Abstract
The Clostridium difficile exotoxin, TcdB, which is a major virulence factor, varies between strains of this pathogen. Herein, we show that TcdB from the epidemic BI/NAP1/027 strain of C. difficile is more lethal, causes more extensive brain hemorrhage, and is antigenically variable from TcdB produced by previously studied strains of this pathogen (TcdB003). In mouse intoxication assays, TcdB from a ribotype 027 strain (TcdB027) was at least four fold more lethal than TcdB003. TcdB027 caused a previously undescribed brain hemorrhage in mice and this correlated with a heightened sensitivity of brain microvascular endothelial cells to the toxin. TcdB003 and TcdB027 also differed in their antigenic profiles and did not share cross-neutralizing epitopes in a major immunogenic region of the protein. Solid phase humoral mapping of epitopes in the carboxy-terminal domains (CTD) of TcdB027 and TcdB003 identified 11 reactive epitopes that varied between the two forms of TcdB, and 13 epitopes that were shared or overlapping. Despite the epitope differences and absence of neutralizing epitopes in the CTD of TcdB027, a toxoid form of this toxin primed a strong protective response. These findings indicate TcdB027 is a more potent toxin than TcdB003 as measured by lethality assays and pathology, moreover the sequence differences between the two forms of TcdB alter antigenic epitopes and reduce cross-neutralization by antibodies targeting the CTD.
Highlights
Clostridium difficile is the leading cause of hospital-acquired diarrhea in developed countries [1,2,3,4]
The results indicate TcdB from a ribotype 027 strain (TcdB027), the toxin from the BI/NAP1/027 strain, is more lethal and causes more extensive brain hemorrhaging than TcdB003, the toxin produced by a reference strain of C. difficile
The results show that the antigenic carboxy-terminal domain (CTD) encodes at least 11 epitopes that differ between the two forms of TcdB
Summary
Clostridium difficile is the leading cause of hospital-acquired diarrhea in developed countries [1,2,3,4] This spore-forming anaerobic bacterium contaminates hospital environments and infects patients undergoing antibiotic therapy within health care facilities [2,5,6]. An absolute association between BI/ NAP1/027 strains and increased disease severity has not been made in all cases [18,19,20,21], extensive clinical surveillance over the past ten years has shown a strong correlation between BI/NAP1/027 frequency and mortality rate [22,23]. The relevance of these factors is still greatly debated [30,31], leaving us with a poor understanding into how this emergent strain correlates with increased mortality
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