SipA activation of caspase-3 is a decisive mediator of host cell survival at early stages of Salmonella enterica serovar typhimurium Infection

McIntosh, A., Meikle, L. M., Ormsby, M. J., McCormick, B. A., Christie, J. M. , Brewer, J. M. , Roberts, M. and Wall, D. M. (2017) SipA activation of caspase-3 is a decisive mediator of host cell survival at early stages of Salmonella enterica serovar typhimurium Infection. Infection and Immunity, 85(9), e00393-17. (doi: 10.1128/IAI.00393-17) (PMID:28630067) (PMCID:PMC5563584)

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Abstract

Salmonella invasion protein A (SipA) is a dual function effector protein that plays roles in both actin polymerization and caspase-3 activation in intestinal epithelial cells. To date its function in other cell types has remained largely unknown despite its expression in multiple cell types and its extracellular secretion during infection. Here we show that in macrophages SipA induces increased caspase-3 activation early in infection. This activation required a threshold level of SipA linked to multiplicity of infection and may be a limiting factor controlling bacterial numbers in infected macrophages. In polymorphonuclear leukocytes SipA, or other Salmonella Pathogenicity Island 1 effectors, had no effect on induction of caspase-3 activation either alone or in the presence of whole bacteria. Tagging of SipA with the small fluorescent phiLOV tag that can pass through the Type Three Secretion System allowed visualisation and quantification of caspase-3 activation by SipA-phiLOV in macrophages. Additionally, SipA-phiLOV activation of caspase-3 could be tracked in the intestine through multiphoton laser scanning microscopy in an ex vivo intestinal model. This allowed visualisation of areas where the intestinal epithelium had been compromised and demonstrated the potential use of this fluorescent tag for in vivo tracking of individual effectors.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McIntosh, Ms Anne and Brewer, Professor James and Ormsby, Dr Michael and Wall, Dr Daniel and Christie, Professor John and Roberts, Professor Mark and Meikle, Dr Lynsey
Authors: McIntosh, A., Meikle, L. M., Ormsby, M. J., McCormick, B. A., Christie, J. M., Brewer, J. M., Roberts, M., and Wall, D. M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Journal Name:Infection and Immunity
Publisher:American Society for Microbiology
ISSN:0019-9567
ISSN (Online):1098-5522
Published Online:19 June 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Infection and Immunity 85(9):e00393-17
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
726481Propionic acid use in agriculture and food production is driving evolution of novel Escherichia coli pathotypesDaniel WallBiotechnology and Biological Sciences Research Council (BBSRC)BB/P003281/1III - BACTERIOLOGY