Abstract
Bacterial products such as toxins can interfere with a variety of cellular processes, leading to severe human diseases. Clostridium difficile toxins, TcdA and TcdB are the primary contributing factors to the pathogenesis of C. difficile-associated diseases (CDAD). While the mechanisms for TcdA and TcdB mediated cellular responses are complex, it has been shown that these toxins can alter chemotactic responses of neutrophils and intestinal epithelial cells leading to innate immune responses and tissue damages. The effects of C. difficile toxins on the migration and trafficking of other leukocyte subsets, such as T lymphocytes, are not clear and may have potential implications for adaptive immunity. We investigated here the direct and indirect effects of TcdA and TcdB on the migration of human blood T cells using conventional cell migration assays and microfluidic devices. It has been found that, although both toxins decrease T cell motility, only TcdA but not TcdB decreases T cell chemotaxis. Similar effects are observed in T cell migration toward the TcdA- or TcdB-treated human epithelial cells. Our study demonstrated the primary role of TcdA (compared to TcdB) in altering T cell migration and chemotaxis, suggesting possible implications for C. difficile toxin mediated adaptive immune responses in CDAD.
Highlights
Clostridium difficile (C. difficile) is a bacterial pathogen and a leading cause of hospital-acquired diarrhea in Europe and North America and of other C. difficile-associated diseases (CDAD) [1,2,3].the occurrence of CDAD has been consistently rising over the past few decades [1,4], in part associated with the increased usage of antibiotics as well as chemotherapies [1]
Because of the unique ability of microfluidic devices of generating stable chemokine gradients with well-defined gradient profiles and of dynamic monitoring and quantitative analysis of cell migration at the single cell level, we further studied T cell chemotaxis using a previously developed microfluidic device [23]
Because TcdA and TcdB can interact with intestinal epithelial cells to mediate neutrophil infiltration to intestinal tissues [1], it is possible that TcdA and TcdB can alter T cell migration indirectly through intestinal epithelial cells
Summary
Clostridium difficile (C. difficile) is a bacterial pathogen and a leading cause of hospital-acquired diarrhea in Europe and North America and of other C. difficile-associated diseases (CDAD) [1,2,3]. Taken together the current knowledge of TcdA and TcdB mediated cellular responses, it is tempting to hypothesize that TcdA and TcdB are able to affect cellular behaviors, the migration and trafficking of other important immune cell types such as T lymphocytes. Such a hypothesis is further supported by previous studies showing that lethal and edema toxins of Bacillus anthracis affect the activation and cellular functions of dendritic cells and lymphocytes [21].
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