Immunological Crosstalk between Human Transforming Growth Factor-β1 and the Malaria Vector Anopheles stephensi

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dc.contributor.authorLieber, Matthew Joshuaen
dc.contributor.committeechairLuckhart, Shirleyen
dc.contributor.committeememberGillaspy, Glenda E.en
dc.contributor.committeememberHuckle, William R.en
dc.contributor.committeememberTu, Zhijian Jakeen
dc.contributor.committeememberMcDowell, John M.en
dc.contributor.departmentBiochemistryen
dc.date.accessioned2014-03-14T21:36:40Zen
dc.date.adate2005-06-30en
dc.date.available2014-03-14T21:36:40Zen
dc.date.issued2005-05-23en
dc.date.rdate2008-06-30en
dc.date.sdate2005-06-01en
dc.description.abstractThe emergence of pesticide-resistant mosquitoes and drug-resistant parasites in the last twenty years has made control of malaria more difficult. One novel strategy to better control malaria is the development and release of transgenic mosquitoes whose enhanced immunity prevents transmission of the parasite to the mammalian host. One candidate effector gene is Anopheles stephensi nitric oxide synthase (AsNOS), whose inducible expression and subsequent synthesis of nitric oxide (NO) limits Plasmodium development in A. stephensi. In mammals, one of the most potent physiological regulators of NOS gene expression and catalytic activity is transforming growth factor-β (TGF-β). Moreover, human TGF-β can activate Drosophila melanogaster Smads, the proteins responsible for TGF-β signal transduction. We have determined that following a bloodmeal, active human TGF-β1 (hTGF-β1) persists in the midgut of A. stephensi for up to 48 hours. My data demonstrate that the midgut epithelium recognizes hTGF-β1 as an immunomodulatory cytokine. Specifically, induction of AsNOS by hTGF-β1 occurs in the midgut within minutes of bloodfeeding. Moreover, hTGF-β1 limits development of the human malaria parasite Plasmodium falciparum in the midgut. In other experiments, provision of the AsNOS catalytic inhibitor L-NAME partially reverses the effect of hTGF-β1 on Plasmodium development. These results suggest that AsNOS is a target of hTGF-β1 signaling and additional effectors that impact parasite development may be regulated by hTGF-β1 as well. The fact that hTGF-β1 signals mosquito cells to limit malaria parasite development suggests that there is an endogenous TGF-β signaling network in place. An analysis of the A. gambiae genome database revealed the presence of six TGF-β ligands, including gene duplication in the 60A gene, the first evidence of ligand gene duplication outside of chordates. In addition to five receptors, three Smads were identified in the A. gambiae genome predicted to support TGF-β/Activin- and BMP-like signaling. Midgut epithelial cells and an immunocompetent A. stephensi cell line express all three Smads, confirming that a signaling pathway is in place to support signaling by divergent exogenous and endogenous TGF-β superfamily proteins. The results presented here provide the first evidence of immunological crosstalk between divergent free living hosts of a single parasite. Further, these results imply that the interface between mammals and the mosquitoes that feed on them provide a unique opportunity for circulating molecules in the blood, including TGF-β and other cytokines, to alter the mosquito immune response.en
dc.description.degreeMaster of Scienceen
dc.identifier.otheretd-06012005-211726en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-06012005-211726/en
dc.identifier.urihttp://hdl.handle.net/10919/42816en
dc.publisherVirginia Techen
dc.relation.haspartImmunologicalCrosstalkBetweenHumanTransformingGrowthFactorBeta1andtheMalariaVectorAnophelesstephensi.pdfen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectTGF-βen
dc.subjectAnophelesen
dc.subjectSmaden
dc.subjectnitric oxide synthaseen
dc.subjectBMPen
dc.subjectsignalingen
dc.subjectmalariaen
dc.titleImmunological Crosstalk between Human Transforming Growth Factor-β1 and the Malaria Vector Anopheles stephensien
dc.typeThesisen
thesis.degree.disciplineBiochemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Scienceen

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