title: The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia.
abstract: Clostridium difficile is the most common hospital acquired pathogen in the USA, and infection is, in many cases, fatal. Toxins A and B are its major virulence factors, but expression of a third toxin, known as C. difficile transferase (CDT), is increasingly common. An adenosine diphosphate (ADP)-ribosyltransferase that causes actin cytoskeletal disruption, CDT is typically produced by the major, hypervirulent strains and has been associated with more severe disease. Here, we show that CDT enhances the virulence of two PCR-ribotype 027 strains in mice. The toxin induces pathogenic host inflammation via a Toll-like receptor 2 (TLR2)-dependent pathway, resulting in the suppression of a protective host eosinophilic response. Finally, we show that restoration of TLR2-deficient eosinophils is sufficient for protection from a strain producing CDT. These findings offer an explanation for the enhanced virulence of CDT-expressing C. difficile and demonstrate a mechanism by which this binary toxin subverts the host immune response.
authors: Departments of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia 22908 USA.
authors: Carrie A
authors: 0000-0002-8225-8261
authors: CA
authors: Cowardin
authors: Departments of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia 22908 USA.
authors: Erica L
authors: EL
authors: Buonomo
authors: Departments of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia 22908 USA.
authors: Mahmoud M
authors: MM
authors: Saleh
authors: Departments of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia 22908 USA.
authors: Madeline G
authors: MG
authors: Wilson
authors: Departments of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia 22908 USA.
authors: Stacey L
authors: SL
authors: Burgess
authors: Clostridia Research Group, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors: Sarah A
authors: SA
authors: Kuehne
authors: Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors: Carsten
authors: C
authors: Schwan
authors: Institute of Immunology, University Medical Center Hamburg-Eppendorf, D20246 Hamburg, Germany.
authors: Anna M
authors: AM
authors: Eichhoff
authors: Institute of Immunology, University Medical Center Hamburg-Eppendorf, D20246 Hamburg, Germany.
authors: Friedrich
authors: F
authors: Koch-Nolte
authors: Department of Microbiology, Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Monash University, Victoria 3800, Australia.
authors: Dena
authors: D
authors: Lyras
authors: Institute of Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany.
authors: Klaus
authors: K
authors: Aktories
authors: Clostridia Research Group, Centre for Biomolecular Sciences, University of Nottingham, Nottingham NG7 2RD, UK.
authors: Nigel P
authors: NP
authors: Minton
authors: Departments of Microbiology, Immunology and Cancer Biology, University of Virginia Health System, Charlottesville, Virginia 22908 USA.|Departments of Medicine, University of Virginia Health System, Charlottesville, Virginia 22908 USA.|Departments of Pathology, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
authors: William A
authors: WA
authors: Petri
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D016360:Clostridioides difficile / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D003015:Clostridium Infections / Q000382:microbiology / Q000473:pathology*; D003106:Colon / Q000276:immunology*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology*; D051379:Mice; D021521:Ribotyping; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D037521:Virulence Factors; D036002:ADP Ribose Transferases; C410164:actin-specific ADP-ribosyltransferase, Clostridium