Repository logo
 

Characterizing the target of ivermectin, the glutamate-gated chloride channel, and other insecticide targets as candidate antigens for an anti-mosquito vaccine

Simple item page
dc.contributor.authorMeyers, Jacob, author
dc.contributor.authorPartin, Kathryn, advisor
dc.contributor.authorFoy, Brian, advisor
dc.contributor.authorVigh, Jozsef, committee member
dc.contributor.authorTsunoda, Susan, committee member
dc.date.accessioned2016-01-11T15:13:40Z
dc.date.available2016-01-11T15:13:40Z
dc.date.issued2015
dc.description.abstractThe latest WHO World Malaria Report estimates that, in 2013, there were 198 million cases worldwide causing 584,000 malaria-related deaths. Current malaria control programs primarily target malaria vectors through the use of long lasting insecticide treated bed nets and indoor residual spraying of pyrethroid-based insecticides. However, pyrethroid resistance is becoming widespread in many An. gambiae populations across Africa (Ranson et al., 2011; Trape et al., 2011). Out of recent efforts to find new vector-targeting interventions with novel modes of action, the endectocide ivermectin (IVM) has arisen as a new candidate to control malaria transmission. IVM, when imbibed by vectors from host-treated blood meals, has proven to efficiently kill or disable An. gambiae s.s. both in the lab and the field (Kobylinski et al., 2010; Sylla et al., 2010). More recently, IVM mass drug administrations in multiple locations across west Africa have been shown to temporarily reduce the proportion of P. falciparum-infected An. gambiae in IVM-treated villages (Kobylinski et al., 2011; Alout et al., 2014). The primary target of IVM is the invertebrate glutamate-gated chloride channel (GluCl) (Cully et al., 1994; Cully et al., 1996; Janssen et al., 2007; McCavera et al., 2009; Janssen et al., 2010; Moreno et al., 2010). The purpose of the first chapter of this thesis was to characterize GluCl from An. gambiae in order to understand the physiological role of GluCl and how IVM may be affecting mosquito physiology. Cloning of the An. gambiae GluCl (AgGluCl) revealed unique splicing sites and products not previously predicted. We expressed AgGluCl clones in Xenopus laevis oocytes to measure its electrophysiological activity in response to glutamate and IVM. We also examined AgGluCl isoform-specific transcript levels across different tissues, ages, blood feeding status and gender and GluCl tissue expression in adult An. gambiae. Given that GluCl can be targeted by drugs found in a blood meal and that GluCl is not expressed in mammals, we wanted to test the efficacy of AgGluCl as a candidate mosquitocidal vaccine antigen. We administered a polyclonal anti-AgGluCl immunoglobulin G (anti-AgGluCl IgG) to An. gambiae mosquitoes through a blood meal or directly into the hemocoel by intrathoracic injections and found it significantly reduced An. gambiae survivorship. By co-administering anti-AgGluCl IgG with a known GluCl agonist, IVM, we discovered anti-AgGluCl IgG reverses the mosquitocidal effects of IVM. Our results describing the mosquitocidal properties of anti-AgGluCl IgG suggest that other neuronal proteins could be used as candidate antigens for a mosquitocidal vaccine. The An. gambiae GABA-gated chloride channel (resistance to dieldrin; AgRDL) is another member of the cys-loop ligand-gated ion channels with a similar structure and physiological function to AgGluCl. The An. gambiae voltage-gated sodium channel (AgVGSC) is the target of dichlorodiphenyltrichloroethane (DDT) and the pyrethroid class of insecticides (Soderlund and Bloomquist, 1989). VGSCs are also the target of multiple classes of spider, scorpion and snail toxins, demonstrating that peptides binding to VGSC extracellular residues can affect channel function (Nicholson, 2007; King et al., 2008; Stevens et al., 2011; Klint et al., 2012). Preliminary results shows that IgG targeting AgRDL or AgVGSC similarly reduce An. gambiae survivorship. Finally we tested anti-AgGluCl IgG against A. aegypti and C. tarsalis to see if this strategy has broad potential across both Anopheline and Culicine mosquitoes. However, blood meals containing anti-AgGluCl IgG had no effect on A. aegypti or C. tarsalis survivorship. We determined that this was due to a barrier in antibody translocation from the blood meal to the hemolymph. Since the IgG target, AgGluCl, is only expressed in the hemocoel, antibody translocation was required for mosquito toxicity.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierMeyers_colostate_0053A_13277.pdf
dc.identifier.urihttp://hdl.handle.net/10217/170308
dc.languageEnglish
dc.language.isoeng
dc.publisherColorado State University. Libraries
dc.relation.ispartof2000-2019
dc.rightsCopyright and other restrictions may apply. User is responsible for compliance with all applicable laws. For information about copyright law, please see https://libguides.colostate.edu/copyright.
dc.subjectanti-mosquito vaccine
dc.subjectglutamate-gated chloride channel
dc.subjectivermectin
dc.subjectmosquito
dc.subjectAnopheles gambiae
dc.titleCharacterizing the target of ivermectin, the glutamate-gated chloride channel, and other insecticide targets as candidate antigens for an anti-mosquito vaccine
dc.typeText
dcterms.rights.dplaThis Item is protected by copyright and/or related rights (https://rightsstatements.org/vocab/InC/1.0/). You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).
thesis.degree.disciplineBiomedical Sciences
thesis.degree.grantorColorado State University
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Meyers_colostate_0053A_13277.pdf
Size:
4.89 MB
Format:
Adobe Portable Document Format
Download

Collections

2000-2019
Theses and Dissertations