Vector arthropods, such as mosquitoes, triatomine bugs and ticks, salivate while they puncture our skin in their search of blood. This saliva contains dozens to hundreds of compounds that have anti-clotting, anti-platelet, vasodilatory, anti-inflammatory, and immunomodullatory functions. While helping the vector to feed, it also modifies the site where pathogens are injected and in many cases facilitates the infection process. For this reason, salivary proteins of vectors can be used as vaccine targets for the diseases they transmit. Salivary proteins can also be used as immuno-epidemiological markers of vector exposure, and in themselves can have potent and novel pharmacological activities. Because the saliva of hematophagous animals is under attack of their host's immune system, their constituents are under a rapid evolutionary pressure in an arms' race scenario with their hosts, causing an enormous variety of unique protein families even in closely related organisms. The section of vector biology aims at uncovering the biodiversity of salivary proteins in the near 500 genera of blood sucking arthropods, and to discover the function of the novel protein families that we encounter. Accordingly we have developed a two pronged approach focusing in sialotranscriptome discovery projects and functional sialomic studies. In addition to these core studies on the saliva of vector arthropods, the section also collaborated with other members of the LMVR and other extramural scientists lending its expertise in bioinformatics, structural biology and vascular biology. In the current fiscal year, members of the Section of Vector Biology contributed to a total of 21 papers and were awarded three previously applied patent applications. Sialotranscriptome discovery and evolution projects: Because host hemostasis (the physiological process that prevents blood loss, consisting of platelet aggregation, blood clotting and vasoconstriction) is a complex and redundant phenomenon, the salivary glands of blood sucking arthropods consist of a magic potion with diverse chemicals that in a redundant way counteract host mechanisms to prevent blood loss, allowing the fast acquisition of a meal. Salivary transcriptome made in the past few years indicate that the magic potion consists of 70-100 different proteins in the case of mosquitoes, for example, to over 1,000 in the case of ticks (Ticks feed for several days and have to disarm host immune reactions, in addition to the hemostatic system). Transcriptome studies also show that the salivary proteins of blood sucking arthropods are at a very fast pace of evolution, perhaps explaining why every genera studied so far has several unique protein families. Indeed there are unique proteins found at the subgenus level. Given we can now describe in detail the sialotranscriptome (from the Greek word sialo = saliva) of a single organism, we can ask now what is the universe of salivary proteins associated to blood feeding, the so called sialoverse. There are near 19,000 species of blood sucking arthropods in 500 different genera. If we find (minimally) 5 novel protein families per genus (within the 70-500 proteins in each sialome), there are at least 2,500 novel proteins to be discovered, each one with an interesting pharmacological property. We have so far explored less than 20 genera of blood sucking arthropods, and it is our goal to extend sialotranscriptome discovery to map this pharmacological mine for future studies, and in the process learn the paths taken by genomes in their evolution to blood feeding, and identify proteins with pharmacological and vaccine potential. In the current fiscal year, we produced seven papers related to sialotranscriptome and proteome discovery and evolution of hematophagous arthropods, including the Chagas disease vectors Rhodnius neglectus (1) and Panstrongylus megistus (2), the male and female sialomes of Aedes aegypti (3), the horse fly Tabanus bromius (4), the sand fly Bichromomyia olmeca (5), the tick Amblyomma americanum (6) and the tissue and time-dependent transcription in the European Lyme disease vector, Ixodes ricinus (7). Functional studies: We advanced our knowledge regarding the function of vector salivary proteins as reported in seven publications, describing the mode of action of two tick salivary anti-clotting peptides (8-9), characterizing a novel mosquito anti-complement protein (10-11), identifying salivary nucleosides from sand flies as immunosuppressants and promoting pathogen transmission (12), and determining the structures of a salivary cysteinyl-leukotriene binding protein (13) and a hookworm platelet aggregation inhibitor (14). Bioinformatic collaborations: Dr. Ribeiro collaborated with extra mural investigators lending his expertise in bioinformatics in several genomic publications related to medical entomology, where he helped the annotation of salivary-coding genes as well as transposable elements. This included publications related to the genomes of the North American vector of Lyme disease, Ixodes scapularis (15), the mosquito Aedes albopictus (16), the bed bug Cimex lectularius (17), the 16 Anopheles genome project (18), and the Chagas disease vector, Rhodnius prolixus (19). Dr. Ribeiro also collaborated in the assembly and annotation of the Ixodes ricinus tick hemocytome (proteins produced by hemocytes) (20) and the discovery and annotation of transposable elements in Rhodnius prolixus (21). Patents issued: During this fiscal year, members of Dr. Ribeiro laboratory were awarded three patents from the US and European Patent Offices as follows: 1. Fischer, L.B., Valenzuela, J.G. and Ribeiro, J. (Date of filing: 05/06/2009) Leishmania vaccine using sand fly salivary immunogen. European Patent Office patent number EP 2 899 203 A3, published on 07/29/2015, Bulletin 2015/31 and on 08/05/2015, bulletin 2015/32. 2. Valenzuela, J.G., Ribeiro, J.M.C., Barral, A., Barral-Netto, M., Brodskyn, C.I., and Gomes, R. (Date of filing: 12/05/2013). Lutzomyia longipalpis polypeptides and methods of use. US Department of Commerce, Patent and Trademark Office. Patent number 9,120,867 issued on Sep 1, 2015. 3. Santos, I.K.F.M, Ribeiro, J.M.C., Ferreira, B.R., Verssimo, C.J., Brando, L.G., Maruyama, S.R.C., Anatriello, E., Garcia, G.R., Mor, D.D. and Valenzuela, J.G. (Date of filing in Brazil: 11/28/2013) Method for selecting tick antigens and antigenic compositions against ticks. Brazilian patent BR20131030662 registered with the European Patent Office WO2014BR00351 published on 06/04/2015.

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Kim, Il Hwan; Pham, Van; Jablonka, Willy et al. (2017) A mosquito hemolymph odorant-binding protein family member specifically binds juvenile hormone. J Biol Chem :
Franzin, Alessandra Mara; Maruyama, Sandra Regina; Garcia, Gustavo Rocha et al. (2017) Immune and biochemical responses in skin differ between bovine hosts genetically susceptible and resistant to the cattle tick Rhipicephalus microplus. Parasit Vectors 10:51
Garcia, Gustavo Rocha; Maruyama, Sandra Regina; Nelson, Kristina T et al. (2017) Immune recognition of salivary proteins from the cattle tick Rhipicephalus microplus differs according to the genotype of the bovine host. Parasit Vectors 10:144
Arcà, Bruno; Lombardo, Fabrizio; Struchiner, Claudio J et al. (2017) Anopheline salivary protein genes and gene families: an evolutionary overview after the whole genome sequence of sixteen Anopheles species. BMC Genomics 18:153
Ribeiro, José M C; Slovák, Mirko; Francischetti, Ivo M B (2017) An insight into the sialome of Hyalomma excavatum. Ticks Tick Borne Dis 8:201-207
Fernández-Medina, Rita D; Carareto, Claudia M A; Struchiner, Cláudio J et al. (2017) Transposable elements in the Anopheles funestus transcriptome. Genetica 145:275-293
Maruyama, Sandra R; Garcia, Gustavo R; Teixeira, Felipe R et al. (2017) Mining a differential sialotranscriptome of Rhipicephalus microplus guides antigen discovery to formulate a vaccine that reduces tick infestations. Parasit Vectors 10:206
Abdeladhim, Maha; V Coutinho-Abreu, Iliano; Townsend, Shannon et al. (2016) Molecular Diversity between Salivary Proteins from New World and Old World Sand Flies with Emphasis on Bichromomyia olmeca, the Sand Fly Vector of Leishmania mexicana in Mesoamerica. PLoS Negl Trop Dis 10:e0004771
Ferreira, Viviana P; Fazito Vale, Vladimir; Pangburn, Michael K et al. (2016) SALO, a novel classical pathway complement inhibitor from saliva of the sand fly Lutzomyia longipalpis. Sci Rep 6:19300
Assumpção, Teresa C; Ma, Dongying; Mizurini, Daniella M et al. (2016) In Vitro Mode of Action and Anti-thrombotic Activity of Boophilin, a Multifunctional Kunitz Protease Inhibitor from the Midgut of a Tick Vector of Babesiosis, Rhipicephalus microplus. PLoS Negl Trop Dis 10:e0004298

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