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Immunogenic and Antioxidant Effects of a Pathogen-Associated Prenyl Pyrophosphate in Anopheles gambiae
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e73868-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 Vγ9Vδ2 T cells, a unique lymphocyte subset that expands during several infections including malaria. In this study, we show that Vγ9Vδ2 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 Vγ9Vδ2 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.

Place, publisher, year, edition, pages
2013. Vol. 8, no 8, p. e73868-
National Category
Immunology
Research subject
Medical Cell Biology
Identifiers
URN: urn:nbn:se:uu:diva-206008DOI: 10.1371/journal.pone.0073868ISI: 000323115800125PubMedID: 23967351OAI: oai:DiVA.org:uu-206008DiVA, id: diva2:643178
Available from: 2013-08-26 Created: 2013-08-26 Last updated: 2018-04-05Bibliographically approved
In thesis
1. Vγ9Vδ2 T cells - response to P. falciparum-derived phosphoantigens and potential for use in colon cancer immunotherapy 
Open this publication in new window or tab >>Vγ9Vδ2 T cells - response to P. falciparum-derived phosphoantigens and potential for use in colon cancer immunotherapy 
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Vγ9Vδ2 T cell is the dominant circulating γδ T cell subset in humans, can expand massively upon malaria infection and are cytotoxic to cancer cells. Vγ9Vδ2 T cells are stimulated by phosphoantigens, primarily isoprenoid pyrophosphates like isopentenyl pyrophosphate and (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP). Vγ9Vδ2 T cell from human blood were studied for proliferation, response to blood-stage malaria parasites and during colon cancer progression. Vγ9Vδ2 T cell proliferation was stimulated by media from P. falciparum-infected erythrocytes from all asexual blood stages - rings, trophozoites, schizonts and rupturing schizonts as well as sexual stage gametocytes assessed by the protocols we developed to obtain pure cultures of all stages. Further, we demonstrated that the molecules that stimulated the Vγ9Vδ2 T cell proliferation are phosphoantigens that are released from intact infected erythrocytes. This does not require schizont rupture.  Interestingly, the parasites consumed all the iron ion of hemoglobins during their development from the ring to the rupturing schizont stage. We found that an Anopheles gambiae immune cell line responds to HMBPP by activation of MAPK and PI3K signaling pathways. Moreover, transcription of dual oxidase and nitric oxide synthase was upregulated by addition of HMBPP in the midgut of Anopheles gambiae which increases cell tolerance to oxidative stress. A range of small isoprenoid pyrophosphates were found to stimulate proliferation of Vγ9Vδ2 T cells from PBMCs as was the isoprenoid monophosphate DMAP. However other isoprenoid monophosphates and alcohols did not. We found that cryopreserved unexpectedly increase the proliferation ability of HMBPP–stimulated PBMCs. To test the cytotoxicity of Vγ9Vδ2 T cells against adherent colon cancer cell lines, a flow cytometry-based assay was developed. Using the assay we found that proliferated Vγ9Vδ2 T cells are cytotoxcitic to various cancer cells and that HMBPP increases cytotoxicity towards adherent colon cancer cells. In a clinical study we found that Vγ9Vδ2 T cells could not always be proliferated from colon cancer patients and that the inflammatory homing receptor CXCR3 was expressed at higher levels in colon cancer patients than the control group. Moreover, at cancer stadium 4 a lower frequency of Vγ9Vδ2 T cells was more common than in the other groups.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1455
National Category
Cell and Molecular Biology Immunology in the medical area
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-347682 (URN)978-91-513-0311-6 (ISBN)
Public defence
2018-05-16, B7:113a, Biomedicum, Husargatan 3, Uppsala, 13:15 (English)
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Supervisors
Available from: 2018-04-24 Created: 2018-04-05 Last updated: 2018-04-24

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