Vanderbilt University School of
6260 MRB III
6260 Medical Research Building III 465 21st Ave. South 37235
olfaction, signal transduction, Anopheles, bioinformatics, genomics, disease vector mosquito,Molecular Biology, Neurobiology, Biochemistry, Developmental biology, Drosophila, Genetics, Genomics, Infectious
modification,Biochemistry,Developmental biology,Drosophila,Genetics,Genome,Infectious disease,Neuroscience,Signal transduction
The comprehensive study of olfaction and olfactory-based behaviors in malaria and other disease vector mosquitoes
The major focus of the laboratory is the characterization of specific genes and their products that control important behavioral processes in the life cycle of eusocial insects and mosquitoes that act as vectors for human disease.
One focus is on host (i.e. blood-meal source) seeking/selection in the mosquito Anopheles gambiae which is the principal vector for malaria in Africa. Malaria is caused by a protozoan parasite of the genus Plasmodium that is transmitted to humans through blood feeding by female Anopheline mosquitoes. In this context, we are examining the molecular events of olfaction as this sense predominates the overall host preference behaviors in mosquitoes and other insects. This aspect of the mosquito's behavior is especially important as it makes a significant contribution to the vectorial capacity of this arthropod vector, as well as playing a similar role in the overall impact of many other insects of economic importance.
The proteins that carry out olfactory signal transduction are present on the inside surface of the olfactory receptor neuron (ORN) dendritic membranes that in insects are located in hair like structures called sensilla. Signal transduction is initiated when odorants (either alone or in complexes with Odorant Binding Proteins) bind to members of seven transmembrane containing odorant receptors (ORs). Originally thought to be G-protein coupled, insect ORs are now almost universally recognized to be novel signaling complexes that combine ligand specificity subunit (conventional ORs) with a widely- expressed, non-conventional OR subunit that most probably acts as a direct ionotropic channel on ORN dendrites- in fruitflies this OR is known as 83b (in light of its position on polytene chromosomes) while in mosquitoes this common component is called OR7. Recent studies in Drosophila (Benton et. al. 2009) have also pointed to the existence of a novel class of chemosensory receptors known as ionotropic receptors (IRs) that have homology to insect glutamate receptors. Current efforts are focused on understanding how ORs, IRs, OBPs and other components of this pathway mediate olfactory signal transduction in anopheline mosquitoes.
We use molecular and informatics based approaches to identify genes that are active in olfactory signal transduction in An. gambiae and other disease vector mosquitoes. The molecular characterization of genes which mediate olfaction in this Anopheline mosquito has started with the generation of cDNA libraries specifically derived from olfactory (i.e. the antennal and maxillary palps) and neural (heads that have been stripped of antennal and maxillary palps) structures of female adult mosquitoes. These hand-dissected structures have been used as substrate for the synthesis of subtracted cDNA libraries using novel PCR based methods that are specifically designed to facilitate the use of picogram amounts of mRNA starting material. More recently we have focused on genomics based approaches that include genome mining and deep sequencing of olfactory transcriptomes that has thus resulted in the isolation of several olfactory genes from An. gambiae that are currently being characterized at the molecular and cellular levels.
Much of the lab's focus is on the molecular, biochemical and functional characterization of ORs An. gambiae (AgORs). Over the years "Team AgOR" has gone from the original characterization of AgORs insofar as their DNA sequence and organization to detailed in vivo expression studies. We have extended this study to include the use of ex vivo expression systems, electrophysiology, cell culture and transgenic insect systems (e.g.Drosophila) in order to study the functional characteristics of AgORs from specific senory appendages to whole genome wide approaches (see publication list).
A long-term objective of our work is the molecular characterization of the olfactory genes in general as well as the mechanisms that which are central in the marked preference for human blood meals (anthropophily) characteristic of An. gambiae s.s. In fact it is this component of the mosquito's behavior which makes it such an important disease vector. In contrast, a preference for bovine blood meals (zoophily) has been observed in the non-vector sibling species An. quadriannulatus. By using subtractive hybridization it may be possible to prepare anthropophilic and zoophilic enriched cDNA pools from which a more defined pool of olfactory and other behavioral genes may be isolated. For the present, we are engaged in a suite of studies to isolate and characterize orthologous ORs from species of anthropophilic and zoophilic mosquitoes as well as from other mosquito vectors for other human pathogens. These include Aedes aegypti, the vector for dengue and yellow fever that is widespread in Central and South America and Culex pipens, the North American mosquito responsible for transmission of West Nile Virus.
On the applied side, we are privileged to lead a broad international network of five laboratories (encompassing Yale University, New Haven, CT; Wageningen University, The Netherlands; ICIPE, Kenya; The MRC Laboratories, The Gambia) that has been selected for a $8.9M Grand Challenge In Global Health grant for the specific purpose to target odorant receptors in order to design a new generation of mosquito repellents and attractants. Together with colleagues at the Vanderbilt Institute for Chemical Biology we are engaged in using state of the art molecular and chemical approaches that target AgOR/AaORs in order to design a new generation of mosquito repellents and attractants that would foster the design of novel programs that target chemosensory pathways and the behaviors they control in vector mosquitoes. These may also include behavioral disruption programs based on specific inhibitors (aka confusants) of OR-mediated olfactory pathways as well as the identification and intelligent design of novel and economically synthesized mosquito attractants and repellents. This approach could be extended to other mosquito vectors as well where reductions in host seeking (through the use of confusants or repellants) could potentially effect disease transmission by targeting adult vectorial capacity. Attractants may be incorporated into novel mosquito management strategies, these include: lures to increase the efficiency of traps for sentinel monitoring of vector populations and insecticide-laden mosquito trapping systems for population reduction; augmentation of insecticide-treated net (ITN)-based strategies as well as otherwise enabling innovative insect/disease control strategies that focus on disrupting and/or taking advantage of vector-host interactions.
We have recently extended our interests to the study the chemosensory elements of pheromone-based eusocial interactions in two divergent species (Camponotus floridanus and Harpegnathos saltator) of ants. This was initiated as part of a recently renewed Collaborative Innovation Award from the Howard Hughes Medical Institute (HHMI). In this context, we have extended our studies on chemosensory-driven behaviors of mosquitoes to ants to take advantage of the large body of work that suggests that behavior and social organization in ants are largely modulated by chemosensory communication, often encoded by complex mixtures of volatile cuticular hydrocarbons (CHCs). Ants are extremely interesting because they exhibit the sophisticated ability to discriminate and respond to a wealth of socially relevant chemical cues that are highly related in structure. The genetics and inherent circuitry that supports this capacity is likely to provide us with a rich reservoir of information regarding the evolution and caste and sex-specific modulation of chemosensory receptor space, as it applies specifically to social organization- an extremely intriguing question that is not applicable to vector mosquitoes.
Hughes, DT, Wang, G, Zwiebel, LJ, Luetje, CW. A Determinant of Odorant Specificity Is Located at the Extracellular Loop 2-Transmembrane Domain 4 Interface of an Anopheles gambiae Odorant Receptor Subunit. Chem Senses, , , 2014.
Pitts, RJ, Liu, C, Zhou, X, Malpartida, JC, Zwiebel, LJ. Odorant receptor-mediated sperm activation in disease vector mosquitoes. Proc Natl Acad Sci U S A, 111(7), 2566-71, 2014.
Romaine, IM, Taylor, RW, Saidu, SP, Kim, K, Sulikowski, GA, Zwiebel, LJ, Waterson, AG. Narrow SAR in odorant sensing Orco receptor agonists. Bioorg Med Chem Lett, 24(12), 2613-6, 2014.
Turner, RM, Derryberry, SL, Kumar, BN, Brittain, T, Zwiebel, LJ, Newcomb, RD, Christie, DL. Mutational analysis of cysteine residues of the insect odorant co-receptor (Orco) from Drosophila melanogaster reveals differential effects on agonist- and odorant/tuning receptor-dependent activation. J Biol Chem, , , 2014.
Liu, C, Zwiebel, LJ. Molecular characterization of larval peripheral thermosensory responses of the malaria vector mosquito Anopheles gambiae. PLoS One, 8(8), e72595, 2013.
Pask, GM, Bobkov, YV, Corey, EA, Ache, BW, Zwiebel, LJ. Blockade of insect odorant receptor currents by amiloride derivatives. Chem Senses, 38(3), 221-9, 2013.
Rinker, DC, Pitts, RJ, Zhou, X, Suh, E, Rokas, A, Zwiebel, LJ. Blood meal-induced changes to antennal transcriptome profiles reveal shifts in odor sensitivities in Anopheles gambiae. Proc Natl Acad Sci U S A, , , 2013.
Rinker, DC, Zhou, X, Pitts, RJ, , , Rokas, A, Zwiebel, LJ. Antennal transcriptome profiles of anopheline mosquitoes reveal human host olfactory specialization in Anopheles gambiae. BMC Genomics, 14, 749, 2013.
Jones, PL, Pask, GM, Romaine, IM, Taylor, RW, Reid, PR, Waterson, AG, Sulikowski, GA, Zwiebel, LJ. Allosteric antagonism of insect odorant receptor ion channels. PLoS One, 7(1), e30304, 2012. PMCID:3260273
Pask, GM, Romaine, IM, Zwiebel, LJ. The Molecular Receptive Range of a Lactone Receptor in Anopheles gambiae. Chem Senses, first published online September 2, 2012 , doi:10.1093/chemse/bjs074, 2012.
Taylor, RW, Romaine, IM, Liu, C, Murthi, P, Jones, PL, Waterson, AG, Sulikowski, GA, Zwiebel, LJ. Structure-Activity Relationship of a Broad-Spectrum Insect Odorant Receptor Agonist. ACS Chem Biol, August 27, 2012 (Letters) , doi:10.1021/cb300331z., 2012.
Zhou, X, Slone, JD, Rokas, A, Berger, SL, Liebig, J, Ray, A, Reinberg, D, Zwiebel, LJ. Phylogenetic and transcriptomic analysis of chemosensory receptors in a pair of divergent ant species reveals sex-specific signatures of odor coding. PLoS Genet, 8(8), e1002930, 2012.
Bohbot, JD, Jones, PL, Wang, G, Pitts, RJ, Pask, GM, Zwiebel, LJ. Conservation of indole responsive odorant receptors in mosquitoes reveals an ancient olfactory trait. Chem Senses, 36(2), 149-60, 2011. PMCID:3126782
Jones, PL, Pask, GM, Rinker, DC, Zwiebel, LJ. Functional agonism of insect odorant receptor ion channels. Proc Natl Acad Sci U S A, 108(21), 8821-5, 2011. PMCID:3126782
Pask, GM, Jones, PL, R??tzler, M, Rinker, DC, Zwiebel, LJ. Heteromeric anopheline odorant receptors exhibit distinct channel properties. PLoS One, 6(12), e28774, 2011. PMCID:3235152
Pitts, RJ, Rinker, DC, Jones, PL, Rokas, A, Zwiebel, LJ. Transcriptome profiling of chemosensory appendages in the malaria vector Anopheles gambiae reveals tissue- and sex-specific signatures of odor coding. BMC Genomics, 12, 271, 2011. PMCID:3126782
Carey, AF, Wang, G, Su, CY, Zwiebel, LJ, Carlson, JR. Odorant reception in the malaria mosquito Anopheles gambiae. Nature, 464(7285), 66-71, 2010.
Liu, C, Pitts, RJ, Bohbot, JD, Jones, PL, Wang, G, Zwiebel, LJ. Distinct olfactory signaling mechanisms in the malaria vector mosquito Anopheles gambiae. PLoS Biol, 8(8), , 2010. PMCID:2930861
Wang, G, Carey, AF, Carlson, JR, Zwiebel, LJ. Molecular basis of odor coding in the malaria vector mosquito Anopheles gambiae. Proc Natl Acad Sci U S A, 107(9), 4418-23, 2010. PMCID:2840125
Wang, G, Qiu, YT, Lu, T, Kwon, HW, Pitts, RJ, Van Loon, JJ, Takken, W, Zwiebel, LJ. Anopheles gambiae TRPA1 is a heat-activated channel expressed in thermosensitive sensilla of female antennae. Eur J Neurosci, 30(6), 967-74, 2009.
Walker, WB, Smith, EM, Jan, T, Zwiebel, LJ. A functional role for Anopheles gambiae Arrestin1 in olfactory signal transduction. J Insect Physiol, 54(4), 680-90, 2008. PMCID:2408752
Xia, Y, Wang, G, Buscariollo, D, Pitts, RJ, Wenger, H, Zwiebel, LJ. The molecular and cellular basis of olfactory-driven behavior in Anopheles gambiae larvae. Proc Natl Acad Sci U S A, 105(17), 6433-8, 2008. PMCID:2359781
Bohbot, J, Pitts, RJ, Kwon, HW, Rutzler, M, Robertson, HM, Zwiebel, LJ. Molecular characterization of the Aedes aegypti odorant receptor gene family. Insect Mol Biol, 16(5), 525-37, 2007.
Lu, T, Qiu, YT, Wang, G, Kwon, JY, Rutzler, M, Kwon, HW, Pitts, RJ, van Loon, JJ, Takken, W, Carlson, JR, Zwiebel, LJ. Odor coding in the maxillary palp of the malaria vector mosquito Anopheles gambiae. Curr Biol, 17(18), 1533-44, 2007.
Kwon, HW, Lu, T, Rutzler, M, Zwiebel, LJ. Olfactory responses in a gustatory organ of the malaria vector mosquito Anopheles
gambiae. Proc Natl Acad Sci U S A, 103(36), 13526-31, 2006. PMCID:1569196
Pitts, RJ, Zwiebel, LJ. Antennal sensilla of two female anopheline sibling species with differing host
ranges. Malar J, 5, 26, 2006. PMCID:1532926
R??tzler, M, Lu, T, Zwiebel, LJ. Galpha encoding gene family of the malaria vector mosquito Anopheles gambiae: expression analysis and immunolocalization of AGalphaq and AGalphao in female antennae. J Comp Neurol, 499(4), 533-45, 2006.
Xia, Y, Zwiebel, LJ. Identification and characterization of an odorant receptor from the West Nile
Virus mosquito, Culex quinquefasciatus. Insect Biochem Mol Biol, 36(3), 169-76, 2006.
Merrill, E.C., Sherertz, T. Walker, W. B. and L.J. Zwiebel. Odorant-Specific Requirements for Arrestin Function in Drosophila Olfaction. J Neurobiol, 1(63), 15-28, 2005.
Rutzler, M, Zwiebel, LJ. Molecular biology of insect olfaction: recent progress and conceptual models. J Comp Physiol A Neuroethol Sens Neural Behav Physiol, 191(9), 777-90, 2005.
Hallem, Elissa A, Nicole Fox, A, Zwiebel, Laurence J, Carlson, John R. Olfaction: mosquito receptor for human-sweat odorant. Nature, 427(6971), 212-3, 2004.
Melo, Ana Claudia A, Rutzler, Michael, Pitts, R Jason, Zwiebel, Laurence J. Identification of a chemosensory receptor from the yellow fever mosquito, Aedes aegypti, that is highly conserved and expressed in olfactory and gustatory organs. Chem Senses, 29(5), 403-10, 2004.
Pitts, R Jason, Fox, A Nicole, Zwiebel, Laurence J. A highly conserved candidate chemoreceptor expressed in both olfactory and gustatory tissues in the malaria vector Anopheles gambiae. Proc Natl Acad Sci U S A, 101(14), 5058-63, 2004. PMCID:387373
Zwiebel, L J, Takken, W. Olfactory regulation of mosquito-host interactions. Insect Biochem Mol Biol, 34(7), 645-52, 2004.
Merrill, C E, Pitts, R J, Zwiebel, L J. Molecular characterization of arrestin family members in the malaria vector mosquito, Anopheles gambiae. Insect Mol Biol, 12(6), 641-50, 2003.
Xu, P X, Zwiebel, L J, Smith, D P. Identification of a distinct family of genes encoding atypical odorant-binding proteins in the malaria vector mosquito, Anopheles gambiae. Insect Mol Biol, 12(6), 549-60, 2003.
Fox, A N, Pitts, R J, Zwiebel, L J. A cluster of candidate odorant receptors from the malaria vector mosquito, Anopheles gambiae. Chem Senses, 27(5), 453-9, 2002.
Hill, Catherine A, Fox, A Nicole, Pitts, R Jason, Kent, Lauren B, Tan, Perciliz L, Chrystal, Mathew A, Cravchik, Anibal, Collins, Frank H, Robertson, Hugh M, Zwiebel, Laurence J. G protein-coupled receptors in Anopheles gambiae. Science, 298(5591), 176-8, 2002.
Merrill, C E, Riesgo-Escovar, J, Pitts, R J, Kafatos, F C, Carlson, J R, Zwiebel, L J. Visual arrestins in olfactory pathways of Drosophila and the malaria vector mosquito Anopheles gambiae. Proc Natl Acad Sci U S A, 99(3), 1633-8, 2002. PMCID:122242
Fox, A N, Pitts, R J, Robertson, H M, Carlson, J R, Zwiebel, L J. Candidate odorant receptors from the malaria vector mosquito Anopheles gambiae and evidence of down-regulation in response to blood feeding. Proc Natl Acad Sci U S A, 98(25), 14693-7, 2001. PMCID:64743
Gomulski, L M, Pitts, R J, Costa, S, Saccone, G, Torti, C, Polito, L C, Gasperi, G, Malacrida, A R, Kafatos, F C, Zwiebel, L J. Genomic organization and characterization of the white locus of the Mediterranean fruitfly, Ceratitis capitata. Genetics, 157(3), 1245-55, 2001. PMCID:1461546
Pitts, R J, Zwiebel, L J. Isolation and characterization of the Xanthine dehydrogenase gene of the Mediterranean fruit fly, Ceratitis capitata. Genetics, 158(4), 1645-55, 2001. PMCID:1461762
Zwiebel, L J, Saccone, G, Zacharopoulou, A, Besansky, N J, Favia, G, Collins, F H, Louis, C, Kafatos, F C. The white gene of Ceratitis capitata: a phenotypic marker for germline transformation. Science, 270(5244), 2005-8, 1995.
Edery, I, Zwiebel, L J, Dembinska, M E, Rosbash, M. Temporal phosphorylation of the Drosophila period protein. Proc Natl Acad Sci U S A, 91(6), 2260-4, 1994. PMCID:43350
Liu, X, Zwiebel, L J, Hinton, D, Benzer, S, Hall, J C, Rosbash, M. The period gene encodes a predominantly nuclear protein in adult Drosophila. J Neurosci, 12(7), 2735-44, 1992.
Liu, X, Yu, Q A, Huang, Z S, Zwiebel, L J, Hall, J C, Rosbash, M. The strength and periodicity of D. melanogaster circadian rhythms are differentially affected by alterations in period gene expression. Neuron, 6(5), 753-66, 1991.
Zwiebel, L J, Hardin, P E, Hall, J C, Rosbash, M. Circadian oscillations in protein and mRNA levels of the period gene of Drosophila melanogaster. Biochem Soc Trans, 19(2), 533-7, 1991.
Zwiebel, L J, Hardin, P E, Liu, X, Hall, J C, Rosbash, M. A post-transcriptional mechanism contributes to circadian cycling of a per-beta-galactosidase fusion protein. Proc Natl Acad Sci U S A, 88(9), 3882-6, 1991. PMCID:51557
Hamblen-Coyle, M, Konopka, R J, Zwiebel, L J, Colot, H V, Dowse, H B, Rosbash, M, Hall, J C. A new mutation at the period locus of Drosophila melanogaster with some novel effects on circadian rhythms. J Neurogenet, 5(4), 229-56, 1989.
Hamblen, M, Zehring, W A, Kyriacou, C P, Reddy, P, Yu, Q, Wheeler, D A, Zwiebel, L J, Konopka, R J, Rosbash, M, Hall, J C. Germ-line transformation involving DNA from the period locus in Drosophila melanogaster: overlapping genomic fragments that restore circadian and ultradian rhythmicity to per0 and per- mutants. J Neurogenet, 3(5), 249-91, 1986.
Zwiebel, L J, Cohn, V H, Wright, D R, Moore, G P. Evolution of single-copy DNA and the ADH gene in seven drosophilids. J Mol Evol, 19(1), 62-71, 1982.
Zwiebel, L J, Inukai, M, Nakamura, K, Inouye, M. Preferential selection of deletion mutations of the outer membrane lipoprotein gene of Escherichia coli by globomycin. J Bacteriol, 145(1), 654-6, 1981. PMCID:217321
Vector Chemosensory Neurobiology & Behavior Post-Doctoral Position Available at Vanderbilt University. An NIH-funded post-doctoral position is available in the Departments of Biological Sciences and Pharmacology at Vanderbilt University. We study mosquito olfaction and its role in modulating and mosquito-host interactions from an molecular neuroscience perspective using diverse approaches and methodologies. We are focused on the role of odorant receptors and other molecular elements of the peripheral sensory apparatus in driving host and oviposition preferences in both Anopheles gambiae and Aedes aegypti. We are looking for a highly motivated, independently-thinking individual, who wants to design and conduct laboratory studies on the peripheral sensory system of disease vectors. A Ph.D. in molecular neuroscience, entomology, behavior, molecular genetics, or related field and at least one first-author publication are required. Experience in chemosensory biology, molecular biology, behavior, and statistical analysis is desirable. No more than 5 years since completion of Ph.D. degree. To apply, please send CV, statement of research interests, reprints of recent papers, and names of three references to LJ Zwiebel (E-mail: email@example.com ) by August 15, 2010.
Additional information can be found in: http://www.cas.vanderbilt.edu/zwiebel/
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