glucosyltransferase domain
- HuMabs, human monoclonal antibodies
- IVIG, intravenous immunoglobulin
- RBD, receptor binding domain
- SLP, surface-layer protein
- TMD, transmembrane domain
- bacterial toxins
- clostridium difficile infection (CDI)
- immunotherapy
- mAb, monoclonal antibody
- monoclonal antibody
- vaccine
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Affiliation(s)
- Song Zhao
- a Department of Infectious Diseases and Global Health ; Tufts University Cummings School of Veterinary Medicine ; North Grafton , MA USA
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28
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Addressing the global need to combat multidrug resistance: carbohydrates may hold the key. Future Med Chem 2015; 6:1539-43. [PMID: 25367388 DOI: 10.4155/fmc.14.109] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
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29
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Guo S, Yan W, McDonough SP, Lin N, Wu KJ, He H, Xiang H, Yang M, Moreira MAS, Chang YF. The recombinant Lactococcus lactis oral vaccine induces protection against C. difficile spore challenge in a mouse model. Vaccine 2015; 33:1586-95. [DOI: 10.1016/j.vaccine.2015.02.006] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 01/26/2015] [Accepted: 02/04/2015] [Indexed: 01/05/2023]
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30
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Abstract
Clostridium difficile is a spore-forming anaerobic gram-positive organism that is the leading cause of antibiotic-associated nosocomial infectious diarrhea in the Western world. This article describes the evolving epidemiology of C difficile infection (CDI) in the twenty-first century, evaluates the importance of vaccines against the disease, and defines the roles of both innate and adaptive host immune responses in CDI. The effects of passive immunotherapy and active vaccination against CDI in both humans and animals are also discussed.
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Affiliation(s)
- Chandrabali Ghose
- Aaron Diamond AIDS Research Center, 455 First Avenue, 7th Floor, New York, NY 10016, USA.
| | - Ciarán P Kelly
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA
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Anish C, Schumann B, Pereira CL, Seeberger PH. Chemical biology approaches to designing defined carbohydrate vaccines. ACTA ACUST UNITED AC 2015; 21:38-50. [PMID: 24439205 DOI: 10.1016/j.chembiol.2014.01.002] [Citation(s) in RCA: 131] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 12/27/2013] [Accepted: 01/02/2014] [Indexed: 01/08/2023]
Abstract
Carbohydrate antigens have shown promise as important targets for developing effective vaccines and pathogen detection strategies. Modifying purified microbial glycans through synthetic routes or completely synthesizing antigenic motifs are attractive options to advance carbohydrate vaccine development. However, limited knowledge on structure-property correlates hampers the discovery of immunoprotective carbohydrate epitopes. Recent advancements in tools for glycan modification, high-throughput screening of biological samples, and 3D structural analysis may facilitate antigen discovery process. This review focuses on advances that accelerate carbohydrate-based vaccine development and various technologies that are driving these efforts. Herein we provide a critical overview of approaches and resources available for rational design of better carbohydrate antigens. Structurally defined and fully synthetic oligosaccharides, designed based on molecular understanding of antigen-antibody interactions, offer a promising alternative for developing future carbohydrate vaccines.
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Affiliation(s)
- Chakkumkal Anish
- Department for Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany.
| | - Benjamin Schumann
- Department for Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany
| | - Claney Lebev Pereira
- Department for Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany
| | - Peter H Seeberger
- Department for Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14424 Potsdam, Germany; Institute of Chemistry and Biochemistry, Freie Universität Berlin, Arnimallee 22, 14195 Berlin, Germany.
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Mathur H, Rea MC, Cotter PD, Ross RP, Hill C. The potential for emerging therapeutic options for Clostridium difficile infection. Gut Microbes 2015; 5:696-710. [PMID: 25564777 PMCID: PMC4615897 DOI: 10.4161/19490976.2014.983768] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Clostridium difficile is mainly a nosocomial pathogen and is a significant cause of antibiotic-associated diarrhea. It is also implicated in the majority of cases of pseudomembranous colitis. Recently, advancements in next generation sequencing technology (NGS) have highlighted the extent of damage to the gut microbiota caused by broad-spectrum antibiotics, often resulting in C. difficile infection (CDI). Currently the treatment of choice for CDI involves the use of metronidazole and vancomycin. However, recurrence and relapse of CDI, even after rounds of metronidazole/vancomycin administration is a problem that must be addressed. The efficacy of alternative antibiotics such as fidaxomicin, rifaximin, nitazoxanide, ramoplanin and tigecycline, as well as faecal microbiota transplantation has been assessed and some have yielded positive outcomes against C. difficile. Some bacteriocins have also shown promising effects against C. difficile in recent years. In light of this, the potential for emerging treatment options and efficacy of anti-C. difficile vaccines are discussed in this review.
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Key Words
- ATCC, American Type Culture Collection
- CDI, Clostridium difficile infection
- CdtLoc, binary toxin locus
- Clostridium difficile
- DNA, deoxyribonucleic acid
- DPC, Dairy Products Collection
- ESCMID, European Society of Clinical Microbiology and Infectious Diseases
- ETEC, enterotoxigenic E. coli
- FDA, Food and Drug Administration
- FMT, faecal microbiota transplantation
- GIT, gastrointestinal tract
- HIV, human immunodeficiency virus
- IDSA, Infectious Diseases Society of America
- IgG, immunoglobulin G
- LTA, lipoteichoic acid
- M21V, methionine to valine substitution at residue 21
- MIC, minimum inhibitory concentration
- NGS, next generation sequencing
- NVB, Novacta Biosystems Ltd
- PMC, pseudomembranous colitis
- PaLoc, pathogenicity locus
- R027, ribotype 027
- RBD
- RBS, ribosome binding site
- RNA, ribonucleic acid
- SHEA, Society for Healthcare Epidemiology of America
- V15F, valine to phenylalanine substitution at residue 15
- antibiotics
- faecal microbiota transplantation
- receptor binding domain
- toxins
- vaccines
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Affiliation(s)
- Harsh Mathur
- School of Microbiology; University College Cork; Cork, Ireland,Teagasc Food Research Center; Moorepark; Fermoy, Ireland
| | - Mary C Rea
- Teagasc Food Research Center; Moorepark; Fermoy, Ireland,Alimentary Pharmabiotic Center; University College Cork; Cork, Ireland
| | - Paul D Cotter
- Teagasc Food Research Center; Moorepark; Fermoy, Ireland,Alimentary Pharmabiotic Center; University College Cork; Cork, Ireland,Correspondence to: Colin Hill; ; Paul D Cotter;
| | - R Paul Ross
- Alimentary Pharmabiotic Center; University College Cork; Cork, Ireland,College of Science; Engineering and Food Science; University College Cork; Cork, Ireland
| | - Colin Hill
- School of Microbiology; University College Cork; Cork, Ireland,Alimentary Pharmabiotic Center; University College Cork; Cork, Ireland,Correspondence to: Colin Hill; ; Paul D Cotter;
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Abstract
Vaccination is one of the key developments in the fight against infectious diseases. It is based on the principle that immunization with pathogen-derived antigens provides protection from the respective infection by inducing an antigen-specific immune response. The discovery by Avery and Heidelberger in the 1920s that capsular polysaccharides (CPS) from Streptococcus pneumoniae are immunoreactive was the starting point of the development of carbohydrate-based vaccines. CPS-specific neutralizing antibodies were found to mediate protection against S. pneumoniae infection. Since the majority of bacterial pathogens carry a dense array of polysaccharides on their surface, the carbohydrate-based vaccine approach was applied to a variety of bacterial strains. The first CPS-based vaccines against S. pneumoniae were licensed in the 1940s. The increasing emergence of antibiotic-resistant bacterial strains since the 1960s boosted the development of carbohydrate-based vaccines and led to the approval of CPS-based vaccines against Neisseria meningitidis, Haemophilus influenzae type b (Hib), and Salmonella typhi. Meanwhile, it was observed that CPS generally do not elicit protective antibody responses in children below the age of 2 years who are at the greatest risk of infection. As a consequence, studies refocused on the conjugation of oligosaccharides to proteins in order to increase vaccine immunogenicity which led to the introduction of the first glycoconjugate vaccine against Hib in 1987. Due to the success of the first glycoconjugate vaccines, higher valent formulations were developed against numerous bacterial infections to achieve broad serotype coverage. Current research also focuses on the development of carbohydrate-based vaccines against other pathogens such as viruses, fungi, protozoan parasites, or helminths.
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34
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Awad MM, Johanesen PA, Carter GP, Rose E, Lyras D. Clostridium difficile virulence factors: Insights into an anaerobic spore-forming pathogen. Gut Microbes 2014; 5:579-93. [PMID: 25483328 PMCID: PMC4615314 DOI: 10.4161/19490976.2014.969632] [Citation(s) in RCA: 107] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The worldwide emergence of epidemic strains of Clostridium difficile linked to increased disease severity and mortality has resulted in greater research efforts toward determining the virulence factors and pathogenesis mechanisms used by this organism to cause disease. C. difficile is an opportunist pathogen that employs many factors to infect and damage the host, often with devastating consequences. This review will focus on the role of the 2 major virulence factors, toxin A (TcdA) and toxin B (TcdB), as well as the role of other putative virulence factors, such as binary toxin, in C. difficile-mediated infection. Consideration is given to the importance of spores in both the initiation of disease and disease recurrence and also to the role that surface proteins play in host interactions.
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Key Words
- AAD, antibiotic associated diarrhea
- C. difficile,Clostridium difficile
- CDI, C. difficile infection
- CDT, Clostridium difficile transferase
- CDTLoc, CDT locus
- CDTa, CDT enzymatic component
- CDTb, CDT binding/translocation component
- CST, Clostridium spiroforme toxin
- CWPs, cell wall protein
- Clostridium
- ECF, extracytoplasmic function
- HMW, high molecular weight
- LMW, low molecular weight
- LSR, lipolysis-stimulated lipoprotein receptor
- PCR, polymerase chain reaction
- PFGE, pulsed field gel electrophoresis
- PaLoc, pathogenicity locus
- REA, restriction endonuclease analysis
- S-layer, surface layer
- SLPs, S-layer proteins
- TcdA, toxin A
- TcdB, toxin B
- antibiotic
- colitis
- difficile
- infection
- nosocomial
- toxin
- virulence factor
- ι-toxin, iota toxin
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Affiliation(s)
- Milena M Awad
- Department of Microbiology; Monash University; Clayton, Victoria, Australia
| | | | - Glen P Carter
- Department of Microbiology; Monash University; Clayton, Victoria, Australia
| | - Edward Rose
- Department of Microbiology; Monash University; Clayton, Victoria, Australia
| | - Dena Lyras
- Department of Microbiology; Monash University; Clayton, Victoria, Australia,Correspondence to: Dena Lyras;
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Hogendorf WFJ, Gisch N, Schwudke D, Heine H, Bols M, Pedersen CM. Total Synthesis of Five Lipoteichoic acids of
Clostridium difficile. Chemistry 2014; 20:13511-6. [DOI: 10.1002/chem.201404336] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Indexed: 11/09/2022]
Affiliation(s)
- Wouter F. J. Hogendorf
- Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100, Copenhagen Ø (Denmark)
| | - Nicolas Gisch
- Division of Bioanalytical Chemistry, Research Center Borstel, Leibniz‐Center for Medicine and Biosciences, Parkallee 1–40, 23845 Borstel (Germany)
| | - Dominik Schwudke
- Division of Bioanalytical Chemistry, Research Center Borstel, Leibniz‐Center for Medicine and Biosciences, Parkallee 1–40, 23845 Borstel (Germany)
| | - Holger Heine
- Division of Innate Immunity, Research Center Borstel, Leibniz‐Center for Medicine and Biosciences, Parkallee 1–40, 23845 Borstel (Germany)
| | - Mikael Bols
- Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100, Copenhagen Ø (Denmark)
| | - Christian Marcus Pedersen
- Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100, Copenhagen Ø (Denmark)
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Recombinant Clostridium difficile toxin fragments as carrier protein for PSII surface polysaccharide preserve their neutralizing activity. Toxins (Basel) 2014; 6:1385-96. [PMID: 24759173 PMCID: PMC4014741 DOI: 10.3390/toxins6041385] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 03/06/2014] [Accepted: 04/09/2014] [Indexed: 11/29/2022] Open
Abstract
Clostridium difficile is a Gram-positive bacterium and is the most commonly diagnosed cause of hospital-associated and antimicrobial-associated diarrhea. Despite the emergence of epidemic C. difficile strains having led to an increase in the incidence of the disease, a vaccine against this pathogen is not currently available. C. difficile strains produce two main toxins (TcdA and TcdB) and express three highly complex cell-surface polysaccharides (PSI, PSII and PSIII). PSII is the more abundantly expressed by most C. difficile ribotypes offering the opportunity of the development of a carbohydrate-based vaccine. In this paper, we evaluate the efficacy, in naive mice model, of PSII glycoconjugates where recombinant toxins A and B fragments (TcdA_B2 and TcdB_GT respectively) have been used as carriers. Both glycoconjugates elicited IgG titers anti-PSII although only the TcdB_GT conjugate induced a response comparable to that obtained with CRM197. Moreover, TcdA_B2 and TcdB_GT conjugated to PSII retained the ability to elicit IgG with neutralizing activity against the respective toxins. These results are a crucial proof of concept for the development of glycoconjugate vaccines against C. difficile infection (CDI) that combine different C. difficile antigens to potentially prevent bacterial colonization of the gut and neutralize toxin activity.
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37
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Leuzzi R, Adamo R, Scarselli M. Vaccines against Clostridium difficile. Hum Vaccin Immunother 2014; 10:1466-77. [PMID: 24637887 DOI: 10.4161/hv.28428] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Clostridium difficile infection (CDI) is recognized as a major cause of nosocomial diseases ranging from antibiotic related diarrhea to fulminant colitis. Emergence during the last 2 decades of C. difficile strains associated with high incidence, severity and lethal outcomes has increased the challenges for CDI treatment. A limited number of drugs have proven to be effective against CDI and concerns about antibiotic resistance as well as recurring disease solicited the search for novel therapeutic strategies. Active vaccination provides the attractive opportunity to prevent CDI, and intense research in recent years led to development of experimental vaccines, 3 of which are currently under clinical evaluation. This review summarizes recent achievements and remaining challenges in the field of C. difficile vaccines, and discusses future perspectives in view of newly-identified candidate antigens.
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Abstract
The incidence and severity of Clostridium difficile infection (CDI) have dramatically increased in the Western world in recent years. In contrast, CDI is rarely reported in China, possibly due to under-diagnosis. This article briefly summarizes CDI incidence, management and preventive strategies. The authors intend to raise awareness of this disease among Chinese physicians and health workers, in order to minimize the medical and economic burden of a potential epidemic in the future.
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Affiliation(s)
- Xinhua Chen
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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39
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Clostridium difficile infection in the twenty-first century. Emerg Microbes Infect 2013; 2:e62. [PMID: 26038491 PMCID: PMC3820989 DOI: 10.1038/emi.2013.62] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2013] [Revised: 08/02/2013] [Accepted: 08/05/2013] [Indexed: 02/07/2023]
Abstract
Clostridium difficile is a spore-forming gram-positive bacillus, and the leading cause of antibiotic-associated nosocomial diarrhea and colitis in the industrialized world. With the emergence of a hypervirulent strain of C. difficile (BI/NAP1/027), the epidemiology of C. difficile infection has rapidly changed in the last decade. C. difficile infection, once thought to be an easy to treat bacterial infection, has evolved into an epidemic that is associated with a high rate of mortality, causing disease in patients thought to be low-risk. In this review, we discuss the changing face of C .difficile infection and the novel treatment and prevention strategies needed to halt this ever growing epidemic.
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40
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Cox AD, St. Michael F, Aubry A, Cairns CM, Strong PCR, Hayes AC, Logan SM. Investigating the candidacy of a lipoteichoic acid-based glycoconjugate as a vaccine to combat Clostridium difficile infection. Glycoconj J 2013; 30:843-55. [DOI: 10.1007/s10719-013-9489-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 07/19/2013] [Accepted: 07/25/2013] [Indexed: 10/26/2022]
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Pequegnat B, Sagermann M, Valliani M, Toh M, Chow H, Allen-Vercoe E, Monteiro MA. A vaccine and diagnostic target for Clostridium bolteae, an autism-associated bacterium. Vaccine 2013; 31:2787-90. [PMID: 23602537 DOI: 10.1016/j.vaccine.2013.04.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Revised: 03/15/2013] [Accepted: 04/05/2013] [Indexed: 12/29/2022]
Abstract
Constipation and diarrhea are common in autistic patients. Treatment with antibiotics against bacteria appears to partially alleviate autistic-related symptoms. Clostridium bolteae is a bacterium that has been shown to be overabundant in the intestinal tract of autistic children suffering from gastric intestinal ailments, and as such is an organism that could potentially aggravate gastrointestinal symptoms. We set out to investigate the cell-wall polysaccharides of C. bolteae in order to evaluate their structure and immunogenicity. Our explorations revealed that C. bolteae produces a conserved specific capsular polysaccharide comprised of rhamnose and mannose units: [→3)-α-D-Manp-(1→4)-β-d-Rhap-(1→], which is immunogenic in rabbits. These findings are the first description of a C. bolteae immunogen and indicate the prospect of using this polysaccharide as a vaccine to reduce or prevent C. bolteae colonization of the intestinal tract in autistic patients, and as a diagnostic marker for the rapid detection of C. bolteae in a clinical setting.
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Affiliation(s)
- Brittany Pequegnat
- Department of Chemistry, University of Guelph, Guelph, ON N1G 2W1, Canada
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42
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Jiao Y, Ma Z, Hodgins D, Pequegnat B, Bertolo L, Arroyo L, Monteiro MA. Clostridium difficile PSI polysaccharide: synthesis of pentasaccharide repeating block, conjugation to exotoxin B subunit, and detection of natural anti-PSI IgG antibodies in horse serum. Carbohydr Res 2013; 378:15-25. [PMID: 23597587 DOI: 10.1016/j.carres.2013.03.018] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2013] [Revised: 03/21/2013] [Accepted: 03/22/2013] [Indexed: 01/08/2023]
Abstract
Clostridium difficile is the most common cause of antimicrobial-associated diarrhea in humans and may cause death. Previously, we discovered that C. difficile expresses three polysaccharides, named PSI, PSII, and PSIII. It has now been established that PSII is a conserved antigen abundantly present on the cell-surface and biofilm of C. difficile. In contrast, the expression of PSI and PSIII appears to be stochastic processes. In this work, the total chemical synthesis of the PSI pentasaccharide repeating unit carrying a linker at the reducing end, α-l-Rhap-(1→3)-β-d-Glcp-(1→4)-[α-l-Rhap-(1→3)]-α-d-Glcp-(1→2)-α-d-Glcp-(1→O(CH2)5NH2, was achieved by a linear synthesis strategy from four monosaccharide building blocks. The synthesized PSI pentasaccharide was conjugated to a subunit of C. difficile exotoxin B yielding a potential dual C. difficile vaccine. More significantly, sera from healthy horses were shown to contain natural anti-PSI IgG antibodies that detected both the synthetic non-phosphorylated PSI repeat and the native PSI polysaccharide, with a slightly higher recognition of the native PSI polysaccharide.
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Affiliation(s)
- Yuening Jiao
- Department of Chemistry, University of Guelph, Guelph, ON, Canada
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43
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Martin CE, Broecker F, Eller S, Oberli MA, Anish C, Pereira CL, Seeberger PH. Glycan arrays containing synthetic Clostridium difficile lipoteichoic acid oligomers as tools toward a carbohydrate vaccine. Chem Commun (Camb) 2013; 49:7159-61. [DOI: 10.1039/c3cc43545h] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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