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Novel Modes of Immune Activation in Anopheles gambiae and Drosophila melanogaster
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.ORCID iD: 0000-0002-0892-9530
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malaria is a disease of poverty and continues to plague a great part of the world’s population. An increased understanding of the interactions between the vector mosquito, the malaria parasite, and also the mosquito gut microbiota are pivotal for the development of novel measures against the disease. The first aim of this thesis was to gain a deeper knowledge of the microbial compounds that elicit immune responses in the main malaria vector Anopheles gambiae and also using the model organism Drosophila melanogaster. The second aim was to analyse the genome characteristics in silico of a bacterial symbiont from the mosquito midgut. In Paper I, we investigated the immunogenic effects of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate in Anopheles. This compound is the primary activator of human Vγ9Vδ2 T cells and is only produced by organisms that use the non-mevalonate pathway for isoprenoid synthesis, such as Plasmodium and most eubacteria but not animals. We show that the parasite releases compounds of this nature and that provision of HMBPP in the bloodmeal induces an immune response in the mosquito. In Paper II, we investigated whether bacteria inactivated by gamma-irradiation could still stimulate potent immune responses in Drosophila cells. We show that E. coli retains the capacity to synthesize and release peptidoglycan de novo for several days after the irradiation event. When cells were stimulated with supernatants from irradiated bacteria, however, a unique response was observed. In Paper III, we presented the draft genome sequence of Elizabethkingia anophelis, a predominant gut symbiont of An. gambiae recently described in our lab and subsequently found in another laboratory strain of the mosquito. The genome data were then annotated in Paper IV to gain insights into the symbiotic characteristics of the bacterium, as well as the genetic background for its strong antibiotic resistance. In conclusion, this thesis work has shed light on novel modes for stimulating immune responses in insects and also led to the characterization of a predominant bacteria in the mosquito gut that may be used in future malaria intervention strategies. 

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2014. , 81 p.
National Category
Biological Sciences
Research subject
Molecular Genetics
Identifiers
URN: urn:nbn:se:su:diva-101395ISBN: 978-91-7447-859-4 (print)OAI: oai:DiVA.org:su-101395DiVA: diva2:703429
Public defence
2014-04-25, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.

Available from: 2014-04-03 Created: 2014-03-06 Last updated: 2014-04-03Bibliographically approved
List of papers
1. Immunogenic and Antioxidant Effects of a Pathogen-Associated Prenyl Pyrophosphate in Anopheles gambiae
Open this publication in new window or tab >>Immunogenic and Antioxidant Effects of a Pathogen-Associated Prenyl Pyrophosphate in Anopheles gambiae
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, e73868- p.Article in journal (Refereed) Published
Abstract [en]

Despite efficient vector transmission, Plasmodium parasites suffer great bottlenecks during their developmental stages within Anopheles mosquitoes. The outcome depends on a complex three-way interaction between host, parasite and gut bacteria. Although considerable progress has been made recently in deciphering Anopheles effector responses, little is currently known regarding the underlying microbial immune elicitors. An interesting candidate in this sense is the pathogen-derived prenyl pyrophosphate and designated phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), found in Plasmodium and most eubacteria but not in higher eukaryotes. HMBPP is the most potent stimulant known of human V gamma 9V delta 2 T cells, a unique lymphocyte subset that expands during several infections including malaria. In this study, we show that V(Y)9V delta 2 T cells proliferate when stimulated with supernatants from intraerythrocytic stages of Plasmodium falciparum cultures, suggesting that biologically relevant doses of phosphoantigens are excreted by the parasite. Next, we used Anopheles gambiae to investigate the immune-and redox-stimulating effects of HMBPP. We demonstrate a potent activation in vitro of all but one of the signaling pathways earlier implicated in the human V(Y)9V delta 2 T cell response, as p38, JNK and PI3K/Akt but not ERK were activated in the A. gambiae 4a3B cell line. Additionally, both HMBPP and the downstream endogenous metabolite isopentenyl pyrophosphate displayed antioxidant effects by promoting cellular tolerance to hydrogen peroxide challenge. When provided in the mosquito blood meal, HMBPP induced temporal changes in the expression of several immune genes. In contrast to meso-diaminopimelic acid containing peptidoglycan, HMBPP induced expression of dual oxidase and nitric oxide synthase, two key determinants of Plasmodium infection. Furthermore, temporal fluctuations in midgut bacterial numbers were observed. The multifaceted effects observed in this study indicates that HMBPP is an important elicitor in common for both Plasmodium and gut bacteria in the mosquito.

National Category
Immunology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-93766 (URN)10.1371/journal.pone.0073868 (DOI)000323115800125 ()
Funder
The Wenner-Gren Foundation
Note

AuthorCount:7;

Available from: 2013-09-19 Created: 2013-09-16 Last updated: 2017-12-06Bibliographically approved
2. Medium from γ-irradiated Escherichia coli Bacteria Stimulates a Unique Immune Response in Drosophila Cells
Open this publication in new window or tab >>Medium from γ-irradiated Escherichia coli Bacteria Stimulates a Unique Immune Response in Drosophila Cells
(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-101393 (URN)
Available from: 2014-03-06 Created: 2014-03-06 Last updated: 2014-03-24
3. Draft Genome Sequences of Elizabethkingia anophelis Strains R26T and Ag1 from the Midgut of the Malaria Mosquito Anopheles gambiae
Open this publication in new window or tab >>Draft Genome Sequences of Elizabethkingia anophelis Strains R26T and Ag1 from the Midgut of the Malaria Mosquito Anopheles gambiae
Show others...
2013 (English)In: Genome Announcements, ISSN 2169-8287, Vol. 1, no 6, e01030-13- p.Article in journal (Refereed) Published
Abstract [en]

Elizabethkingia anophelis is a species in the family Flavobacteriaceae. It is a dominant resident in the mosquito gut and also a human pathogen. We present the draft genome sequences of two strains of E. anophelis, R26T and Ag1, which were isolated from the midgut of the malaria mosquito Anopheles gambiae.

National Category
Microbiology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-101392 (URN)10.1128/genomeA.01030-13 (DOI)
Available from: 2014-03-06 Created: 2014-03-06 Last updated: 2014-03-07Bibliographically approved
4. Insights from the genome annotation of Elizabethkingia anophelis from the malaria vector Anopheles gambiae
Open this publication in new window or tab >>Insights from the genome annotation of Elizabethkingia anophelis from the malaria vector Anopheles gambiae
(English)Manuscript (preprint) (Other academic)
National Category
Microbiology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-101394 (URN)
Available from: 2014-03-06 Created: 2014-03-06 Last updated: 2014-03-07

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