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Lindgren, Lena
Publications (3 of 3) Show all publications
Rigard, M., Bröms, J. E., Mosnier, A., Hologne, M., Martin, A., Lindgren, L., . . . Henry, T. (2016). Francisella tularensis IglG Belongs to a Novel Family of PAAR-Like T6SS Proteins and Harbors a Unique N-terminal Extension Required for Virulence. PLoS Pathogens, 12(9), Article ID e1005821.
Open this publication in new window or tab >>Francisella tularensis IglG Belongs to a Novel Family of PAAR-Like T6SS Proteins and Harbors a Unique N-terminal Extension Required for Virulence
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2016 (English)In: PLoS Pathogens, ISSN 1553-7366, E-ISSN 1553-7374, Vol. 12, no 9, article id e1005821Article in journal (Refereed) Published
Abstract [en]

The virulence of Francisella tularensis, the etiological agent of tularemia, relies on an atypical type VI secretion system ( T6SS) encoded by a genomic island termed the Francisella Pathogenicity Island ( FPI). While the importance of the FPI in F. tularensis virulence is clearly established, the precise role of most of the FPI-encoded proteins remains to be deciphered. In this study, using highly virulent F. tularensis strains and the closely related species F. novicida, IglG was characterized as a protein featuring a unique alpha-helical N-terminal extension and a domain of unknown function ( DUF4280), present in more than 250 bacterial species. Three dimensional modeling of IglG and of the DUF4280 consensus protein sequence indicates that these proteins adopt a PAAR-like fold, suggesting they could cap the T6SS in a similar way as the recently described PAAR proteins. The newly identified PAAR-like motif is characterized by four conserved cysteine residues, also present in IglG, which may bind a metal atom. We demonstrate that IglG binds metal ions and that each individual cysteine is required for T6SS-dependent secretion of IglG and of the Hcp homologue, IglC and for the F. novicida intracellular life cycle. In contrast, the Francisella-specific N-terminal alpha-helical extension is not required for IglG secretion, but is critical for F. novicida virulence and for the interaction of IglG with another FPI-encoded protein, IglF. Altogether, our data suggest that IglG is a PAAR-like protein acting as a bi-modal protein that may connect the tip of the Francisella T6SS with a putative T6SS effector, IglF.

National Category
Biochemistry and Molecular Biology
urn:nbn:se:umu:diva-127634 (URN)10.1371/journal.ppat.1005821 (DOI)000385621900013 ()
Available from: 2016-11-23 Created: 2016-11-16 Last updated: 2018-06-09Bibliographically approved
Lindgren, H., Lindgren, L., Golovliov, I. & Sjöstedt, A. (2015). Mechanisms of heme utilization by Francisella tularensis. PLoS ONE, 10(3), Article ID e0119143.
Open this publication in new window or tab >>Mechanisms of heme utilization by Francisella tularensis
2015 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0119143Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis is a highly virulent facultative intracellular pathogen causing the severe disease tularemia in mammals. As for other bacteria, iron is essential for its growth but very few mechanisms for iron acquisition have been identified. Here, we analyzed if and how F. tularensis can utilize heme, a major source of iron in vivo. This is by no means obvious since the bacterium lacks components of traditional heme-uptake systems. We show that SCHU S4, the prototypic strain of subspecies tularensis, grew in vitro with heme as the sole iron source. By screening a SCHU S4 transposon insertion library, 16 genes were identified as important to efficiently utilize heme, two of which were required to avoid heme toxicity. None of the identified genes appeared to encode components of a potential heme-uptake apparatus. Analysis of SCHU S4 deletion mutants revealed that each of the components FeoB, the siderophore system, and FupA, contributed to the heme-dependent growth. In the case of the former two systems, iron acquisition was impaired, whereas the absence of FupA did not affect iron uptake but led to abnormally high binding of iron to macromolecules. Overall, the present study demonstrates that heme supports growth of F. tularensis and that the requirements for the utilization are highly complex and to some extent novel.

National Category
Microbiology in the medical area
urn:nbn:se:umu:diva-102224 (URN)10.1371/journal.pone.0119143 (DOI)000351275700039 ()25756756 (PubMedID)
Available from: 2015-05-05 Created: 2015-04-22 Last updated: 2018-06-07Bibliographically approved
Binesse, J., Lindgren, H., Lindgren, L., Conlan, W. & Sjöstedt, A. (2015). Roles of Reactive Oxygen Species-Degrading Enzymes of Francisella tularensis SCHU S4. Infection and Immunity, 83(6), 2255-2263
Open this publication in new window or tab >>Roles of Reactive Oxygen Species-Degrading Enzymes of Francisella tularensis SCHU S4
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2015 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 83, no 6, p. 2255-2263Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis is a facultative intracellular bacterium utilizing macrophages as its primary intracellular habitat and is therefore highly capable of resisting the effects of reactive oxygen species (ROS), potent mediators of the bactericidal activity of macrophages. We investigated the roles of enzymes presumed to be important for protection against ROS. Four mutants of the highly virulent SCHU S4 strain with deletions of the genes encoding catalase (katG), glutathione peroxidase (gpx), a DyP-type peroxidase (FTT0086), or double deletion of FTT0086 and katG showed much increased susceptibility to hydrogen peroxide (H2O2) and slightly increased susceptibility to paraquat but not to peroxynitrite (ONOO-) and displayed intact intramacrophage replication. Nevertheless, mice infected with the double deletion mutant showed significantly longer survival than SCHU S4-infected mice. Unlike the aforementioned mutants, deletion of the gene coding for alkyl-hydroperoxide reductase subunit C (ahpC) generated a mutant much more susceptible to paraquat and ONOO- but not to H2O2. It showed intact replication in J774 cells but impaired replication in bone marrow-derived macrophages and in internal organs of mice. The live vaccine strain, LVS, is more susceptible than virulent strains to ROS-mediated killing and possesses a truncated form of FTT0086. Expression of the SCHU S4 FTT0086 gene rendered LVS more resistant to H2O2, which demonstrates that the SCHU S4 strain possesses additional detoxifying mechanisms. Collectively, the results demonstrate that SCHU S4 ROS-detoxifying enzymes have overlapping functions, and therefore, deletion of one or the other does not critically impair the intracellular replication or virulence, although AhpC appears to have a unique function.

National Category
Immunology Infectious Medicine
urn:nbn:se:umu:diva-106020 (URN)10.1128/IAI.02488-14 (DOI)000356243000006 ()25802058 (PubMedID)
Available from: 2015-07-06 Created: 2015-07-03 Last updated: 2018-06-07Bibliographically approved

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