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 immunomodulatory 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. We have also contributed review articles on the subject. In the current fiscal year, members of the Section of Vector Biology contributed to a total of 13 papers as detailed below: 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 two papers related to sialotranscriptome and proteome discovery and evolution of hematophagous arthropods, including the annotation of the sialome of 18 species of anopheline mosquitoes (1) and the first disclosure of the sialotranscriptome of the tick Hyalomma excavatum (2). Functional studies: We advanced our knowledge regarding the function of vector salivary proteins as reported in two publications, describing the structure and function of a sodium ion channel blocker from a flea (3) and the structure and function of a constitutive D7 mosquito protein (4). Bioinformatic collaborations: Dr. Ribeiro collaborated with extra mural investigators lending his expertise in bioinformatics in seven publications related to vectors of human disease or nematode parasites. With a group from the Czech Republic, we investigated the midgut sialome of tick vectors of Lyme disease as they feed on heme rich or heme poor media, thus detecting their responses to defend from the heme rich diet (5). With a Brazilian group from the Fiocruz, Rio de Janeiro, we annotated several families of transposable elements identified from RNAseq data from the malaria vector, Anopheles funestus (6). With another Brazilian group we participated in three publications related to the discovery of tick salivary antigens to protect cattle from the tick Rhipicephalus microplus (7-9). These papers were crucial for a patent that was awarded last fiscal year. We continued our collaboration with Dr. Thomas Nutman from LPD, collaborating in two publications related to the transcriptome analysis of Onchocerca volvulus, and in the genome annotation of the same organism (10-11). Review articles.: During this fiscal year, two publications reviewed the opportunities generated by the genome sequencing of the Lyme disease vector, Ixodes scapularis (12) and the kratagonistic mode of action of salivary compounds of hematophagous arthropods (13).

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2017
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Assumpção, Teresa C; Mizurini, Daniella M; Ma, Dongying et al. (2018) Ixonnexin from Tick Saliva Promotes Fibrinolysis by Interacting with Plasminogen and Tissue-Type Plasminogen Activator, and Prevents Arterial Thrombosis. Sci Rep 8:4806
Martin-Martin, Ines; Chagas, Andrezza Campos; Guimaraes-Costa, Anderson B et al. (2018) Immunity to LuloHya and Lundep, the salivary spreading factors from Lutzomyia longipalpis, protects against Leishmania major infection. PLoS Pathog 14:e1007006
Ribeiro, Jose M; Garriga, Meera; Potchen, Nicole et al. (2018) Guide RNA selection for CRISPR-Cas9 transfections in Plasmodium falciparum. Int J Parasitol 48:825-832
Bansal, Abhisheka; Molina-Cruz, Alvaro; Brzostowski, Joseph et al. (2018) PfCDPK1 is critical for malaria parasite gametogenesis and mosquito infection. Proc Natl Acad Sci U S A 115:774-779
Nevoa, Jessica C; Mendes, Maria T; da Silva, Marcos V et al. (2018) An insight into the salivary gland and fat body transcriptome of Panstrongylus lignarius (Hemiptera: Heteroptera), the main vector of Chagas disease in Peru. PLoS Negl Trop Dis 12:e0006243
Schuchman, Ryan; Kilianski, Andy; Piper, Amanda et al. (2018) Comparative Characterization of the Sindbis Virus Proteome from Mammalian and Invertebrate Hosts Identifies nsP2 as a Component of the Virion and Sorting Nexin 5 as a Significant Host Factor for Alphavirus Replication. J Virol 92:
Perner, Jan; Kropá?ková, Sára; Kopá?ek, Petr et al. (2018) Sialome diversity of ticks revealed by RNAseq of single tick salivary glands. PLoS Negl Trop Dis 12:e0006410
Ribeiro, José M C; Martin-Martin, Ines; Moreira, Fernando R et al. (2018) A deep insight into the male and female sialotranscriptome of adult Culex tarsalis mosquitoes. Insect Biochem Mol Biol 95:1-9
Mendes-Sousa, Antonio F; do Vale, Vladimir Fazito; Silva, Naylene C S et al. (2017) The Sand Fly Salivary Protein Lufaxin Inhibits the Early Steps of the Alternative Pathway of Complement by Direct Binding to the Proconvertase C3b-B. Front Immunol 8:1065
Anderson, Jennifer M; Moore, Ian N; Nagata, Bianca M et al. (2017) Ticks, Ixodes scapularis, Feed Repeatedly on White-Footed Mice despite Strong Inflammatory Response: An Expanding Paradigm for Understanding Tick-Host Interactions. Front Immunol 8:1784

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