title: Immunogenic and antioxidant effects of a pathogen-associated prenyl pyrophosphate in Anopheles gambiae.
abstract: 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.
authors: Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors: Bo G
authors: BG
authors: Lindberg
authors: Eleanor A
authors: EA
authors: Merritt
authors: Melanie
authors: M
authors: Rayl
authors: Chenxiao
authors: C
authors: Liu
authors: Ingela
authors: I
authors: Parmryd
authors: Berit
authors: B
authors: Olofsson
authors: Ingrid
authors: I
authors: Faye
mesh_terms: D000818:Animals; D000852:Anopheles / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D000975:Antioxidants / Q000494:pharmacology*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D005260:Female; D041981:Gastrointestinal Tract / Q000382:microbiology; D020869:Gene Expression Profiling; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010755:Organophosphates / Q000276:immunology* / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: C467061:4-hydroxy-3-methyl-2-butenyl diphosphate; D000975:Antioxidants; D017077:Culture Media, Conditioned; D010755:Organophosphates; D016692:Receptors, Antigen, T-Cell, gamma-delta; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D020928:Mitogen-Activated Protein Kinases
references: Nat Immunol. 2009 Sep;10(9):949-57
references: 19668222
references: PLoS Pathog. 2010 Oct 07;6(10):e1001143
references: 20949079
references: PLoS Pathog. 2009 Aug;5(8):e1000542
references: 19662170
references: Science. 2010 Mar 26;327(5973):1644-8
references: 20223948
references: Dev Comp Immunol. 2009 Feb;33(2):216-23
references: 18822312
references: J Immunol. 2009 Sep 15;183(6):3848-57
references: 19710470
references: Evolution. 2005 Dec;59(12):2560-72
references: 16526504
references: Int Immunol. 2007 May;19(5):657-73
references: 17446209
references: Infect Immun. 1996 Aug;64(8):2892-6
references: 8757809
references: BMC Genomics. 2011 Nov 23;12:574
references: 22111877
references: J Biol Chem. 2008 Feb 8;283(6):3217-3223
references: 18065421
references: Science. 2011 May 13;332(6031):855-8
references: 21566196
references: Parasitology. 2004 Dec;129(Pt 6):663-76
references: 15648689
references: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8814-9
references: 12077297
references: Science. 1976 Aug 20;193(4254):673-5
references: 781840
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14139-44
references: 14623973
references: Infect Immun. 2005 May;73(5):2778-89
references: 15845481
references: PLoS One. 2010 Jun 17;5(6):e11168
references: 20567517
references: Infect Immun. 2007 Aug;75(8):4012-9
references: 17526741
references: Mutat Res. 2004 Oct 4;554(1-2):33-43
references: 15450402
references: Curr Biol. 2005 Jul 12;15(13):1185-95
references: 16005290
references: EMBO J. 1998 Nov 2;17(21):6115-23
references: 9799221
references: EMBO J. 2000 Nov 15;19(22):6030-40
references: 11080150
references: Science. 2005 Nov 4;310(5749):847-50
references: 16272120
references: Dev Cell. 2009 Mar;16(3):386-97
references: 19289084
references: Microbiology (Reading). 2002 Jan;148(Pt 1):257-266
references: 11782518
references: Am J Trop Med Hyg. 1996 Feb;54(2):214-8
references: 8619451
references: PLoS Pathog. 2009 May;5(5):e1000423
references: 19424427
references: Immunol Rev. 2007 Feb;215:59-76
references: 17291279
references: J Immunol. 2010 Jun 1;184(11):6209-22
references: 20483784
references: J Immunol. 1995 Feb 1;154(3):998-1006
references: 7529807
references: Cold Spring Harb Symp Quant Biol. 1989;54 Pt 1:1-13
references: 2700931
references: Antioxid Redox Signal. 2011 Mar 15;14(6):943-55
references: 21126166
references: Trends Parasitol. 2005 Dec;21(12):573-80
references: 16236552
references: Dev Comp Immunol. 2011 Jan;35(1):44-50
references: 20708028
references: PLoS Pathog. 2011 May;7(5):e1002040
references: 21589907
references: PLoS One. 2009 May 21;4(5):e5657
references: 19479075
references: J Biol Chem. 1999 Apr 23;274(17):11727-35
references: 10206988
references: PLoS Pathog. 2009 Apr;5(4):e1000366
references: 19343212
references: PLoS Pathog. 2006 Jun;2(6):e52
references: 16789837
references: Int Immunol. 1992 Jan;4(1):33-41
references: 1531764
references: Springer Semin Immunopathol. 2000;22(3):191-217
references: 11116953
references: Eur J Immunol. 1991 Oct;21(10):2613-6
references: 1833205