Interferons are considered a first line of immune defense restricted to vertebrates. In this issue of Cell Host & Microbe, Smith et al. (2016) demonstrate that mammalian interferon γ activates an antimicrobial response within ticks feeding on blood. The study suggests that arthropods have a parallel interferon-like defense system

De Silva, A.M.

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Ticks Take Cues from Mammalian InterferonAravinda M. de Silva1,*1Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA*Correspondence: desilva@med.unc.eduhttp://dx.doi.org/10.1016/j.chom.2016.06.016Interferons are considered a first line of immune defense restricted to vertebrates. In this issue of Cell Host & Microbe, Smith et al. (2016) demonstrate that mammalian interferon g activates an antimicrobial response within ticks feeding on blood. The study suggests that arthropods have a parallel interferon-like defense system.Blood-feeding arthropods such as ticks,mites, fleas, and mosquitoes transmitmany different microbes to vertebrates,including humans. Unlike direct animal-to-animal transmission of pathogens,vector-borne transmission is complexand fascinating because three organisms(arthropod vector, vertebrate host, andmicrobial pathogen) interact in ways topromote or counter each other. In thecase of Lyme disease, blacklegged ticksacquire the infection when larval ornymphal ticks feed on a mouse that is in-fected with Borrelia burgdorferi, the spiro-chete responsible for Lyme disease. Onceinfected, ticks can transmit the infectionto another mouse or person during a sub-sequent blood meal.Many groups have studied the complexinteractions between vector, host, and theLyme disease spirochete during transmis-sion from an infected tick to amouse (Cai-mano et al., 2016). Ticks require severaldays of continuous blood feeding to com-plete a blood meal. To promote success-ful blood feeding, tick salivary glandscontain a veritable pharmacy of differentmolecules that modulate vertebrate bloodphysiology and immunity (Francischettiet al., 2009). Microbes transmitted byticks are bystander beneficiaries of theseactivities, and many studies have demon-strated how pathogens directly and indi-rectly benefit from the salivary proteinsof their arthropod vectors (de Silva et al.,2009). Lyme disease spirochetes alsodirectly coat their surfaces with vectorsalivary molecules to evade host immu-nity and establish infection in themamma-lian host (Narasimhan et al., 2007; Rama-moorthi et al., 2005). While we know quitea bit about spirochete transmission fromtick to host, the process by which unin-fected ticks acquire the infection from in-fected mice has been less well-studied.In this issue of Cell Host and Microbe,Smith and colleagues describe an antimi-crobial defense pathway in ticks that isactivated by mouse interferon g acquiredin a blood meal. When blacklegged ticksfedonmice infectedwith the Lymediseasespirochete, interferon g in the bloodmealactivatedan ‘‘interferon-like’’ defensemechanism in the tick and controlled thespirochete infection within the tick. Thebroad implications of the study are that(1) arthropods have a parallel ‘‘interferon’’system and (2) antimicrobial effects ofvertebrate interferon can extend to arthro-pods during blood feeding.To examine how ticks acquire Lymedisease spirochetes when feeding on in-fected mice, Smith and colleagues al-lowed ticks to feed on mice that werenaive or infected with B. burgdorferi andcompared the expression 270 tick geneswith potential roles in immune pathways.They identified a Rho GTPase (IGTPase)that was selectively induced in ticks thatfed on infected mice compared to unin-fected mice. Knockdown studies estab-lished that the IGTPase controlled theburden of spirochetes within the feedingtick. The investigators also made the un-expected and intriguing observation thatthe tick IGTPase was induced by mouseinterferon g in the blood meal and notthe actual bacteria entering the tick gut.In other words, ticks appear to be testingthe ‘‘purity’’ of their bloodmeal by sensingvertebrate cytokines present in the blood.The fundamental components of thevertebrate interferon system are a familytranscription factors designated as inter-feron regulatory factors (IRFs), whichinduce the expression of interferons.Secreted interferons bind to cell-surfaceinterferon receptors, which are linked viaJanus kinase (JAK)-signaling transduceractivator of transcription (STAT) signalingpathways to downstream transcriptionfactors to increase the expression ofmany interferon-stimulated genes (ISGs)with specific antiviral and other effectorfunctions. While the interferon systemhas long been considered a vertebrate-specific immune pathway, recent studiessuggest a parallel system exists in someinvertebrates as well. Li and colleaguesrecently described an antiviral system inshrimps with remarkable similarities tothe vertebrate interferon system. This anti-viral pathway in shrimps has an IRF-liketranscription factor, a secreted interferon-like cytokine that activates a JAK/STATsignaling pathway, which induced theexpression of proteins and an antiviralstate in shrimps (Li et al., 2015). Moreover,the shrimp IRFwas capable of recognizingmammalian ISG elements and inducingthe expressing of mammalian ISGs.In this most recent work, Smith and col-leagues go on to demonstrate that mouseinterferon g activated the tick IGTPasein a STAT-dependent manner, providingfurther evidence for an interferon-likesystem in ticks. Activation of the pathwayin ticks led to the secretion of an antimi-crobial protein designated Dae2 (Domes-ticated amidase effector2) that sup-pressed the replication of Lyme diseasespirochetes within the tick. It is worthnoting that shrimps, ticks, and insectsare all arthropods, and these studiesmay be the beginning of the uncoveringof a parallel interferon system in this classof organisms that include blood-feedingarthropods.Another interesting twist to this study isthe fact that Dae2 is an antimicrobial pep-tide that ticks have acquired from pro-karyotes (Dunning Hotopp and Estes,2014). Chou et al. recently describedmany examples of horizontal gene trans-fer of antimicrobial peptides betweenbacteria and eukaryotes (Chou et al.,2015). The emerging theme from thesestudies is that eukaryotes, including ticks,have been able to augment their innateimmune defenses by acquiring prokary-otic antimicrobial genes and incorpo-rating them into existing defense path-ways. Thus, arthropods appear to haveinterferon-like systems that have beenaugmented by horizontal gene transferfrom prokaryotes and that can cross-communicate with vertebrate interferons.The next step is to determine if theseexamples from ticks and shrimps areinteresting outliers or representative of awidespread parallel interferon system inarthropods. It is conceivable that the sys-tem may be nonfunctional in some spe-cies and well-developed in others, espe-cially arthropods that rely on vertebrateblood as their main food source. In verte-brates, the primary role of the interferonresponse is to defend against viruses,and similarly the system may also haveevolved in arthropods primarily as an anti-viral defense mechanism. We need toexplore if arboviruses such as dengue,Zika, tick-borne encephalitis, and chikun-gunya are also regulated by cross-talkbetween interferon systems in theirarthropod vectors and vertebrate hosts.REFERENCESCaimano, M.J., Drecktrah, D., Kung, F., and Sam-uels, D.S. (2016). Cell. Microbiol. 18, 919–927.Chou, S., Daugherty, M.D., Peterson, S.B., Biboy,J., Yang, Y., Jutras, B.L., Fritz-Laylin, L.K., Ferrin,M.A., Harding, B.N., Jacobs-Wagner, C., et al.(2015). Nature 518, 98–101.de Silva, A.M., Tyson, K.R., and Pal, U. (2009).Front. Biosci. (Landmark Ed.) 14, 3051–3063.Dunning Hotopp, J.C., and Estes, A.M. (2014). CellHost Microbe 16, 701–703.Francischetti, I.M., Sa-Nunes, A., Mans, B.J., San-tos, I.M., and Ribeiro, J.M. (2009). Front. Biosci.(Landmark Ed.) 14, 2051–2088.Li, C., Li, H., Chen, Y., Chen, Y., Wang, S., Weng,S.P., Xu, X., and He, J. (2015). Sci. Rep. 5, 15078.Narasimhan, S., Sukumaran, B., Bozdogan, U.,Thomas, V., Liang, X., DePonte, K., Marcantonio,N., Koski, R.A., Anderson, J.F., Kantor, F., and Fik-rig, E. (2007). Cell Host Microbe 2, 7–18.Ramamoorthi, N., Narasimhan, S., Pal, U., Bao, F.,Yang, X.F., Fish, D., Anguita, J., Norgard, M.V.,Kantor, F.S., Anderson, J.F., et al. (2005). Nature436, 573–577.Smith, A.A., Navasa, N., Yang, X., Wilder, C.N.,Buyuktanir, O., Marques, A., Anguita, J., and Pal,U. (2016). Cell Host Microbe 20, this issue, 91–98.

Ticks Take Cues from Mammalian Interferon

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Ticks Take Cues from Mammalian Interferon

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