Clostridium Difficile Infection (CDI)

• Hillary Danz
• Charles Shoemaker
• Gillian Beamer
• Saul Tzipori

Clostridium difficile infection (CDI) causes antibiotic associated diarrhea and pseudomemberous colitis, mostly in the elderly and in hospitalized patients. The main cause of pathology is colonic expression of two large glucosylating toxins, TcdA and TcdB. Research in the Department of Infectious Diseases and Global Health aims to understand the mechanisms of toxin-mediated inflammation and to investigate the role of each toxin in the pathogenesis of C. difficile-associated diseases. The Department is developing CDI models in the gnotobiotic pig model transplanted with the human microbiome and generating recombinant CDI vaccines. In addition, we are evaluating antimicrobial agents and immune-based therapies, including separately, the Merck and the MedImmune human monoclonal antibodies and hyperimmune bovine colostrum, to treat and/or prevent CDI disease. We are also advancing development of single-domain antibodies (sdAbs) derived from alpacas, called VHHs, that target and neutralize the C. difficile toxins, TcdA and TcdB. The VHHs are engineered into heteromultimers resulting in potent antitoxin VHH-based neutralizing agents (VNAs) that have demonstrated efficacy in mouse and pig models of CDI when administered as proteins or by gene therapy. More details on VNAs are available at the Novel Antitoxin Agents webpage. More recently we have embarked on attempting to define the precise role of each of the CDI virulence factors contributing to diarrhea, mucosal lesions and to systemic disease, using a panel of 6 isogenic mutants expressing a single virulence factor. We are also attempting to understand why monoclonal antibody directed against TcdA exasperate the clinical symptoms rather than provide protection against the toxin in pigs and in humans.

Publications

• Schmidt DJ, Beamer G, Tremblay JM, Steele JA, Kim HB, Wang Y, Debatis M, Sun X, Kashentseva EA, Dmitriev IP, Curiel DT, Shoemaker CB, Tzipori S. 2016. A Tetraspecific VHH-Based Neutralizing Antibody Modifies Disease Outcome in Three Animal Models of Clostridium difficile Infection. Clin Vaccine Immunol. 23:774-84.
• Kaleko M, Bristol JA, Hubert S, Parsley T, Widmer G, Tzipori S, Subramanian P, Hasan N, Koski P, Kokai-Kun J, Sliman J, Jones A, Connelly S. 2016. Development of SYN-004, an oral beta-lactamase treatment to protect the gut microbiome from antibiotic-mediated damage and prevent Clostridium difficile infection. Anaerobe. 41:58-67.
• Wang YK, Yan YX, Kim HB, Ju X, Zhao S, Zhang K, Tzipori S, Sun X. 2015. A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity against Clostridium difficile infection in mice and hamsters. Hum Vaccin Immunother. 2215-22.
• Bouillaut L, McBride S, Sorg JA, Schmidt DJ, Suarez JM, Tzipori S, Mascio C, Chesnel L, Sonenshein AL. 2015. Effects of surotomycin on Clostridium difficile viability and toxin production in vitro. Antimicrob Agents Chemother. 59:4199-205.
• Yang Z, Schmidt D, Liu W, Li S, Shi L, Sheng J, Chen K, Yu H, Tremblay JM, Chen X, Piepenbrink KH, Sundberg EJ, Kelly CP, Bai G, Shoemaker CB, Feng H. 2014. A novel multivalent, single-domain antibody targeting TcdA and TcdB prevents fulminant Clostridium difficile infection in mice. J Infect Dis. 210:964-72.
• Zhao S, Ghose-Paul C, Zhang K, Tzipori S, Sun X. 2014. Immune-based treatment and prevention of Clostridium difficile infection. Hum Vaccin Immunother. 10:3522-30.
• Sponseller JK, Steele JA, Schmidt DJ, Kim HB, Beamer G, Sun X, Tzipori S. 2014. Hyperimmune bovine colostrum as a novel therapy to combat Clostridium difficile infection. J Infect Dis. 211:1334-41.
• Cohen OR, Steele JA, Zhang Q, Schmidt DJ, Wang Y, Hamel PE, Beamer G, Xu B, Tzipori S. 2014. Systemically administered IgG anti-toxin antibodies protect the colonic mucosa during infection with Clostridium difficile in the piglet model. PLoS One. 9:e111075.
• Kim HB, Zhang Q, Sun X, Beamer G, Wang Y, Tzipori S. 2014. Beneficial effect of oral tigecycline treatment on Clostridium difficile infection in gnotobiotic piglets. Antimicrob Agents Chemother. 58:7560-4.
• Steele J, Parry N, Tzipori S. 2013. The roles of toxin A and toxin B in Clostridium difficile infection: insights from the gnotobiotic piglet model. Gut Microbes. 5:53-7.
• Steele J, Zhang Q, Beamer G, Butler M, Bowlin T, Tzipori S. 2013. MBX-500 is effective for treatment of Clostridium difficile infection in gnotobiotic piglets. Antimicrob Agents Chemother. 57:4039-41.
• Steele J, Sponseller J, Schmidt D, Cohen O, Tzipori S. 2013. Hyperimmune bovine colostrum for treatment of GI infections: A review and update on Clostridiumdifficile. Hum Vaccin Immunother. 9(7). [Epub ahead of print]. PMID:23435084
• Steele J, Mukherjee J, Parry N, Tzipori S.. 2013. Antibody against TcdB, but not TcdA, prevents development of gastrointestinal and systemic Clostridiumdifficile disease. J Infect Dis. 207:323-30. PMID:23125448
• Butler MM, Shinabarger DL, Citron DM, Kelly CP, Dvoskin S, Wright GE, Feng H, Tzipori S, Bowlin TL. 2012. MBX-500, a hybrid antibiotic with in vitro and in vivo efficacy against toxigenic Clostridiumdifficile. Antimicrob Agents Chemother. 564786-92. PMID:22733075
• Wang H, Sun X, Zhang Y, Li S, Chen K, Shi L, Nie W, Kumar R, Tzipori S, Wang J, Savidge T, Feng H. 2012. A chimeric toxin vaccine protects against primary and recurrent Clostridium difficile infection. Infect Immun. 80:2678-88. PMID:22615245
• Steele J, Chen K, Sun X, Zhang Y, Wang H, Tzipori S, Feng H. 2012. Systemic dissemination of Clostridiumdifficile toxins A and B is associated with severe, fatal disease in animal models. J Infect Dis. 205:384-91. PMID:22147798
• Sun X, Wang H, Zhang Y, Chen K, Davis B, Feng H. 2011. Mouse relapse model of Clostridium difficile infection. Infect Immun. 79:2856-64. PMID: 21576341
• Steele J, Feng H, Parry N, Tzipori S. 2010. Piglet models of acute or chronic Clostridiumdifficile illness. Infect Dis. 201:428-34. PMID: 20039803
• Sun X, Savidge T, Feng H. 2010. The enterotoxicity of Clostridium difficile toxins. Toxins (Basel). 2:1848-80. PMID:22069662
• He X, Wang J, Steele J, Sun X, Nie W, Tzipori S, Feng H. 2009. An ultrasensitive rapid immunocytotoxicity assay for detecting Clostridiumdifficile toxins. J Microbiol Methods. 78:97-100. PMID:19393695
• Sun X, He X, Tzipori S, Gerhard R, Feng H. 2009. Essential role of the glucosyltransferase activity in Clostridiumdifficile toxin-induced secretion of TNF-alpha by macrophages. Microb Pathog. 46:298-305. PMID:19324080
• He X, Sun X, Wang J, Wang X, Zhang Q, Tzipori S, Feng H. 2009. Antibody-enhanced, Fc gamma receptor-mediated endocytosis of Clostridiumdifficile toxin A. Infect Immun. 77:2294-303. PMID:19307220
• Yang G, Zhou B, Wang J, He X, Sun X, Nie W, Tzipori S, Feng H. 2008. Expression of recombinant Clostridiumdifficile toxin A and B in Bacillus megaterium. BMC Microbiol. 8:192. PMID:18990232

Research in the Department of Infectious Diseases and Global Health aims to understand the mechanisms of toxin-mediated inflammation and to investigate the role of each toxin in the pathogenesis of C. difficile-associated diseases.