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Role of type IV pilin encoding genes in virulence of Francisella tularensis subspecies holarctica
Umeå University, Faculty of Medicine, Molecular Biology.
Umeå University, Faculty of Medicine, Molecular Biology.
CBRN Defence and Security, FOI Swedish Defence Research Agency, Sweden..
School of Biosciences, University of Exeter, Devon, UK.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

The number of virulence factors identified in Francisella tularensis, the causative agent of tularemia, is so far relatively few. The F. tularensis genome contains some genes with homology to known virulence factors. One of these is the type IV pili system, which is known to have a key role in virulence of other bacterial species. When we compared different F. tularensis subspecies we could identify distinct differences in Type IV pilin genes between the highly virulent type A strains and the less pathogenic type B strains. In this work we addressed the role in virulence of the different pilin genes in a virulent type B strain. Of all the pilin genes only PilA and the pseudopilins FTT1621-1622 were proven to have a role in virulence. In addition we also verified that the gene encoding the PilT ATPase is non-functional due to a non-sense mutation and we also confirmed that the truncated pilT has no role in mouse virulence. Furthermore we also provide evidence that the F. tularensis pilins are posttranslationally modified presumably by glycosylation by a PilO dependent mechanism.

National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-30932OAI: oai:DiVA.org:umu-30932DiVA: diva2:288888
Available from: 2010-01-22 Created: 2010-01-22 Last updated: 2010-01-25
In thesis
1. Identification of new virulence factors in Francisella tularensis
Open this publication in new window or tab >>Identification of new virulence factors in Francisella tularensis
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Umeå: Institutionen för Molekylärbiologi, Umeå universitet, 2010. 55 p.
Keyword
Francisella tularensis, regulation, virulence, Hfq, DsbA, type IV pili, membrane
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-30857 (URN)978-91-7264-916-3 (ISBN)
Public defence
2010-02-12, Major Groove,, byggnad 6L, Norrlands universitetssjukhus, Umeå, 10:00 (English)
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Available from: 2010-01-22 Created: 2010-01-20 Last updated: 2010-01-22Bibliographically approved

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