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      Immunogenicity and protective efficacy of recombinant Clostridium difficile flagellar protein FliC

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          Abstract

          Clostridium difficile is a Gram-positive bacillus and is the leading cause of toxin-mediated nosocomial diarrhea following antibiotic use. C. difficile flagella play a role in colonization, adherence, biofilm formation, and toxin production, which might contribute to the overall virulence of certain strains. Human and animal studies indicate that anti-flagella immune responses may play a role in protection against colonization by C. difficile and subsequent disease outcome. Here we report that recombinant C. difficile flagellin (FliC) is immunogenic and protective in a murine model of C. difficile infection (CDI) against a clinical C. difficile strain, UK1. Passive protection experiments using anti-FliC polyclonal serum in mice suggest this protection to be antibody-mediated. FliC immunization also was able to afford partial protection against CDI and death in hamsters following challenge with C. difficile 630Δ erm. Additionally, immunization against FliC does not have an adverse effect on the normal gut flora of vaccinated hamsters as evidenced by comparing the fecal microbiome of vaccinated and control hamsters. Therefore, the use of FliC as a vaccine candidate against CDI warrants further testing.

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          Toll-like receptors: critical proteins linking innate and acquired immunity.

          S Akira, K Takeda, T Kaisho (2001)
          Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns (pathogen-associated molecular patterns), which are shared by large groups of microorganisms. Toll-like receptors (TLRs) function as the PRRs in mammals and play an essential role in the recognition of microbial components. The TLRs may also recognize endogenous ligands induced during the inflammatory response. Similar cytoplasmic domains allow TLRs to use the same signaling molecules used by the interleukin 1 receptors (IL-1Rs): these include MyD88, IL-1R--associated protein kinase and tumor necrosis factor receptor--activated factor 6. However, evidence is accumulating that the signaling pathways associated with each TLR are not identical and may, therefore, result in different biological responses.
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            An integrated semiconductor device enabling non-optical genome sequencing.

            Jonathan Rothberg, Wolfgang Hinz, Todd M. Rearick … (2011)
            The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.
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              Evasion of Toll-like receptor 5 by flagellated bacteria.

              Alan Aderem, B Cookson, Nicola S Logan … (2005)
              Toll-like receptor 5 (TLR5) recognizes an evolutionarily conserved site on bacterial flagellin that is required for flagellar filament assembly and motility. The alpha and epsilon Proteobacteria, including the important human pathogens Campylobacter jejuni, Helicobacter pylori, and Bartonella bacilliformis, require flagellar motility to efficiently infect mammalian hosts. In this study, we demonstrate that these bacteria make flagellin molecules that are not recognized by TLR5. We map the site responsible for TLR5 evasion to amino acids 89-96 of the N-terminal D1 domain, which is centrally positioned within the previously defined TLR5 recognition site. Salmonella flagellin is strongly recognized by TLR5, but mutating residues 89-96 to the corresponding H. pylori flaA sequence abolishes TLR5 recognition and also destroys bacterial motility. To preserve bacterial motility, alpha and epsilon Proteobacteria possess compensatory amino acid changes in other regions of the flagellin molecule, and we engineer a mutant form of Salmonella flagellin that evades TLR5 but retains motility. These results suggest that TLR5 evasion is critical for the survival of this subset of bacteria at mucosal sites in animals and raise the intriguing possibility that flagellin receptors provided the selective force to drive the evolution of these unique subclasses of bacterial flagellins.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Emerg Microbes Infect
                Journal ID (iso-abbrev): Emerg Microbes Infect
                Title: Emerging Microbes & Infections
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2222-1751
                Publication date (Print): February 2016
                Publication date (Electronic): 03 February 2016
                Publication date PMC-release: 1 February 2016
                Volume: 5
                Issue: 2
                Page: e8
                Affiliations
                [1 ]Aaron Diamond AIDS Research Center , New York, NY 10075, USA
                [2 ]Tufts University, Cummings School of Veterinary Medicine , North Grafton, MA 01536, USA
                [3 ]Department of Microbiology and Immunology, Emory University School of Medicine , Atlanta, GA 30322, USA
                [4 ]Departments of Pathology and Medicine, University of California , San Diego, La Jolla, CA 92093, USA
                [5 ]Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA 02215, USA
                [6 ]The Rockefeller University , New York, NY 10065, USA
                Author notes
                Article
                Publisher Item ID: emi20168
                DOI: 10.1038/emi.2016.8
                PMC ID: 4777929
                PubMed ID: 26839147
                SO-VID: 7e621fed-e1d6-47b1-a721-0e67cb53bd7e
                Copyright © Copyright © 2016 Shanghai Shangyixun Cultural Communication Co., Ltd
                License:

                This work is licensed under a Creative Commons Attribution 4.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                Date received : 13 July 2015
                Date revision received : 13 October 2015
                Date accepted : 12 November 2015
                Categories
                Subject: Original Article

                Keywords: c. difficile,flagella,flic,vaccine
                Data availability:
                Keywords: c. difficile, flagella, flic, vaccine

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