Surface layer proteins from virulent Clostridium difficile ribotypes exhibit signatures of positive selection with consequences for innate immune response

BMC Evolutionary Biology

Research Article

Thomas A. Walsh¹  Andrew E. Webb¹  Mary J. O’Connell²  Micheál MacAogain³  Thomas R. Rogers³  Dermot Kelleher⁴  Izabela Marszalowska⁵  Mark Lynch⁵  Christine E. Loscher⁵  Henry Windle⁶ 

[1] Bioinformatics and Molecular Evolution Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland;Bioinformatics and Molecular Evolution Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland;Computational and Molecular Evolutionary Biology Research Group, School of Biology, Faculty of Biological Sciences, The University of Leeds, LS2 9JT, Leeds, UK;Department of Clinical Microbiology, Trinity College Dublin, St James Hospital Dublin, Dublin, Ireland;Faculty of Medicine, Imperial College London, SW7 2AZ, London, UK;Immunomodulation Research Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland;Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland;

关键词: Clostridium difficile;    Surface layer protein;    Positive selection;    Protein functional shift;    Protein evolution;    Virulence;   

DOI  :  10.1186/s12862-017-0937-8

 received in 2016-11-01, accepted in 2017-03-15,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundClostridium difficile is a nosocomial pathogen prevalent in hospitals worldwide and increasingly common in the community. Sequence differences have been shown to be present in the Surface Layer Proteins (SLPs) from different C. difficile ribotypes (RT) however whether these differences influence severity of infection is still not clear.ResultsWe used a molecular evolutionary approach to analyse SLPs from twenty-six C. difficile RTs representing different slpA sequences. We demonstrate that SLPs from RT 027 and 078 exhibit evidence of positive selection (PS). We compared the effect of these SLPs to those purified from RT 001 and 014, which did not exhibit PS, and demonstrate that the presence of sites under positive selection correlates with ability to activate macrophages. SLPs from RTs 027 and 078 induced a more potent response in macrophages, with increased levels of IL-6, IL-12p40, IL-10, MIP-1α, MIP-2 production relative to RT 001 and 014. Furthermore, RTs 027 and 078 induced higher expression of CD40, CD80 and MHC II on macrophages with decreased ability to phagocytose relative to LPS.ConclusionsThese results tightly link sequence differences in C. difficile SLPs to disease susceptibility and severity, and suggest that positively selected sites in the SLPs may play a role in driving the emergence of hyper-virulent strains.

【 授权许可】

CC BY   
© The Author(s). 2017