Kafatos:George K. Christophides

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Prof. George K. Christophides Division of Cell & Molecular Biology Faculty of Natural Sciences Imperial College London Room 6167, Sir Alexander Fleming Building London SW7 2AZ UK Tel: +44 (0) 20 759 45342 Fax: +44 (0) 20 759 41759 g.christophides@imperial.ac.uk

Senior Lecturer at Imperial College, London

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Research Interests My research focuses on infectious diseases, especially insect-borne. I am particularly interested on the interactions between the innate immune system of disease vectors and pathogens. Among the three leading global infectious diseases is malaria (others are AIDS and TB) that threatens almost half of the global population, infects over 400 million people every year and kills 1-3 million people, mostly young children in sub-Saharan Africa. It is caused by the protozoan parasite, Plasmodium, transmitted between humans through Anopheles mosquitoes. To study the interactions between vectors and pathogens, we use genomics, functional genomics technologies and reverse genetics, combined together in a systems biology approach. Below are some of our recent scientific discoveries and future directions. We have pioneered the development of a series of functional genomics platforms for Anopheles research, including various microarray platforms and a full genome RNAi library. The first microarray platform consisted of 4,000 ESTs of the major African malaria vector A. gambiae and was used to study the mosquito immune response and refractoriness to Plasmodium. Later, we produced a 20,000 EST microarray that encompassed approximately 8,000 genes and used extensively by us and others in the research community to address various biological problems, including mosquito responses to viruses, insecticide resistance and developmental programmes. While this platform is still in use, we have generated new full-genome amplicon microarray (MMC2) and, more recently, oligonucleotide microarray platforms, which serve as the main tools in our transcriptomics research to study immune signalling and responses to specific pathogens. The design of MMC2 amplicons have allowed us to also create a double-stranded RNA library of all the mosquito genes. We are currently using this library to finely dissect immune modules and, in collaboration with mathematicians, to study the Anopheles immune system from a systems biological perspective. To complete our genomics toolkit, we called Single Nucleotide Polymorphisms (SNPs) in the A. gambiae genome using sequence traces from past and ongoing genome sequencing projects and are currently developing a SNP chip. We aim to use this to understand the genetic diversity in field mosquitoes that regulates susceptibility vs. refractoriness to P. falciparum and thus contributes malaria transmission. Transcription profiling of A. gambiae has identified a Leucine-rich repeat encoding gene, LRIM1, as a key player in the mosquito immune system. LRIM1 is a potent antagonist of the development of the rodent malaria parasite, P. berghei, mediating lysis or melanization of ookinetes during their invasion of the mosquito midgut. Genetic epistasis experiments have revealed that the inhibitor of parasite melanization, CTL4, is part of the same immune module and acts downstream of LRIM1. In A. gambiae infections with the human parasite P. falciparum, this module appears not to have the same effects on parasite development. We are currently investigating whether this difference between the human and rodent parasites relates to their differential ability to evade the mosquito immune system or to differences in their levels of infection. In either case, this is thought to be the result of evolutionary co-adaptation between the host and the parasite, which we aim to study using population genetics approaches. Recent data show that LRIM1 is a member of a mosquito-specific gene family, which comprises additional parasite antagonists. Although A. gambiae is a highly competent vector of human malaria, its sibling A. quadriannulatus is a non-vector. We have shown that A. quadriannulatus is resistant to infections by P. falciparum and the rodent model P. berghei. Resistance is controlled by quantitative heritable traits and manifested by lysis or melanization of ookinetes in the midgut as well as by killing of parasites at subsequent stages of their development in the mosquito. Orthologs of the Leucine-rich repeat proteins, LRIM1 and LRIM2, and the complement-like protein TEP1 are required in this reaction and their silencing transforms A. quadriannulatus into a highly permissive vector. Additional genes involved in this phenotype have been identified and are currently being investigated. We have shown that the A. gambiae equivalent of the Drosophila Imd pathway is activated in response to bacterial infections and is essential for the survival of adult mosquitoes. This pathway is also involved in the killing of P. berghei in the mosquito midgut, perhaps through transcriptional control of the parasite antagonist, LRIM1. The key recognition receptor of this pathway is PGRPLC, as in Drosophila. PGRPLC exists as three main isoforms, all of which can bind peptidoglycan. Structural modelling has provided insights into how PGRPLC functions to control Imd pathway activation. The Imd pathway and its transcription factor REL2 are not involved with the mosquito fungal infections. A genome-wide analysis of A. gambiae gene expression revealed a series of developmental transcription programs and tissue-specific patterns. Comparative analysis of these data together with Drosophila developmental expression has revealed a conservation of orthologous gene expression between these two insects. This similarity of expression is not correlated with the CDS similarity, indicating that expression profiles and coding sequences evolve independently. This is the first large-scale comparative transcriptomic analysis between two distantly related organisms. It has also identified clusters of co-regulated antiparasitic immunity genes which are currently being investigated. In addition to being vectors of devastating parasitic diseases, mosquitoes act as vectors of several viral diseases including Dengue and Yellow fever, various encephalitides and Chikungunya (CHIK). The latter has recently become a major threat in countries of the European Union, with a major outbreak in Italy in 2007. We have developed a research programme to study insect responses to viruses, which may help develop future strategies to control spread of such diseases. The alphavirus O’Nyong Nyong (ONN), which is very closely related to CHIK and transmitted by A. gambiae and A. funestus, is used as a model system. Genome-wide transcriptional analysis of the A. gambiae responses to infection with the ONN virus identified a number of regulated genes; however, only few are part of the classical mosquito immune repertoire. This suggested that the mosquito response against viral infections is distinct from the immune response against bacterial, fungal or parasitic infections. The study of candidate genes and pathways is ongoing. The genome sequence of the mosquito Aedes aegypti, which is vector of the viral diseases yellow fever, Dengue and CHIK, has allowed us to perform a comparative phylogenomic analysis of the insect immune repertoire. This analysis has revealed distinct and seemingly contrasting modes of evolution of genes involved in the different phases of immune signalling and the melanization genetic module. These dynamics reflect in part continuous readjustment between accommodation and rejection of pathogens and suggest how innate immunity may have evolved. The impact of these modes of evolution on the interactions of the vector with different pathogens is currently under investigation.

Education & Research Diploma in Biology, 1994, University of Athens, Greece PhD in Molecular Biology, 2000, University of Athens, Greece Research Assistant, 1994-1995, University of Athens, Greece Research Assistant, 1996-1999, University of Athens, Greece Marie Curie fellow, 2000-2002, European Molecular Biology Laboratory, Heidelberg, Germany Research Associate, 2003-2004, European Molecular Biology Laboratory, Heidelberg, Germany Staff Scientist, 2004-2005, European Molecular Biology Laboratory, Heidelberg, Germany Senior Lecturer, 2005-present, Division of Cell& Molecular Biology, Imperial College London, London, Untited Kingdom

Publications Habtewold T, Povelones M, Blagborough AM, and Christophides GK. Transmission blocking immunity in the malaria non-vector mosquito Anopheles quadriannulatus species A. PLoS Pathog. 2008 May 23;4(5):e1000070. DOI:10.1371/journal.ppat.1000070 | Mendes AM, Schlegelmilch T, Cohuet A, Awono-Ambene P, De Iorio M, Fontenille D, Morlais I, Christophides GK, Kafatos FC, and Vlachou D. Conserved mosquito/parasite interactions affect development of Plasmodium falciparum in Africa. PLoS Pathog. 2008 May 16;4(5):e1000069. DOI:10.1371/journal.ppat.1000069 | Jaubert-Possamai S, Le Trionnaire G, Bonhomme J, Christophides GK, Rispe C, and Tagu D. Gene knockdown by RNAi in the pea aphid Acyrthosiphon pisum. BMC Biotechnol. 2007 Sep 28;7:63. DOI:10.1186/1472-6750-7-63 | Pindyurin AV, Moorman C, de Wit E, Belyakin SN, Belyaeva ES, Christophides GK, Kafatos FC, van Steensel B, and Zhimulev IF. SUUR joins separate subsets of PcG, HP1 and B-type lamin targets in Drosophila. J Cell Sci. 2007 Jul 15;120(Pt 14):2344-51. DOI:10.1242/jcs.006007 | Waterhouse RM, Kriventseva EV, Meister S, Xi Z, Alvarez KS, Bartholomay LC, Barillas-Mury C, Bian G, Blandin S, Christensen BM, Dong Y, Jiang H, Kanost MR, Koutsos AC, Levashina EA, Li J, Ligoxygakis P, Maccallum RM, Mayhew GF, Mendes A, Michel K, Osta MA, Paskewitz S, Shin SW, Vlachou D, Wang L, Wei W, Zheng L, Zou Z, Severson DW, Raikhel AS, Kafatos FC, Dimopoulos G, Zdobnov EM, and Christophides GK. Evolutionary dynamics of immune-related genes and pathways in disease-vector mosquitoes. Science. 2007 Jun 22;316(5832):1738-43. DOI:10.1126/science.1139862 | Koutsos AC, Blass C, Meister S, Schmidt S, MacCallum RM, Soares MB, Collins FH, Benes V, Zdobnov E, Kafatos FC, and Christophides GK. Life cycle transcriptome of the malaria mosquito Anopheles gambiae and comparison with the fruitfly Drosophila melanogaster. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11304-9. DOI:10.1073/pnas.0703988104 | Vontas J, David JP, Nikou D, Hemingway J, Christophides GK, Louis C, and Ranson H. Transcriptional analysis of insecticide resistance in Anopheles stephensi using cross-species microarray hybridization. Insect Mol Biol. 2007 Jun;16(3):315-24. DOI:10.1111/j.1365-2583.2007.00728.x | Lawson D, Arensburger P, Atkinson P, Besansky NJ, Bruggner RV, Butler R, Campbell KS, Christophides GK, Christley S, Dialynas E, Emmert D, Hammond M, Hill CA, Kennedy RC, Lobo NF, MacCallum MR, Madey G, Megy K, Redmond S, Russo S, Severson DW, Stinson EO, Topalis P, Zdobnov EM, Birney E, Gelbart WM, Kafatos FC, Louis C, and Collins FH. VectorBase: a home for invertebrate vectors of human pathogens. Nucleic Acids Res. 2007 Jan;35(Database issue):D503-5. DOI:10.1093/nar/gkl960 | Cohuet A, Osta MA, Morlais I, Awono-Ambene PH, Michel K, Simard F, Christophides GK, Fontenille D, and Kafatos FC. Anopheles and Plasmodium: from laboratory models to natural systems in the field. EMBO Rep. 2006 Dec;7(12):1285-9. DOI:10.1038/sj.embor.7400831 | Vontas J, Blass C, Koutsos AC, David JP, Kafatos FC, Louis C, Hemingway J, Christophides GK, and Ranson H. Gene expression in insecticide resistant and susceptible Anopheles gambiae strains constitutively or after insecticide exposure. Insect Mol Biol. 2005 Oct;14(5):509-21. DOI:10.1111/j.1365-2583.2005.00582.x | Sim C, Hong YS, Vanlandingham DL, Harker BW, Christophides GK, Kafatos FC, Higgs S, and Collins FH. Modulation of Anopheles gambiae gene expression in response to o'nyong-nyong virus infection. Insect Mol Biol. 2005 Oct;14(5):475-81. DOI:10.1111/j.1365-2583.2005.00578.x | Meister S, Kanzok SM, Zheng XL, Luna C, Li TR, Hoa NT, Clayton JR, White KP, Kafatos FC, Christophides GK, and Zheng L. Immune signaling pathways regulating bacterial and malaria parasite infection of the mosquito Anopheles gambiae. Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11420-5. DOI:10.1073/pnas.0504950102 | Vlachou D, Schlegelmilch T, Christophides GK, and Kafatos FC. Functional genomic analysis of midgut epithelial responses in Anopheles during Plasmodium invasion. Curr Biol. 2005 Jul 12;15(13):1185-95. DOI:10.1016/j.cub.2005.06.044 | Belyakin SN, Christophides GK, Alekseyenko AA, Kriventseva EV, Belyaeva ES, Nanayev RA, Makunin IV, Kafatos FC, and Zhimulev IF. Genomic analysis of Drosophila chromosome underreplication reveals a link between replication control and transcriptional territories. Proc Natl Acad Sci U S A. 2005 Jun 7;102(23):8269-74. DOI:10.1073/pnas.0502702102 | Kriventseva EV, Koutsos AC, Blass C, Kafatos FC, Christophides GK, and Zdobnov EM. AnoEST: toward A. gambiae functional genomics. Genome Res. 2005 Jun;15(6):893-9. DOI:10.1101/gr.3756405 | Christophides GK. Transgenic mosquitoes and malaria transmission. Cell Microbiol. 2005 Mar;7(3):325-33. DOI:10.1111/j.1462-5822.2005.00495.x | Hall N, Karras M, Raine JD, Carlton JM, Kooij TW, Berriman M, Florens L, Janssen CS, Pain A, Christophides GK, James K, Rutherford K, Harris B, Harris D, Churcher C, Quail MA, Ormond D, Doggett J, Trueman HE, Mendoza J, Bidwell SL, Rajandream MA, Carucci DJ, Yates JR 3rd, Kafatos FC, Janse CJ, Barrell B, Turner CM, Waters AP, and Sinden RE. A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses. Science. 2005 Jan 7;307(5706):82-6. DOI:10.1126/science.1103717 | Meister S, Koutsos AC, and Christophides GK. The Plasmodium parasite--a 'new' challenge for insect innate immunity. Int J Parasitol. 2004 Dec;34(13-14):1473-82. DOI:10.1016/j.ijpara.2004.10.004 | Osta MA, Christophides GK, Vlachou D, and Kafatos FC. Innate immunity in the malaria vector Anopheles gambiae: comparative and functional genomics. J Exp Biol. 2004 Jul;207(Pt 15):2551-63. DOI:10.1242/jeb.01066 | Christophides GK, Vlachou D, and Kafatos FC. Comparative and functional genomics of the innate immune system in the malaria vector Anopheles gambiae. Immunol Rev. 2004 Apr;198:127-48. DOI:10.1111/j.0105-2896.2004.0127.x | Osta MA, Christophides GK, and Kafatos FC. Effects of mosquito genes on Plasmodium development. Science. 2004 Mar 26;303(5666):2030-2. DOI:10.1126/science.1091789 | Komitopoulou K, Christophides GK, Kalosaka K, Chrysanthis G, Theodoraki MA, Savakis C, Zacharopoulou A, and Mintzas AC. Medfly promoters relevant to the sterile insect technique. Insect Biochem Mol Biol. 2004 Feb;34(2):149-57. DOI:10.1016/j.ibmb.2003.06.016 | Kumar S, Christophides GK, Cantera R, Charles B, Han YS, Meister S, Dimopoulos G, Kafatos FC, and Barillas-Mury C. The role of reactive oxygen species on Plasmodium melanotic encapsulation in Anopheles gambiae. Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14139-44. DOI:10.1073/pnas.2036262100 | Christophides GK, Zdobnov E, Barillas-Mury C, Birney E, Blandin S, Blass C, Brey PT, Collins FH, Danielli A, Dimopoulos G, Hetru C, Hoa NT, Hoffmann JA, Kanzok SM, Letunic I, Levashina EA, Loukeris TG, Lycett G, Meister S, Michel K, Moita LF, Müller HM, Osta MA, Paskewitz SM, Reichhart JM, Rzhetsky A, Troxler L, Vernick KD, Vlachou D, Volz J, von Mering C, Xu J, Zheng L, Bork P, and Kafatos FC. Immunity-related genes and gene families in Anopheles gambiae. Science. 2002 Oct 4;298(5591):159-65. DOI:10.1126/science.1077136 | Zdobnov EM, von Mering C, Letunic I, Torrents D, Suyama M, Copley RR, Christophides GK, Thomasova D, Holt RA, Subramanian GM, Mueller HM, Dimopoulos G, Law JH, Wells MA, Birney E, Charlab R, Halpern AL, Kokoza E, Kraft CL, Lai Z, Lewis S, Louis C, Barillas-Mury C, Nusskern D, Rubin GM, Salzberg SL, Sutton GG, Topalis P, Wides R, Wincker P, Yandell M, Collins FH, Ribeiro J, Gelbart WM, Kafatos FC, and Bork P. Comparative genome and proteome analysis of Anopheles gambiae and Drosophila melanogaster. Science. 2002 Oct 4;298(5591):149-59. DOI:10.1126/science.1077061 | Holt RA, Subramanian GM, Halpern A, Sutton GG, Charlab R, Nusskern DR, Wincker P, Clark AG, Ribeiro JM, Wides R, Salzberg SL, Loftus B, Yandell M, Majoros WH, Rusch DB, Lai Z, Kraft CL, Abril JF, Anthouard V, Arensburger P, Atkinson PW, Baden H, de Berardinis V, Baldwin D, Benes V, Biedler J, Blass C, Bolanos R, Boscus D, Barnstead M, Cai S, Center A, Chaturverdi K, Christophides GK, Chrystal MA, Clamp M, Cravchik A, Curwen V, Dana A, Delcher A, Dew I, Evans CA, Flanigan M, Grundschober-Freimoser A, Friedli L, Gu Z, Guan P, Guigo R, Hillenmeyer ME, Hladun SL, Hogan JR, Hong YS, Hoover J, Jaillon O, Ke Z, Kodira C, Kokoza E, Koutsos A, Letunic I, Levitsky A, Liang Y, Lin JJ, Lobo NF, Lopez JR, Malek JA, McIntosh TC, Meister S, Miller J, Mobarry C, Mongin E, Murphy SD, O'Brochta DA, Pfannkoch C, Qi R, Regier MA, Remington K, Shao H, Sharakhova MV, Sitter CD, Shetty J, Smith TJ, Strong R, Sun J, Thomasova D, Ton LQ, Topalis P, Tu Z, Unger MF, Walenz B, Wang A, Wang J, Wang M, Wang X, Woodford KJ, Wortman JR, Wu M, Yao A, Zdobnov EM, Zhang H, Zhao Q, Zhao S, Zhu SC, Zhimulev I, Coluzzi M, della Torre A, Roth CW, Louis C, Kalush F, Mural RJ, Myers EW, Adams MD, Smith HO, Broder S, Gardner MJ, Fraser CM, Birney E, Bork P, Brey PT, Venter JC, Weissenbach J, Kafatos FC, Collins FH, and Hoffman SL. The genome sequence of the malaria mosquito Anopheles gambiae. Science. 2002 Oct 4;298(5591):129-49. DOI:10.1126/science.1076181 | Dimopoulos G, Christophides GK, Meister S, Schultz J, White KP, Barillas-Mury C, and Kafatos FC. Genome expression analysis of Anopheles gambiae: responses to injury, bacterial challenge, and malaria infection. Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8814-9. DOI:10.1073/pnas.092274999 | Christophides GK, Savakis C, Mintzas AC, and Komitopoulou K. Expression and function of the Drosophila melanogaster ADH in male Ceratitis capitata adults: a potential strategy for medfly genetic sexing based on gene-transfer technology. Insect Mol Biol. 2001 Jun;10(3):249-54. DOI:10.1046/j.1365-2583.2001.00265.x | Christophides GK, Livadaras I, Savakis C, and Komitopoulou K. Two medfly promoters that have originated by recent gene duplication drive distinct sex, tissue and temporal expression patterns. Genetics. 2000 Sep;156(1):173-82. DOI:10.1093/genetics/156.1.173 | Christophides GK, Mintzas AC, and Komitopoulou K. Organization, evolution and expression of a multigene family encoding putative members of the odourant binding protein family in the medfly Ceratitis capitata. Insect Mol Biol. 2000 Apr;9(2):185-95. DOI:10.1046/j.1365-2583.2000.00176.x | Lygerou Z, Christophides G, and Séraphin B. A novel genetic screen for snRNP assembly factors in yeast identifies a conserved protein, Sad1p, also required for pre-mRNA splicing. Mol Cell Biol. 1999 Mar;19(3):2008-20. DOI:10.1128/MCB.19.3.2008 |