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Tick saliva is a complex mixture of bioactive proteins, lipids and immunomodulators, such as <jats:italic>I.\u00a0scapularis<\/jats:italic> sphingomyelinase (<jats:italic>Is<\/jats:italic>SMase)<jats:italic>\u2010<\/jats:italic>like protein, an ortholog of dermonecrotoxin SMase D found in the venom of <jats:italic>Loxosceles<\/jats:italic> spp. of spiders. <jats:italic>Is<\/jats:italic>SMase modulates the host immune response towards Th2, which suppresses Th1\u2010mediated cytokines to facilitate pathogen transmission. Arboviruses utilize exosomes for their transmission from tick to the vertebrate host, and exosomes derived from tick saliva\/salivary glands suppress C\u2010X\u2010C motif chemokine ligand 12 and interleukin\u20108 immune response(s) in human skin to delay wound healing and repair processes. <jats:italic>Is<\/jats:italic>SMase affects also viral replication and exosome biogenesis, thereby inhibiting tick\u2010to\u2010vertebrate host transmission of pathogenic exosomes. 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