Clostridium difficile 027/BI/NAP1 Encodes a Hypertoxic and Antigenically Variable Form of TcdB

Lanis JM, Heinlen LD

, James JA, Ballard JD. PLoS Pathog 2013 Aug; 9(8):e1003523.

Speaker: Beatrice Lin (林怡慈)                            Time: 15:00~16:00, Dec. 4, 2013

Commentator: Dr. Lien-I Hor (何漣漪 老師)     Place: Room 601

Abstract

Clostridium difficile is a spore-forming bacterium and is the main cause of antibiotic-associated diarrhea. ³ The two major toxins of C. difficile are toxin A (TcdA) and toxin B (TcdB), which can cause extensive tissue damage. Previous study identified several genetic variations between epidemic and historical strains of C. difficile and found that TcdB from 027/BI/NAP1 strain was more cytotoxic than the historical strains. ² Hence, the authors hypothesize that variation between TcdB, from historical strains (TcdB₀₀₃) and from 027/BI/NAP1 strains (TcdB₀₂₇), is major contributing factor to the increased virulence of the recently emerged forms of C. difficile. In lethality and systemic intoxication assays, TcdB₀₂₇ was more cytotoxic and cause at least four time higher lethality and extensive brain hemorrhaging than TcdB₀₀₃. Antibodies raised against the antigenic carboxy-terminal domain (CTD), which is the putative binding region, ³ neutralized TcdB₀₀₃ but not TcdB_027. Furthermore, the resulst of solid phase peptide based ELISAs to map antibody reactive sequences in the CTD showed that 11 reactive epitopes differed between TcdB₀₀₃and TcdB_027. These results suggested that the CTD of TcdB may contribute to not only differences in tropism, but also accounts for variability in the antigenic make-up of this domain. In addition, although past studies had found that TcdB toxoid was not a highly effective vaccine, ¹ in this study the authors found that mouse antiserum raised toward the toxoid form of TcdB₀₂₇ protected against both TcdB₀₀₃ and TcdB_027. Collectively, the data demonstrated that sequence variations within TcdB027 affected its function and antigenic make-up, and might also contribute to the overall elevated virulence of C. difficile BI/NAP1/027 strains. The finding presented here will help us understand the virulence and systemic effects of C. difficile associated disease.

References

1. Giannasca PJ, Warny M

 (2004) Active and passive immunization against Clostridium difficile diarrhea and colitis. Vaccine 17;22(7):848-56.

2.     Lanis JM, Barua S, Ballard JD (2010) Variations in TcdB activity and the hypervirulence of emerging strains of Clostridium difficile. PLoS Pathog 6: e1001061.

3.     Rupnik M, Wilcox MH, Gerding DN (2009) Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nat Rev Microbiol 7(7):526-36.