title: Trypanosome infection establishment in the tsetse fly gut is influenced by microbiome-regulated host immune barriers.
abstract: Tsetse flies (Glossina spp.) vector pathogenic African trypanosomes, which cause sleeping sickness in humans and nagana in domesticated animals. Additionally, tsetse harbors 3 maternally transmitted endosymbiotic bacteria that modulate their host's physiology. Tsetse is highly resistant to infection with trypanosomes, and this phenotype depends on multiple physiological factors at the time of challenge. These factors include host age, density of maternally-derived trypanolytic effector molecules present in the gut, and symbiont status during development. In this study, we investigated the molecular mechanisms that result in tsetse's resistance to trypanosomes. We found that following parasite challenge, young susceptible tsetse present a highly attenuated immune response. In contrast, mature refractory flies express higher levels of genes associated with humoral (attacin and pgrp-lb) and epithelial (inducible nitric oxide synthase and dual oxidase) immunity. Additionally, we discovered that tsetse must harbor its endogenous microbiome during intrauterine larval development in order to present a parasite refractory phenotype during adulthood. Interestingly, mature aposymbiotic flies (Gmm(Apo)) present a strong immune response earlier in the infection process than do WT flies that harbor symbiotic bacteria throughout their entire lifecycle. However, this early response fails to confer significant resistance to trypanosomes. Gmm(Apo) adults present a structurally compromised peritrophic matrix (PM), which lines the fly midgut and serves as a physical barrier that separates luminal contents from immune responsive epithelial cells. We propose that the early immune response we observe in Gmm(Apo) flies following parasite challenge results from the premature exposure of gut epithelia to parasite-derived immunogens in the absence of a robust PM. Thus, tsetse's PM appears to regulate the timing of host immune induction following parasite challenge. Our results document a novel finding, which is the existence of a positive correlation between tsetse's larval microbiome and the integrity of the emerging adult PM gut immune barrier.
authors: Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, Connecticut, United States of America. brian.weiss@yale.edu
authors: Brian L
authors: BL
authors: Weiss
authors: Jingwen
authors: J
authors: Wang
authors: Michele A
authors: MA
authors: Maltz
authors: Yineng
authors: Y
authors: Wu
authors: Serap
authors: S
authors: Aksoy
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis; D005260:Female; D041981:Gastrointestinal Tract / Q000276:immunology / Q000469:parasitology; D019476:Insect Proteins / Q000096:biosynthesis; D064307:Microbiota; D019255:NADPH Oxidases / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D013559:Symbiosis; D016833:Trypanosoma brucei rhodesiense / Q000276:immunology* / Q000472:pathogenicity; D014353:Trypanosomiasis, African / Q000635:transmission; D014370:Tsetse Flies / Q000254:growth & development / Q000276:immunology* / Q000382:microbiology / Q000469:parasitology*
chemical_list: D002352:Carrier Proteins; D019476:Insect Proteins; C039711:attacin antibacterial protein, insect; C118897:peptidoglycan recognition protein; D052247:Nitric Oxide Synthase Type II; D019255:NADPH Oxidases
references: Appl Environ Microbiol. 2008 Oct;74(19):5965-74
references: 18689507
references: Arch Insect Biochem Physiol. 2001 Jun;47(2):119-25
references: 11376458
references: Parasitology. 1971 Dec;63(3):507-12
references: 5139030
references: Annu Rev Entomol. 1997;42:525-50
references: 15012322
references: Cell Host Microbe. 2011 Oct 20;10(4):307-10
references: 22018231
references: Genes Dev. 2003 Jan 1;17(1):115-25
references: 12514104
references: Trends Parasitol. 2011 Nov;27(11):514-22
references: 21697014
references: Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10552-7
references: 22689989
references: Parasitol Today. 2000 Mar;16(3):114-8
references: 10689331
references: Science. 2010 Sep 10;329(5997):1353-5
references: 20829487
references: Free Radic Biol Med. 2004 Jun 15;36(12):1496-504
references: 15182852
references: Insect Biochem Mol Biol. 2005 May;35(5):413-23
references: 15804575
references: Adv Parasitol. 2003;53:1-83
references: 14587696
references: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12133-8
references: 19587241
references: PLoS Biol. 2011 May;9(5):e1000619
references: 21655301
references: PLoS Negl Trop Dis. 2008 Mar 12;2(3):e192
references: 18335067
references: Mol Microbiol. 2006 Jun;60(5):1194-204
references: 16689795
references: J Mol Med (Berl). 2010 Sep;88(9):865-71
references: 20526573
references: Science. 2010 Mar 26;327(5973):1644-8
references: 20223948
references: Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11508-13
references: 9326640
references: Med Vet Entomol. 1991 Oct;5(4):495-501
references: 1773127
references: Appl Environ Microbiol. 2007 Mar;73(6):1984-91
references: 17277211
references: Trends Parasitol. 2009 Nov;25(11):517-24
references: 19747880
references: Insect Biochem Mol Biol. 2005 Feb;35(2):105-15
references: 15681221
references: PLoS Negl Trop Dis. 2012;6(6):e1708
references: 22724039
references: Proc Natl Acad Sci U S A. 2007 May 29;104(22):9481-6
references: 17517651
references: Science. 2005 Nov 4;310(5749):847-50
references: 16272120
references: Nature. 1977 Jun 30;267(5614):834-5
references: 895841
references: Med Vet Entomol. 1994 Jan;8(1):81-7
references: 8161852
references: Immunol Rev. 2007 Oct;219:8-16
references: 17850478
references: Proc Natl Acad Sci U S A. 1998 May 12;95(10):5700-5
references: 9576947
references: Trends Microbiol. 2004 Jul;12(7):325-36
references: 15223060
references: Proc Natl Acad Sci U S A. 2011 Sep 20;108(38):15966-71
references: 21896728
references: PLoS Pathog. 2009 May;5(5):e1000423
references: 19424427
references: Ann Trop Med Parasitol. 1992 Oct;86(5):529-36
references: 1288435
references: Trop Med Parasitol. 1988 Mar;39(1):56-8
references: 3387828
references: J Insect Physiol. 2008 Aug;54(8):1236-42
references: 18647605
references: Insect Biochem Mol Biol. 2003 Nov;33(11):1155-64
references: 14563366
references: J Insect Physiol. 2000 Sep 1;46(9):1313-1320
references: 10844150
references: Dev Comp Immunol. 2012 Apr;36(4):638-47
references: 22085781
references: Curr Opin Microbiol. 2008 Aug;11(4):345-51
references: 18621142
references: PLoS Pathog. 2008 Jul 04;4(7):e1000098
references: 18604274
references: Annu Rev Entomol. 2009;54:285-302
references: 19067633
references: Proc Natl Acad Sci U S A. 2001 Oct 23;98(22):12648-53
references: 11592981
references: J Parasitol. 2000 Apr;86(2):228-32
references: 10780537
references: PLoS Pathog. 2011 Dec;7(12):e1002415
references: 22174680
references: Med Vet Entomol. 2006 Dec;20(4):388-92
references: 17199750
references: Parasitology. 1999 May;118 ( Pt 5):469-78
references: 10363280
references: J Immunol. 2012 Apr 1;188(7):3395-403
references: 22368278
references: Appl Environ Microbiol. 2012 Nov;78(21):7760-8
references: 22941073
references: Science. 2011 May 13;332(6031):855-8
references: 21566196
references: J Exp Biol. 1975 Oct;63(2):381-90
references: 1202130
references: Kinetoplastid Biol Dis. 2003 Apr 10;2(1):1
references: 12769824
references: PLoS One. 2011;6(11):e26984
references: 22087240
references: Parasitology. 2007 Jun;134(Pt 6):827-31
references: 17306056
references: PLoS Pathog. 2010 Mar 05;6(3):e1000793
references: 20221444