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A mutagenesis-based approach identifies amino acids in the N-terminal part of Francisella tularensis IglE that critically control type VI system-mediated secretion
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS).
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology. Department of Experimental Medical Science, Section for Immunology, Lund University, Lund, Sweden.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Bacteriology.
2017 (English)In: Virulence, ISSN 2150-5594, E-ISSN 2150-5608, Vol. 8, no 6, 821-847 p.Article in journal (Refereed) Published
Abstract [en]

The Gram-negative bacterium Francisella tularensis is the etiological agent of the zoonotic disease tularemia. Its life cycle is characterized by an ability to survive within phagocytic cells through phagosomal escape and replication in the cytosol, ultimately causing inflammasome activation and host cell death. Required for these processes is the Francisella Pathogenicity Island (FPI), which encodes a Type VI secretion system (T6SS) that is active during intracellular infection. In this study, we analyzed the role of the FPI-component IglE, a lipoprotein which we previously have shown to be secreted in a T6SS-dependent manner. We demonstrate that in F. tularensis LVS, IglE is an outer membrane protein. Upon infection of J774 cells, an Delta iglE mutant failed to escape from phagosomes, and subsequently, to multiply and cause cytopathogenicity. Moreover, Delta iglE was unable to activate the inflammasome, to inhibit LPS-stimulated secretion of TNF-alpha, and showed marked attenuation in the mouse model. In F. novicida, IglE was required for in vitro secretion of IglC and VgrG. A mutagenesis-based approach involving frameshift mutations and alanine substitution mutations within the first similar to 38 residues of IglE revealed that drastic changes in the sequence of the extreme N-terminus (residues 2-6) were well tolerated and, intriguingly, caused hyper-secretion of IglE during intracellular infection, while even subtle mutations further downstream lead to impaired protein function. Taken together, this study highlights the importance of IglE in F. tularensis pathogenicity, and the contribution of the N-terminus for all of the above mentioned processes.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS INC , 2017. Vol. 8, no 6, 821-847 p.
Keyword [en]
Francisella pathogenicity island, Francisella tularensis, IglE, type VI secretion
National Category
Microbiology in the medical area
Identifiers
URN: urn:nbn:se:umu:diva-141228DOI: 10.1080/21505594.2016.1258507ISI: 000412306100029PubMedID: 27830989OAI: oai:DiVA.org:umu-141228DiVA: diva2:1153125
Available from: 2017-10-27 Created: 2017-10-27 Last updated: 2017-11-06Bibliographically approved

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Bröms, Jeanette E.Meyer, LenaSjöstedt, Anders
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