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The role of JNK signaling in Francisella tularensis infection of Drosophila melanogaster
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

The causative agent of tularemia, Francisella tularensis, inhibits immune signaling pathways during infection and thus reduces the production of proinflammatory cytokines. NF-kB and MAPK pathways are initially activated, but subsequently down-regulated in macrophages. The mechanism(s) of inhibition, or which host proteins that F. tularensis interacts with are not known. Here, we have used Drosophila melanogaster as a genetically amendable model host to study the interaction between F. tularensis LVS and host immune signaling. We found that similar as in mammalian macrophages, LVS inhibits the JNK pathway in flies. LVS interferes with the JNK pathway upstream or at the same level as the JNKK Hemipterous. Expression of an activated Hemipterous in fly macrophage-like cells had a protective effect on fly survival, while inhibiting the JNK pathway in the fly fat body, an important immune tissue, had no effect on fly survival.

Keyword [en]
Francisella tularensis, LVS, Drosophila melanogaster, JNK, Hemipterous
National Category
Microbiology in the medical area
Research subject
Clinical Bacteriology
Identifiers
URN: urn:nbn:se:umu:diva-54411OAI: oai:DiVA.org:umu-54411DiVA: diva2:523730
Available from: 2012-04-26 Created: 2012-04-26 Last updated: 2012-05-04Bibliographically approved
In thesis
1. Host-pathogen interactions between Francisella tularensis and Drosophila melanogaster
Open this publication in new window or tab >>Host-pathogen interactions between Francisella tularensis and Drosophila melanogaster
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Francisella tularensis is a highly virulent Gram-negative bacterium causing the zoonotic disease tularemia. Arthropod-borne transmission plays an important role in transferring the disease to humans. F. tularensis induces very low amounts of pro-inflammatory cytokines during infection, due to inhibition of immune signaling pathways and an unusual structure of its lipopolysaccharide (LPS). To date, there is no vaccine available that is approved for public use, although an attenuated live vaccine strain (LVS) is commonly used as a model of the more infectious Francisella strains. To produce an effective vaccine it is important to understand the lifecycle of F. tularensis, including the interaction with the arthropod hosts. Drosophila melanogaster is a widely used model organism, which is increasingly being used in host-pathogen interaction studies as the immune pathways in flies are evolutionary conserved to the immune pathways in humans. An important part of the immune defense of D. melanogaster as well as of arthropods in general is the production of antimicrobial peptides. These peptides primarily target the bacterial membrane, inhibiting bacterial proliferation or directly killing the bacteria.

The aim of this thesis was to establish D. melanogaster as a model for F. tularensis infection and as a model for arthropod vectors of F. tularensis. Also, to use D. melanogaster to further study the interaction between F. tularensis and arthropod vectors, with specific regard to the host immune signaling and arthropod antimicrobial peptides.

F. tularensis LVS infects and kills D. melanogaster in a dose-dependent manner. During an infection, bacteria are found inside fly hemocytes, phagocytic blood cells, similar as in human infections. In mammals genes of the intracellular growth locus (igl) are important for virulence. In this work it is shown that the igl genes are also important for virulence in flies. These results demonstrate that D. melanogaster can be used as a model to study F. tularensis-host interactions.

LVS induces a prolonged activation of several immune signaling pathways in the fly, but seem to interfere with the JNK signaling pathway, similarly as in mammals. Overexpression of the JNK pathway in flies has a protective effect on fly survival.

Relish mutant flies, essentially lacking a production of antimicrobial peptides, succumb quickly to a F. tularensis infection, however, F. tularensis is relatively resistant to individual D. melanogaster antimicrobial peptides. Overexpressing antimicrobial peptide genes in wildtype flies has a protective effect on F. tularensis infection, suggesting that a combination of several antimicrobial peptides is necessary to control F. tularensis. The production of numerous antimicrobial peptides might be why D. melanogaster survives relatively long after infection. An intact structure of the lipid A and of the Kdo core of Francisella LPS is necessary for resistance to antimicrobial peptides and full virulence in flies. These results are similar to previous studies in mammals. In contrast to studies in mammals, genes affecting the O-antigen of F. tularensis LPS are not necessary for virulence in flies.

In conclusion, this thesis work shows that D. melanogaster can be used as a model for studying F. tularensis-host interactions. LVS activates several immune pathways during infection, but interfere with the JNK pathway. Overexpressing the JNK pathway results in increased survival of flies infected with LVS. Despite rather high resistance to individual antimicrobial peptides, exposure to a combination of several D. melanogaster antimicrobial peptides reduces the virulence of F. tularensis.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. 45 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1504
Keyword
arthropod vector, JNK, lipopolysaccharide, antimicrobial peptides
National Category
Microbiology in the medical area
Research subject
Clinical Bacteriology; Molecular Biology
Identifiers
urn:nbn:se:umu:diva-54604 (URN)978-91-7459-432-4 (ISBN)
Public defence
2012-05-25, E04, by 6E, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2012-05-04 Created: 2012-05-02 Last updated: 2012-05-04Bibliographically approved

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