Potential mechanisms implied in tick infection by arboviruses and their transmission to vertebrate hosts

Abstract

Ticks can transmit many pathogens, including arboviruses, to their vertebrate hosts. Arboviruses must overcome or evade defense mechanisms during their passage from the tick gut to the hemolymph, salivary glands, and the feeding site in the host skin. This review summarizes current knowledge of defense mechanisms in specific tick tissues and at the feeding site in the host skin. We discuss the possible roles of these defense mechanisms in viral infection and transmission. The responses of tick salivary proteins to arbovirus infection are also discussed. This review provides information that may help accelerate research on virus–tick interactions.

Keywords

antiviral immunity / arbovirus / RNAi / tick / vector

References

[1] Abraham NM, Liu L, Jutras BL et al. (2017). Pathogen-mediated manipulation of arthropod microbiota to promote infection. PNAS 114, E781-E790.

[2] Ali A, Parizi LF, Guizzo MG et al. (2015). Immunoprotective potential of a Rhipicephalus (Boophilus) microplus metalloprotease. Veterinary Parasitology 207, 107-114.

[3] Al-Khafaji AM, Armstrong SD, Varotto Boccazzi I et al. (2020). Rickettsia buchneri, symbiont of the deer tick Ixodes scapularis, can colonise the salivary glands of its host. Ticks and Tick-borne Diseases 11, 101299.

[4] Ant TH, Mancini MV, Mcnamara CJ, Rainey SM, Sinkins SP (2023). Wolbachia-Virus interactions and arbovirus control through population replacement in mosquitoes. Pathogens and Global Health 117, 245-258.

[5] Aounallah H, Bensaoud C, M'ghirbi Y, Faria F, Chmelar JI, Kotsyfakis M (2020). Tick salivary compounds for targeted immunomodulatory therapy. Frontiers in Immunology 11, 583845.

[6] Bath PM, Coleman CM, Gordon AL, Lim WS, Webb AJ (2021). Nitric oxide for the prevention and treatment of viral, bacterial, protozoal and fungal infections. F1000Research 10, 536.

[7] Beaute J, Spiteri G, Warns-Petit E, Zeller H (2018). Tick-borne encephalitis in Europe, 2012 to 2016. Eurosurveillance 23, 1800201.

[8] Bereczky S, Lindegren G, Karlberg H, Akerstrom S, Klingstrom J, Mirazimi A (2010). Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice. Journal of General Virology 91, 1473-1477.

[9] Bergman DK, Palmer MJ, Caimano MJ, Radolf JD, Wikel SK (2000). Isolation and molecular cloning of a secreted immunosuppressant protein from Dermacentor andersoni salivary gland. Journal of Parasitology 86, 516-525.

[10] Booth TF, Davies CR, Jones LD, Staunton D, Nuttall PA (1989). Anatomical basis of Thogoto virus infection in BHK cell culture and in the ixodid tick vector, Rhipicephalus appendiculatus. Journal of General Virology 70, 1093-1104.

[11] Borovickova B, Hypsa V (2005). Ontogeny of tick hemocytes: A comparative analysis of Ixodes ricinus and Ornithodoros moubata. Experimental & Applied Acarology 35, 317-333.

[12] Bouchard C, Dibernardo A, Koffi J, Wood H, Leighton PA, Lindsay LR (2019). N Increased risk of tick-borne diseases with climate and environmental changes. Canada Communicable Disease Report 45, 83-89.

[13] Bouwknegt C, Van Rijn PA, Schipper JJ et al. (2010). Potential role of ticks as vectors of bluetongue virus. Experimental & Applied Acarology 52, 183-192.

[14] Budachetri K, Browning RE, Adamson SW et al. (2014). An insight into the microbiome of the Amblyomma maculatum (Acari: Ixodidae). Journal of Medical Entomology 51, 119-129.

[15] Buresova V, Hajdusek O, Franta Z et al. (2011). Functional genomics of tick thioester-containing proteins reveal the ancient origin of the complement system. Journal of Innate Immunity 3, 623-630.

[16] Capelli-Peixoto J, Carvalho DD, Johnson WC et al. (2017). The transcription factor Relish controls Anaplasma marginale infection in the bovine tick Rhipicephalus microplus. Developmental and Comparative Immunology 74, 32-39.

[17] Carissimo G, Pondeville E, Mcfarlane M et al. (2015). Antiviral immunity of Anopheles gambiae is highly compartmentalized, with distinct roles for RNA interference and gut microbiota. PNAS 112, E176-185.

[18] Casel MA, Park SJ, Choi YK (2021). Severe fever with thrombocytopenia syndrome virus: Emerging novel phlebovirus and their control strategy. Experimental & Molecular Medicine 53, 713-722.

[19] Ceraul SM, Sonenshine DE, Hynes WL (2002). Resistance of the tick Dermacentor variabilis (Acari: Ixodidae) following challenge with the bacterium Escherichia coli (Enterobacteriales: Enterobacteriaceae). Journal of Medical Entomology 39, 376-383.

[20] Cerenius L, Lee BL, Soderhall K (2008). The proPO-system: Pros and cons for its role in invertebrate immunity. Trends in Immunology 29, 263-271.

[21] Cubillos C, Caceres JC, Villablanca C, Barriga A, Cabrera R, Veloso C (2021). Comparative characterization of the hemocyanin-derived phenol oxidase activity from spiders inhabiting different thermal habitats. Comparative Biochemistry and Physiology. Part B, Biochemistry & Molecular Biology 253, 110548.

[22] Culbertson EM, Culotta VC (2021). Copper in infectious disease: Using both sides of the penny. Seminars in Cell & Developmental Biology 115, 19-26.

[23] da Silva SB, Savastano G, Bittencourt VR (2006). Cellular types involved in the immune response of females engorged of Boophilus microplus inoculated with Metarhizium anisopliae and Penicillium sp. Revista Brasileira de Parasitologia Veterinária 15, 128-131.

[24] Dai J, Narasimhan S, Zhang L, Liu L, Wang P, Fikrig E (2010). Tick histamine release factor is critical for Ixodes scapularis engorgement and transmission of the lyme disease agent. PLoS Pathogens 6, e1001205.

[25] Dai S, Deng F, Wang H, Ning Y (2021). Crimean-congo hemorrhagic fever virus: Current advances and future prospects of antiviral strategies. Viruses 13, 1195.

[26] Daix V, Schroeder H, Praet N et al. (2007). Ixodes ticks belonging to the Ixodes ricinus complex encode a family of anticomplement proteins. Insect Molecular Biology 16, 155-166.

[27] Darnell JE , Kerr IM, Stark GR (1994). Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264, 1415-1421.

[28] Dong F, Li D, Wen D et al. (2019). Single dose of a rVSV-based vaccine elicits complete protection against severe fever with thrombocytopenia syndrome virus. NPJ Vaccines 4, 5.

[29] Dunkelberger JR, Song WC (2010). Complement and its role in innate and adaptive immune responses. Cell Research 20, 34-50.

[30] Erlandson MA, Toprak U, Hegedus DD (2019). Role of the peritrophic matrix in insect-pathogen interactions. Journal of Insect Physiology 117, 103894.

[31] Feitosa AP, Alves LC, Chaves MM et al. (2015). Hemocytes of Rhipicephalus sanguineus (Acari: Ixodidae): Characterization, population abundance, and ultrastructural changes following challenge with Leishmania infantum. Journal of Medical Entomology 52, 1193-1202.

[32] Feitosa APS, Chaves MM, Veras DL et al. (2018). Assessing the cellular and humoral immune response in Rhipicephalus sanguineus sensu lato (Acari: Ixodidae) infected with Leishmania infantum (Nicolle, 1908). Ticks and Tick-borne Diseases 9, 1421-1430.

[33] Ferreira AG, Naylor H, Esteves SS, Pais IS, Martins NE, Teixeira L (2014). The Toll-dorsal pathway is required for resistance to viral oral infection in Drosophila. PLoS Pathogens 10, e1004507.

[34] Fialova A, Cimburek Z, Iezzi G, Kopecky J (2010). Ixodes ricinus tick saliva modulates tick-borne encephalitis virus infection of dendritic cells. Microbes and Infection 12, 580-585.

[35] Fiorotti J, Urbanova V, Golo PS, Bittencourt V, Kopacek P (2022). The role of complement in the tick cellular immune defense against the entomopathogenic fungus Metarhizium robertsii. Developmental and Comparative Immunology 126, 104234.

[36] Francischetti IM, Mather TN, Ribeiro JM (2003). Cloning of a salivary gland metalloprotease and characterization of gelatinase and fibrin(ogen)lytic activities in the saliva of the Lyme disease tick vector Ixodes scapularis. Biochemical and Biophysical Research Communications 305, 869-875.

[37] Gall CA, Reif KE, Scoles GA et al. (2016). The bacterial microbiome of Dermacentor andersoni ticks influences pathogen susceptibility. The ISME Journal 10, 1846-1855.

[38] Gonzalez JP, Cornet JP, Wilson ML, Camicas JL (1991). Crimean-Congo haemorrhagic fever virus replication in adult Hyalomma truncatum and Amblyomma variegatum ticks. Research in Virology 142, 483-488.

[39] Grubaugh ND, Ruckert C, Armstrong PM et al. (2016). Transmission bottlenecks and RNAi collectively influence tick-borne flavivirus evolution. Virus Evolution 2, vew033.

[40] Gulia-Nuss M, Nuss AB, Meyer JM et al. (2016). Genomic insights into the Ixodes scapularis tick vector of Lyme disease. Nature Communications 7, 10507.

[41] Hannier S, Liversidge J, Sternberg JM, Bowman AS (2004). Characterization of the B-cell inhibitory protein factor in Ixodes ricinus tick saliva: A potential role in enhanced Borrelia burgdoferi transmission. Immunology 113, 401-408.

[42] Hart CE, Ribeiro JM, Kazimirova M, Thangamani S (2020). Tick-borne encephalitis virus infection alters the sialome of Ixodes ricinus ticks during the earliest stages of feeding. Frontiers in Cellular and Infection Microbiology 10, 41.

[43] Hart CE, Thangamani S (2021). Tick-virus interactions: Current understanding and future perspectives. Parasite Immunology 43, e12815.

[44] Hermance ME, Santos RI, Kelly BC, Valbuena G, Thangamani S (2016). Immune cell targets of infection at the tick-skin interface during Powassan virus transmission. PLoS ONE 11, e0155889.

[45] Hermance ME, Thangamani S (2014). Proinflammatory cytokines and chemokines at the skin interface during Powassan virus transmission. Journal of Investigative Dermatology 134, 2280-2283.

[46] Hermance ME, Thangamani S (2015). Tick saliva enhances powassan virus transmission to the host, influencing its dissemination and the course of disease. Journal of Virology 89, 7852-7860.

[47] Hoffmann HH, Schneider WM, Rice CM (2015). Interferons and viruses: An evolutionary arms race of molecular interactions. Trends in Immunology 36, 124-138.

[48] Honig Mondekova H, Sima R, Urbanova V et al. (2017). Characterization of Ixodes ricinus fibrinogen-related proteins (Ixoderins) discloses their function in the tick innate immunity. Frontiers in Cellular and Infection Microbiology 7, 509.

[49] Hourcade DE, Akk AM, Mitchell LM, Zhou HF, Hauhart R, Pham CT (2016). Anti-complement activity of the Ixodes scapularis salivary protein Salp20. Molecular Immunology 69, 62-69.

[50] Hu YY, Zhuang L, Liu K et al. (2020). Role of three tick species in the maintenance and transmission of severe fever with thrombocytopenia syndrome Virus. PLoS Neglected Tropical Diseases 14, e0008368.

[51] Huang X, Li J, Li A, Wang S, Li D (2021). Epidemiological characteristics of severe fever with thrombocytopenia syndrome from 2010 to 2019 in Mainland China. International Journal of Environmental Research and Public Health 18, 3092.

[52] Jia N, Wang J, Shi W et al. (2020). Large-scale comparative analyses of tick genomes elucidate their genetic diversity and vector capacities. Cell 182, 1328-1340e13.

[53] Johns R, Ohnishi J, Broadwater A, Sonenshine DE, De Silva AM, Hynes WL (2001). Contrasts in tick innate immune responses to Borrelia burgdorferi challenge: Immunotolerance in Ixodes scapularis versus immunocompetence in Dermacentor variabilis (Acari: Ixodidae). Journal of Medical Entomology 38, 99-107.

[54] Johns R, Sonenshine DE, Hynes WL (2000). Response of the tick Dermacentor variabilis (Acari: Ixodidae) to hemocoelic inoculation of Borrelia burgdorferi (Spirochetales). Journal of Medical Entomology 37, 265-270.

[55] Johnson KN (2015). The impact of Wolbachia on virus infection in mosquitoes. Viruses 7, 5705-5717.

[56] Johnson N (2017). Tick-virus interactions: Toll sensing. Frontiers in Cellular and Infection Microbiology 7, 293.

[57] Jones LD, Davies CR, Steele GM, Nuttall PA (1987). A novel mode of arbovirus transmission involving a nonviremic host. Science 237, 775-777.

[58] Jones LD, Nuttall PA (1989). The effect of virus-immune hosts on Thogoto virus infection of the tick, Rhipicephalus appendiculatus. Virus Research 14, 129-139.

[59] Kadota K, Satoh E, Ochiai M et al. (2002). Existence of phenol oxidase in the argasid tick Ornithodoros moubata. Parasitology Research 88, 781-784.

[60] Kazimirova M, Stibraniova I (2013). Tick salivary compounds: Their role in modulation of host defences and pathogen transmission. Frontiers in Cellular and Infection Microbiology 3, 43.

[61] Kim KH, Kim J, Ko M et al. (2019). An anti-Gn glycoprotein antibody from a convalescent patient potently inhibits the infection of severe fever with thrombocytopenia syndrome virus. PLoS Pathogens 15, e1007375.

[62] Kim SG, Jung BW, Kim H (2011). Hemocyanin-derived phenoloxidase activity with broad temperature stability extending into the cold environment in hemocytes of the hair crab Erimacrus isenbeckii. Comparative Biochemistry and Physiology Part B: Biochemistry & Molecular Biology 159, 103-108.

[63] Kitsou C, Foor SD, Dutta S, Bista S, Pal U (2021). Tick gut barriers impacting tick-microbe interactions and pathogen persistence. Molecular Microbiology 116, 1241-1248.

[64] Klyachko O, Stein BD, Grindle N, Clay K, Fuqua C (2007). Localization and visualization of a coxiella-type symbiont within the lone star tick, Amblyomma americanum. Applied and Environmental Microbiology 73, 6584-6594.

[65] Konno K, Mitsuhashi W (2019). The peritrophic membrane as a target of proteins that play important roles in plant defense and microbial attack. Journal of Insect Physiology 117, 103912.

[66] Kopacek P, Hajdusek O, Buresova V (2012). Tick as a model for the study of a primitive complement system. Advances in Experimental Medicine and Biology 710, 83-93.

[67] Kotal J, Langhansova H, Lieskovska J et al. (2015). Modulation of host immunity by tick saliva. Journal of Proteomics 128, 58-68.

[68] Kotsyfakis M, Anderson JM, Andersen JF et al. (2008). Cutting edge: Immunity against a “silent” salivary antigen of the Lyme vector Ixodes scapularis impairs its ability to feed. Journal of Immunology 181, 5209-5212.

[69] Kubinski M, Beicht J, Gerlach T, Volz A, Sutter G, Rimmelzwaan GF (2020). Tick-borne encephalitis virus: A quest for better vaccines against a virus on the rise. Vaccines (Basel) 8, 451.

[70] Kuhn KH, Uhlir J, Grubhoffer L (1996). Ultrastructural localization of a sialic acid-specific hemolymph lectin in the hemocytes and other tissues of the hard tick Ixodes ricinus (Acari; Chelicerata). Parasitology Research 82, 215-221.

[71] Kumar S, Molina-Cruz A, Gupta L, Rodrigues J, Barillas-Mury C (2010). A peroxidase/dual oxidase system modulates midgut epithelial immunity in Anopheles gambiae. Science 327, 1644-1648.

[72] Kurokawa C, Lynn GE, Pedra JHF, Pal U, Narasimhan S, Fikrig E (2020). Interactions between Borrelia burgdorferi and ticks. Nature Reviews Microbiology 18, 587-600.

[73] Labuda M, Austyn JM, Zuffova E et al. (1996). Importance of localized skin infection in tick-borne encephalitis virus transmission. Virology 219, 357-366.

[74] Labuda M, Trimnell AR, Lickova M et al. (2006). An antivector vaccine protects against a lethal vector-borne pathogen. PLoS Pathogens 2, e27.

[75] Leboulle G, Crippa M, Decrem Y et al. (2002). Characterization of a novel salivary immunosuppressive protein from Ixodes ricinus ticks. Journal of Biological Chemistry 277, 10083-10089.

[76] Lepore LS, Roelvink PR, Granados RR (1996). Enhancin, the granulosis virus protein that facilitates nucleopolyhedrovirus (NPV) infections, is a metalloprotease. Journal of Invertebrate Pathology 68, 131-140.

[77] Lieskovska J, Kopecky J (2012). Tick saliva suppresses IFN signalling in dendritic cells upon Borrelia afzelii infection. Parasite Immunology 34, 32-39.

[78] Lieskovska J, Palenikova J, Langhansova H, Chmelar J, Kopecky J (2018). Saliva of Ixodes ricinus enhances TBE virus replication in dendritic cells by modulation of pro-survival Akt pathway. Virology 514, 98-105.

[79] Lin FC, Young HA (2014). Interferons: Success in anti-viral immunotherapy. Cytokine & Growth Factor Reviews 25, 369-376.

[80] Lin YL, Huang YL, Ma SH et al. (1997). Inhibition of Japanese encephalitis virus infection by nitric oxide: Antiviral effect of nitric oxide on RNA virus replication. Journal of Virology 71, 5227-5235.

[81] Liu L, Dai J, Zhao YO et al. (2012). Ixodes scapularis JAK-STAT pathway regulates tick antimicrobial peptides, thereby controlling the agent of human granulocytic anaplasmosis. Journal of Infectious Diseases 206, 1233-1241.

[82] Liu L, Narasimhan S, Dai J, Zhang L, Cheng G, Fikrig E (2011). Ixodes scapularis salivary gland protein P11 facilitates migration of Anaplasma phagocytophilum from the tick gut to salivary glands. EMBO Reports 12, 1196-1203.

[83] Loof TG, Morgelin M, Johansson L et al. (2011). Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense. Blood 118, 2589-2598.

[84] Ma E, Zhu Y, Liu Z, Wei T, Wang P, Cheng G (2021). Interaction of viruses with the insect intestine. Annual Review of Virology 8, 115-131.

[85] Maningas MB, Kondo H, Hirono I, Saito-Taki T, Aoki T (2008). Essential function of transglutaminase and clotting protein in shrimp immunity. Molecular Immunology 45, 1269-1275.

[86] Mansfield KL, Cook C, Ellis RJ et al. (2017). Tick-borne pathogens induce differential expression of genes promoting cell survival and host resistance in Ixodes ricinus cells. Parasites & Vectors 10, 81.

[87] Maqbool M, Sajid MS, Saqib M et al. (2022). Potential mechanisms of transmission of tick-borne viruses at the virus-tick interface. Frontiers in Microbiology 13, 846884.

[88] Masoud HMM, Helmy MS, Darwish DA, Abdel-Monsef MM, Ibrahim MA (2020). Apyrase with anti-platelet aggregation activity from the nymph of the camel tick Hyalomma dromedarii. Experimental & Applied Acarology 80, 349-361.

[89] Matsuno K, Orba Y, Maede-White K et al. (2017). Animal models of emerging tick-borne Phleboviruses: Determining target cells in a lethal model of SFTSV infection. Frontiers in Microbiology 8, 104.

[90] Mcclure Carroll EE, Wang X, Shaw DK et al. (2019). p47 licenses activation of the immune deficiency pathway in the tick Ixodes scapularis. PNAS 116, 205-210.

[91] Mcnally KL, Mitzel DN, Anderson JM et al. (2012). Differential salivary gland transcript expression profile in Ixodes scapularis nymphs upon feeding or flavivirus infection. Ticks and Tick-borne Diseases 3, 18-26.

[92] Min YQ, Shi C, Yao T et al. (2020). The nonstructural protein of Guertu Virus disrupts host defenses by blocking antiviral interferon induction and action. ACS Infectious Diseases 6, 857-870.

[93] Narasimhan S, Booth CJ, Philipp MT, Fikrig E, Embers ME (2023). Repeated tick infestations impair borrelia burgdorferi transmission in a non-human primate model of tick feeding. Pathogens 12, 132.

[94] Narasimhan S, Rajeevan N, Liu L et al. (2014). Gut microbiota of the tick vector Ixodes scapularis modulate colonization of the Lyme disease spirochete. Cell Host & Microbe 15, 58-71.

[95] Nava S, Venzal JM, González-Acuña D, Martins TF, Guglielmone AA (2017). Tick classification, external tick anatomy with a glossary, and biological cycles. In: Ticks of the Southern Cone of America: Diagnosis, Distribution, and Hosts with Taxonomy, Ecology and Sanitary Importance. Academic Press London, UK, pp. 1-23.

[96] Ning YJ, Mo Q, Feng K et al. (2019). Interferon-gamma-directed inhibition of a novel high-pathogenic phlebovirus and viral antagonism of the antiviral signaling by targeting STAT1. Frontiers in Immunology 10, 1182.

[97] Olivieri E, Epis S, Castelli M et al. (2019). Tissue tropism and metabolic pathways of Midichloria mitochondrii suggest tissue-specific functions in the symbiosis with Ixodes ricinus. Ticks and Tick-borne Diseases 10, 1070-1077.

[98] Ortiz DI, Piche-Ovares M, Romero-Vega LM, Wagman J, Troyo A (2021). The impact of deforestation, urbanization, and changing land use patterns on the ecology of mosquito and tick-borne diseases in Central America. Insects 13, 20.

[99] Pingen M, Bryden SR, Pondeville E et al. (2016). Host inflammatory response to mosquito bites enhances the severity of arbovirus infection. Immunity 44, 1455-1469.

[100] Puig-Pijuan T, Souza LRQ, Pedrosa C et al. (2022). Copper regulation disturbance linked to oxidative stress and cell death during Zika virus infection in human astrocytes. Journal of Cellular Biochemistry 123, 1997-2008.

[101] Ribeiro JM, Makoul GT, Levine J, Robinson DR, Spielman A (1985). Antihemostatic, antiinflammatory, and immunosuppressive properties of the saliva of a tick, Ixodes dammini. Journal of Experimental Medicine 161, 332-344.

[102] Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010). Complement: A key system for immune surveillance and homeostasis. Nature Immunology 11, 785-797.

[103] Rosa RD, Capelli-Peixoto J, Mesquita RD et al. (2016). Exploring the immune signalling pathway-related genes of the cattle tick Rhipicephalus microplus: From molecular characterization to transcriptional profile upon microbial challenge. Developmental and Comparative Immunology 59, 1-14.

[104] Schnettler E, Tykalova H, Watson M et al. (2014). Induction and suppression of tick cell antiviral RNAi responses by tick-borne flaviviruses. Nucleic Acids Research 42, 9436-9446.

[105] Severo MS, Choy A, Stephens KD et al. (2013). The E3 ubiquitin ligase XIAP restricts Anaplasma phagocytophilum colonization of Ixodes scapularis ticks. Journal of Infectious Diseases 208, 1830-1840.

[106] Shaw DK, Wang X, Brown LJ et al. (2017). Infection-derived lipids elicit an immune deficiency circuit in arthropods. Nature Communications 8, 14401.

[107] Silva FD, Rezende CA, Rossi DC et al. (2009). Structure and mode of action of microplusin, a copper II-chelating antimicrobial peptide from the cattle tick Rhipicephalus (Boophilus) microplus. Journal of Biological Chemistry 284, 34735-34746.

[108] Smith AA, Navasa N, Yang X et al. (2016). Cross-species interferon signaling boosts microbicidal activity within the tick vector. Cell Host & Microbe 20, 91-98.

[109] Smith AA, Pal U (2014). Immunity-related genes in Ixodes scapularis-perspectives from genome information. Frontiers in Cellular and Infection Microbiology 4, 116.

[110] Song X, Zhong Z, Gao L, Weiss BL, Wang J (2022). Metabolic interactions between disease-transmitting vectors and their microbiota. Trends in Parasitology 38, 697-708.

[111] Souza-Neto JA, Sim S, Dimopoulos G (2009). An evolutionary conserved function of the JAK-STAT pathway in anti-dengue defense. PNAS 106, 17841-17846.

[112] Spengler JR, Bente DA, Bray M et al. (2018). Second international conference on Crimean-Congo hemorrhagic fever. Antiviral Research 150, 137-147.

[113] Sri-In C, Weng SC, Chen WY, Wu-Hsieh BA, Tu WC, Shiao SH (2019). A salivary protein of Aedes aegypti promotes dengue-2 virus replication and transmission. Insect Biochemistry and Molecular Biology 111, 103181.

[114] Stark GR (2007). How cells respond to interferons revisited: From early history to current complexity. Cytokine & Growth Factor Reviews 18, 419-423.

[115] Sucipto TH, Churrotin S, Setyawati H et al. (2018). A new copper (Ii)-imidazole derivative effectively inhibits replication of Denv-2 in vero cell. African Journal of Infectious Diseases 12, 116-119.

[116] Sun J, Min YQ, Li Y et al. (2021). Animal model of severe fever with thrombocytopenia syndrome virus infection. Frontiers in Microbiology 12, 797189.

[117] Sun T, Wang F, Pan W, Wu Q, Wang J, Dai J (2018). An immunosuppressive tick salivary gland protein DsCystatin interferes with toll-like receptor signaling by downregulating TRAF6. Frontiers in Immunology 9, 1245.

[118] Sun Y, Chen C, Zeng C, Xia Q, Yuan C, Pei H (2024). Severe fever with thrombocytopenia syndrome virus infection shapes gut microbiome of the tick vector Haemaphysalis longicornis. Parasit Vectors 17, 107.

[119] Talactac MR, Hernandez EP, Fujisaki K, Tanaka T (2018). A continuing exploration of tick-virus interactions using various experimental viral infections of hard ticks. Frontiers in Physiology 9, 1728.

[120] Talactac MR, Yoshii K, Maeda H et al. (2016). Virucidal activity of Haemaphysalis longicornis longicin P4 peptide against tick-borne encephalitis virus surrogate Langat virus. Parasites & Vectors 9, 59.

[121] Thangamani S, Hermance ME, Santos RI et al. (2017). Transcriptional immunoprofiling at the tick-virus-host interface during early stages of tick-borne encephalitis virus transmission. Frontiers in Cellular and Infection Microbiology 7, 494.

[122] Tyson K, Elkins C, Patterson H, Fikrig E, de Silva A (2007). Biochemical and functional characterization of Salp20, an Ixodes scapularis tick salivary protein that inhibits the complement pathway. Insect Molecular Biology 16, 469-479.

[123] Urbanova V, Hajdusek O, Sima R et al. (2018). IrC2/Bf—A yeast and Borrelia responsive component of the complement system from the hard tick Ixodes ricinus. Developmental and Comparative Immunology 79, 86-94.

[124] Urbanova V, Hartmann D, Grunclova L et al. (2014). IrFC—An Ixodes ricinus injury-responsive molecule related to Limulus Factor C. Developmental and Comparative Immunology 46, 439-447.

[125] Urbanova V, Sima R, Sauman I, Hajdusek O, Kopacek P (2015). Thioester-containing proteins of the tick Ixodes ricinus: Gene expression, response to microbial challenge and their role in phagocytosis of the yeast Candida albicans. Developmental and Comparative Immunology 48, 55-64.

[126] Valenzuela JG, Charlab R, Mather TN, Ribeiro JM (2000). Purification, cloning, and expression of a novel salivary anticomplement protein from the tick, Ixodes scapularis. Journal of Biological Chemistry 275, 18717-18723.

[127] Vancova I, Hajnicka V, Slovak M, Kocakova P, Paesen GC, Nuttall PA (2010). Evasin-3-like anti-chemokine activity in salivary gland extracts of ixodid ticks during blood-feeding: A new target for tick control. Parasite Immunology 32, 460-463.

[128] Voyiatzaki C, Papailia SI, Venetikou MS, Pouris J, Tsoumani ME, Papageorgiou EG (2022). Climate changes exacerbate the spread of Ixodes ricinus and the occurrence of lyme borreliosis and tick-borne encephalitis in Europe—how climate models are used as a risk assessment approach for tick-borne diseases. International Journal of Environmental Research and Public Health 19, 6516.

[129] Wang J, Ji M, Yuan B et al. (2021). Peptide OPTX-1 from ornithodoros papillipes tick inhibits the pS273R protease of African swine fever virus. Frontiers in Microbiology 12, 778309.

[130] Wang Z, Wilhelmsson C, Hyrsl P et al. (2010). Pathogen entrapment by transglutaminase-A conserved early innate immune mechanism. PLoS Pathogens 6, e1000763.

[131] Wen S, Wang F, Ji Z et al. (2019). Salp15, a multifunctional protein from tick saliva with potential pharmaceutical effects. Frontiers in Immunology 10, 3067.

[132] Weng SC, Li HH, Li JC, Liu WL, Chen CH, Shiao SH (2021). A thioester-containing protein controls dengue virus infection in Aedes aegypti through modulating immune response. Frontiers in Immunology 12, 670122.

[133] Wiesinger A, Wenderlein J, Ulrich S, Hiereth S, Chitimia-Dobler L, Straubinger RK (2023). Revealing the tick microbiome: Insights into midgut and salivary gland microbiota of female ixodes ricinus ticks. International Journal of Molecular Sciences 24, 1100.

[134] Wyler R, Wiesendanger W (1975). The enhancing effect of copper, nickel, and cobalt ions on plaque formation by Semliki Forest virus (SFV) in chicken embryo fibroblasts. Archives of Virology 47, 57-69.

[135] Xiao X, Liu Y, Zhang X et al. (2014). Complement-related proteins control the flavivirus infection of Aedes aegypti by inducing antimicrobial peptides. PLoS Pathogens 10, e1004027.

[136] Xu Y, Wang J (2024). The vector competence of Asian longhorned ticks in Langat virus transmission. Viruses 16, 304.

[137] Xu Y, Zhong Z, Ren Y et al. (2021). Antiviral RNA interference in disease vector (Asian longhorned) ticks. PLoS Pathogens 17, e1010119.

[138] Yang X, Smith AA, Williams MS, Pal U (2014). A dityrosine network mediated by dual oxidase and peroxidase influences the persistence of Lyme disease pathogens within the vector. Journal of Biological Chemistry 289, 12813-12822.

[139] Yin C, Sun P, Yu X, Wang P, Cheng G (2020). Roles of symbiotic microorganisms in arboviral infection of arthropod vectors. Trends in Parasitology 36, 607-615.

[140] Yoo JR, Heo ST, Song SW et al. (2020). Severe fever with thrombocytopenia syndrome virus in ticks and SFTS incidence in humans, South Korea. Emerging Infectious Diseases 26, 2292-2294.

[141] Yoshikawa T (2021). Vaccine development for severe fever with thrombocytopenia syndrome. Viruses 13, 627.

[142] Yu D, Liang J, Yu H et al. (2006). A tick B-cell inhibitory protein from salivary glands of the hard tick, Hyalomma asiaticum asiaticum. Biochemical and Biophysical Research Communications 343, 585-590.

[143] Yu Y, Cao J, Zhou Y, Zhang H, Zhou J (2013). Isolation and characterization of two novel serpins from the tick Rhipicephalus haemaphysaloides. Ticks and Tick-borne Diseases 4, 297-303.

[144] Yuan C, Lu Y, Li J et al. (2023). Infection and transovarial transmission of severe fever with thrombocytopenia syndrome virus in Rhipicephalus sanguineus in Hainan Island, China. Integrative Zoology 18, 1009-1013.

[145] Yuan C, Wu J, Peng Y et al. (2020). Transcriptome analysis of the innate immune system of Hyalomma asiaticum. Journal of Invertebrate Pathology 177, 107481.

[146] Yuan C, Xing L, Wang M et al. (2017). Inhibition of melanization by serpin-5 and serpin-9 promotes baculovirus infection in cotton bollworm Helicoverpa armigera. PLoS Pathogens 13, e1006645.

[147] Yuan C, Xing L, Wang M, Hu Z, Zou Z (2021). Microbiota modulates gut immunity and promotes baculovirus infection in Helicoverpa armigera. Insect Science 28, 1766-1779.

[148] Yuan C, Yang Q, Wu J et al. (2022). Proteomics reveals the hemolymph components of partially fed Hyalomma asiaticum ticks. Ticks and Tick-borne Diseases 13, 102032.

[149] Zhu KY, Palli SR (2020). Mechanisms, Applications, and Challenges of Insect RNA Interference. Annual Review of Entomology 65, 293-311.

RIGHTS & PERMISSIONS

2024 The Author(s). Integrative Zoology published by International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.