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Hfq, a novel pleiotropic regulator of virulence-associated genes in Francisella tularensis
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet).
Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS). Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet). Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
FOI Swedish Defence Research Agency, Division of CBRN Defence and Security.
Université Paris Descartes, Faculté de Médecine Necker-Enfants Malades; INSERM, U570, Unit of Pathogenesis of Systemic Infections.
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2009 (Engelska)Ingår i: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 77, nr 5, s. 1866-80Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Francisella tularensis is a highly infectious pathogen that infects animals and humans, causing tularemia. The ability to replicate within macrophages is central for virulence and relies on expression of genes located in the Francisella pathogenicity island (FPI), as well as expression of other genes. Regulation of FPI-encoded virulence gene expression in F. tularensis involves at least four regulatory proteins and is not fully understood. Here we studied the RNA-binding protein Hfq in F. tularensis and particularly the role that it plays as a global regulator of gene expression in stress tolerance and pathogenesis. We demonstrate that Hfq promotes resistance to several cellular stresses (including osmotic and membrane stresses). Furthermore, we show that Hfq is important for the ability of the F. tularensis vaccine strain LVS to induce disease and persist in organs of infected mice. We also demonstrate that Hfq is important for stress tolerance and full virulence in a virulent clinical isolate of F. tularensis, FSC200. Finally, microarray analyses revealed that Hfq regulates expression of numerous genes, including genes located in the FPI. Strikingly, Hfq negatively regulates only one of two divergently expressed putative operons in the FPI, in contrast to the other known regulators, which regulate the entire FPI. Hfq thus appears to be a new pleiotropic regulator of virulence in F. tularensis, acting mostly as a repressor, in contrast to the other regulators identified so far. Moreover, the results obtained suggest a novel regulatory mechanism for a subset of FPI genes.

Ort, förlag, år, upplaga, sidor
American society for microbiology , 2009. Vol. 77, nr 5, s. 1866-80
Nationell ämneskategori
Biokemi och molekylärbiologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Identifikatorer
URN: urn:nbn:se:umu:diva-30849DOI: 10.1128/IAI.01496-08PubMedID: 19223477OAI: oai:DiVA.org:umu-30849DiVA, id: diva2:287897
Tillgänglig från: 2010-01-20 Skapad: 2010-01-20 Senast uppdaterad: 2019-01-23Bibliografiskt granskad
Ingår i avhandling
1. Identification of new virulence factors in Francisella tularensis
Öppna denna publikation i ny flik eller fönster >>Identification of new virulence factors in Francisella tularensis
2010 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Francisella tularensis, the causative agent of tularemia, is a highly virulent bacterium with an infection dose of less than ten bacteria. The ability of a pathogen to cause infection relies on different virulence mechanisms, but in Francisella tularensis relatively few virulence factors are known. Two F. tularensis subspecies are virulent in humans; the highly virulent subspecies tularensis, also referred to as type A, and the less virulent subspecies holarctica, also called type B. The aim of this thesis has been to improve the knowledge regarding the ability of Francisella to cause disease, with the emphasis on surface located and membrane associated proteins and structures. In addition I have also investigated how virulence is regulated by studying the role of the small RNA chaperone, Hfq.

The genome of Francisella appears to encode few regulatory genes. In my work I found that Hfq has an important role in regulation of virulence associated genes in Francisella. Similar to what has been found in other pathogens, Hfq functions in negative regulation, and this is the first time a negative regulation has been described for genes in the Francisella pathogenicity island. Another protein with a key role in virulence is a homologue to a disulphide oxidoreductase, DsbA, which was identified as an outer membrane lipoprotein in Francisella. A dsbA mutant was found to be severely attenuated for virulence and also induced protection against wild-type infections, thus making it a candidate for exploration as a new live vaccine. Additional genes with homology to known virulence determinants include a type IV pilin system. The pilin homologue, PilA, was identified to be required for full virulence in both type A and type B strains. In addition, genes involved in pili assembly and secretion, pilC and pilQ, were also found to be virulence associated in the type A strain.

In summary, dsbA, hfq and type IV pili associated genes were indentified to be virulence determinants in F. tularensis. DsbA is a potential target for drug development and a dsbA mutant a candidate for a new live vaccine strain. Furthermore the identification of Hfq as a novel regulatory factor opens new insights into the virulence regulatory network in Francisella.

Ort, förlag, år, upplaga, sidor
Umeå: Institutionen för Molekylärbiologi, Umeå universitet, 2010. s. 55
Nyckelord
Francisella tularensis, regulation, virulence, Hfq, DsbA, type IV pili, membrane
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärbiologi
Identifikatorer
urn:nbn:se:umu:diva-30857 (URN)978-91-7264-916-3 (ISBN)
Disputation
2010-02-12, Major Groove,, byggnad 6L, Norrlands universitetssjukhus, Umeå, 10:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2010-01-22 Skapad: 2010-01-20 Senast uppdaterad: 2019-01-23Bibliografiskt granskad

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Forslund, Anna-LenaForsberg, Åke

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Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet)Umeå Centre for Microbial Research (UCMR)Molekylär Infektionsmedicin, Sverige (MIMS)Institutionen för molekylärbiologi (Medicinska fakulteten)
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Infection and Immunity
Biokemi och molekylärbiologiMedicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

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