Having emerged during the early part of the Cretaceous period, ticks are an ancient group of hematophagous ectoparasites with significant veterinary and public health importance worldwide. The success of their life strategy can be attributed, in part, to saliva. As we enter into a scientific era where the collection of massive data sets and structures for biological application is possible, we suggest that understanding the molecular mechanisms that govern the life cycle of ticks is within grasp. With this in mind, we discuss what is currently known regarding the manipulation of Toll-like (TLR) and Nod-like (NLR) receptor signaling pathways by tick salivary proteins, and how these molecules impact pathogen transmission.

Department of Microbiology and Immunology University of Maryland School of Medicine Baltimore Maryland USA

Institute of Parasitology Biology Centre Czech Academy of Sciences Budweis Czech Republic

Zobrazit více v PubMed

Sonenshine DE, Roe RM. Biology of Ticks. 2. Vol. 1. New York: Oxford University Press; 2014. p. 560.

Sonenshine DE, Roe RM. Biology of Ticks. 2. Vol. 2. New York: Oxford University Press; 2014. p. 560.

Mans BJ, de Klerk D, Pienaar R, Latif AA. Nuttalliella namaqua: A Living Fossil and Closest Relative to the Ancestral Tick Lineage: Implications for the Evolution of Blood-Feeding in Ticks. PLoS ONE. 2011;6:e23675. PubMed PMC

Baneth G. Tick-borne infections of animals and humans: a common ground. Int J Parasitol. 2014;44:591–6. PubMed

Kotál J, Langhansová H, Lieskovská J, Andersen JF, Francischetti IMB, Chavakis T, et al. Modulation of host immunity by tick saliva. J Proteomics. 2015;128:58–68. A comprehensive review covering what is known about the effect of tick saliva on hemostasis, cellular, humoral and innate immunity. PubMed PMC

Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate Immune Pattern Recognition: A Cell Biological Perspective. Annu Rev Immunol. 2015;33:257–90. An excellent review discussing pattern recognition receptor signaling in the context of receptor location and compartmentalization. PubMed PMC

Kawai T, Akira S. Toll-like Receptors and Their Crosstalk with Other Innate Receptors in Infection and Immunity. Immunity. 2011;34:637–50. PubMed

Lemaitre B, Nicolas E, Michaut L, Reichhart J-M, Hoffmann JA. The Dorsoventral Regulatory Gene Cassette spätzle/Toll/cactus Controls the Potent Antifungal Response in Drosophila Adults. Cell. 1996;86:973–83. PubMed

Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol. 2015;16:343–53. PubMed PMC

Bortoluci KR, Medzhitov R. Control of infection by pyroptosis and autophagy: role of TLR and NLR. Cell Mol Life Sci. 2010;67:1643–51. PubMed PMC

Caruso R, Warner N, Inohara N, Núñez G. NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease. Immunity. 2014;41:898–908. This article reviews what is currently known about recognition, activation and regulation of NOD1 and NOD2 signaling and the implications this has for both microbial and sterile inflammatory diseases. PubMed PMC

Motta V, Soares F, Sun T, Philpott DJ. NOD-Like Receptors: Versatile Cytosolic Sentinels. Physiol Rev. 2015;95:149–78. This is an in-depth review discussing the diversity of NLRs, the distribution in the animal kingdom, the involvement in both immunity and other biological functions and the molecular mechanisms underlying these processes. PubMed

Inohara N, Ogura Y, Chen FF, Muto A, Nuñez G. Human Nod1 Confers Responsiveness to Bacterial Lipopolysaccharides. J Biol Chem. 2001;276:2551–4. PubMed

Chamaillard M, Hashimoto M, Horie Y, Masumoto J, Qiu S, Saab L, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003;4:702–7. PubMed

Hasegawa M, Yang K, Hashimoto M, Park J-H, Kim Y-G, Fujimoto Y, et al. Differential Release and Distribution of Nod1 and Nod2 Immunostimulatory Molecules among Bacterial Species and Environments. J Biol Chem. 2006;281:29054–63. PubMed

Girardin SE, Boneca IG, Carneiro LAM, Antignac A, Jéhanno M, Viala J, et al. Nod1 Detects a Unique Muropeptide from Gram-Negative Bacterial Peptidoglycan. Science. 2003;300:1584–7. PubMed

Girardin SE, Boneca IG, Viala J, Chamaillard M, Labigne A, Thomas G, et al. Nod2 Is a General Sensor of Peptidoglycan through Muramyl Dipeptide (MDP) Detection. J Biol Chem. 2003;278:8869–72. PubMed

Kobayashi K, Inohara N, Hernandez LD, Galán JE, Núñez G, Janeway CA, et al. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature. 2002;416:194–9. PubMed

Inohara N, Koseki T, Peso L, del Hu Y, Yee C, Chen S, et al. Nod1, an Apaf-1-like Activator of Caspase-9 and Nuclear Factor-κB. J Biol Chem. 1999;274:14560–7. PubMed

Park J-H, Kim Y-G, Shaw M, Kanneganti T-D, Fujimoto Y, Fukase K, et al. Nod1/RICK and TLR Signaling Regulate Chemokine and Antimicrobial Innate Immune Responses in Mesothelial Cells. J Immunol. 2007;179:514–21. PubMed

Windheim M, Lang C, Peggie M, Plater LA, Cohen P. Molecular mechanisms involved in the regulation of cytokine production by muramyl dipeptide. Biochem J. 2007;404:179–90. PubMed PMC

Guo H, Callaway JB, Ting JP-Y. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat Med. 2015;21:677–87. This review focuses on the mechanisms underlying assembly of the best characterized inflammasomes (NLRP3, NLRC4 and AIM2) and discusses these in the context of neurodegenerative diseases, sterile inflammatory disease and potential therapeutics targeting them. PubMed PMC

Lage SL, Longo C, Branco LM, da Costa TB, de Buzzo CL, Bortoluci KR. Emerging Concepts about NAIP/NLRC4 Inflammasomes. Front Immunol. 2014;5:309. PubMed PMC

Vance RE. The NAIP/NLRC4 inflammasomes. Curr Opin Immunol. 2015;32:84–9. An in-depth review of NLRC4 inflammasome assembly, the involvement of NAIPs and how this benefits host defense against microbial infection vs. inappropriate activation leading to inflammatory disease. PubMed PMC

Chavarría-Smith J, Vance RE. The NLRP1 inflammasomes. Immunol Rev. 2015;265:22–34. PubMed

Moltke J, von Ayres JS, Kofoed EM, Chavarría-Smith J, Vance RE. Recognition of Bacteria by Inflammasomes. Annu Rev Immunol. 2013;31:73–106. PubMed

Lin M, Rikihisa Y. Ehrlichia chaffeensis and Anaplasma phagocytophilum lack genes for lipid A biosynthesis and incorporate cholesterol for their survival. Infect Immun. 2003;71:5324–31. PubMed PMC

Takayama K, Rothenberg RJ, Barbour AG. Absence of lipopolysaccharide in the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun. 1987;55:2311–3. PubMed PMC

Amano K, Tamura A, Ohashi N, Urakami H, Kaya S, Fukushi K. Deficiency of peptidoglycan and lipopolysaccharide components in Rickettsia tsutsugamushi. Infect Immun. 1987;55:2290–2. PubMed PMC

Min C-K, Yang J-S, Kim S, Choi M-S, Kim I-S, Cho N-H. Genome-based construction of the metabolic pathways of Orientia tsutsugamushi and comparative analysis within the Rickettsiales order. Comp Funct Genomics. 2008:623145. PubMed PMC

Gunn JS, Ernst RK. The Structure and Function of Francisella Lipopolysaccharide. Ann N Y Acad Sci. 2007;1105:202–18. PubMed PMC

Girardin SE, Travassos LH, Hervé M, Blanot D, Boneca IG, Philpott DJ, et al. Peptidoglycan Molecular Requirements Allowing Detection by Nod1 and Nod2. J Biol Chem. 2003;278:41702–8. PubMed

Center for Disease Control and Prevention (CDC) Reported Cases of Lyme Disease by Year. United States: Division of Vector-Borne Infectious Diseases, Centers for Disease Control and Prevention; 1995–2009.

Hirschfeld M, Kirschning CJ, Schwandner R, Wesche H, Weis JH, Wooten RM, et al. Cutting edge: inflammatory signaling by Borrelia burgdorferi lipoproteins is mediated by toll-like receptor 2. J Immunol. 1999;163:2382–6. PubMed

Wooten RM, Ma Y, Yoder RA, Brown JP, Weis JH, Zachary JF, et al. Toll-like receptor 2 is required for innate, but not acquired, host defense to Borrelia burgdorferi. J Immunol. 2002;168:348–55. PubMed

Petzke MM, Brooks A, Krupna MA, Mordue D, Schwartz I. Recognition of Borrelia burgdorferi, the Lyme disease spirochete, by TLR7 and TLR9 induces a type I IFN response by human immune cells. J Immunol. 2009;183:5279–92. PubMed

Cervantes JL, Dunham-Ems SM, La Vake CJ, Petzke MM, Sahay B, Sellati TJ, et al. Phagosomal signaling by Borrelia burgdorferi in human monocytes involves Toll-like receptor (TLR) 2 and TLR8 cooperativity and TLR8-mediated induction of IFN-β. Proc Natl Acad Sci U S A. 2011;108:3683–8. PubMed PMC

Salazar JC, Duhnam-Ems S, La Vake C, Cruz AR, Moore MW, Caimano MJ, et al. Activation of Human Monocytes by Live Borrelia burgdorferi Generates TLR2-Dependent and -Independent Responses Which Include Induction of IFN-β. PLoS Pathog. 2009;5:e1000444. PubMed PMC

Shin OS, Isberg RR, Akira S, Uematsu S, Behera AK, Hu LT. Distinct Roles for MyD88 and Toll-Like Receptors 2, 5, and 9 in Phagocytosis of Borrelia burgdorferi and Cytokine Induction. Infect Immun. 2008;76:2341–51. PubMed PMC

Petnicki-Ocwieja T, Chung E, Acosta DI, Ramos LT, Shin OS, Ghosh S, et al. TRIF Mediates Toll-Like Receptor 2-Dependent Inflammatory Responses to Borrelia burgdorferi. Infect Immun. 2013;81:402–10. PubMed PMC

Petnicki-Ocwieja T, Kern A, Killpack TL, Bunnell SC, Hu LT. Adaptor Protein-3-Mediated Trafficking of TLR2 Ligands Controls Specificity of Inflammatory Responses but Not Adaptor Complex Assembly. J Immunol. 2015;195:4331–40. This study highlights the immunoregulatory role of cellular compartmentalization by demonstrating that cytokine production differs depending on cellular localization of pattern recognition receptors. PubMed PMC

Pechová J, Stĕpánová G, Kovár L, Kopecký J. Tick salivary gland extract-activated transmission of Borrelia afzelii spirochaetes. Folia Parasitol (Praha) 2002;49:153–9. PubMed

Zeidner NS, Schneider BS, Nuncio MS, Gern L, Piesman J. Coinoculation of Borrelia spp. with tick salivary gland lysate enhances spirochete load in mice and is tick species-specific. J Parasitol. 2002;88:1276–8. PubMed

Horká H, Cerná-Kýcková K, Skallová A, Kopecký J. Tick saliva affects both proliferation and distribution of Borrelia burgdorferi spirochetes in mouse organs and increases transmission of spirochetes to ticks. Int J Med Microbiol IJMM. 2009;299:373–80. PubMed

Montgomery RR, Lusitani D, de Boisfleury Chevance A, Malawista SE. Tick Saliva Reduces Adherence and Area of Human Neutrophils. Infect Immun. 2004;72:2989–94. PubMed PMC

Ramamoorthi N, Narasimhan S, Pal U, Bao F, Yang XF, Fish D, et al. The Lyme disease agent exploits a tick protein to infect the mammalian host. Nature. 2005;436:573–7. PubMed PMC

Tyson K, Elkins C, Patterson H, Fikrig E, de Silva A. Biochemical and functional characterization of Salp20, an Ixodes scapularis tick salivary protein that inhibits the complement pathway. Insect Mol Biol. 2007;16:469–79. PubMed

Schuijt TJ, Coumou J, Narasimhan S, Dai J, DePonte K, Wouters D, et al. A tick mannose-binding lectin inhibits the vertebrate complement cascade to enhance transmission of the Lyme disease agent. Cell Host Microbe. 2011;10:136–46. PubMed PMC

Páleníková J, Lieskovská J, Langhansová H, Kotsyfakis M, Chmelař J, Kopecký J. Ixodes ricinus salivary serpin IRS-2 affects Th17 differentiation via inhibition of the interleukin-6/STAT-3 signaling pathway. Infect Immun. 2015;83:1949–56. PubMed PMC

Kotsyfakis M, Horka H, Salat J, Andersen JF. The crystal structures of two salivary cystatins from the tick Ixodes scapularis and the effect of these inhibitors on the establishment of Borrelia burgdorferi infection in a murine model. Mol Microbiol. 2010;77:456–70. PubMed PMC

Bernard Q, Gallo RL, Jaulhac B, Nakatsuji T, Luft B, Yang X, et al. Ixodes tick saliva suppresses the keratinocyte cytokine response to TLR2/TLR3 ligands during early exposure to Lyme borreliosis. Exp Dermatol. 2015 An interesting study that address the additive effects of both PAMPs and DAMPs on the localized immune response that are both inevitably present at the site of a tick bite and the impact of tick saliva on this. PubMed

Gavrilin MA, Wewers MD. Francisella Recognition by Inflammasomes: Differences between Mice and Men. Front Microbiol. 2011:2. PubMed PMC

Jones CL, Weiss DS. TLR2 signaling contributes to rapid inflammasome activation during F. novicida infection. PloS One. 2011;6:e20609. PubMed PMC

Meunier E, Wallet P, Dreier RF, Costanzo S, Anton L, Rühl S, et al. Guanylate-binding proteins promote activation of the AIM2 inflammasome during infection with Francisella novicida. Nat Immunol. 2015;16:476–84. PubMed PMC

Choi K-S, Scorpio DG, Dumler JS. Anaplasma phagocytophilum Ligation to Toll-Like Receptor (TLR) 2, but Not to TLR4, Activates Macrophages for Nuclear Factor-κB Nuclear Translocation. J Infect Dis. 2004;189:1921–5. PubMed

Chen G, Severo MS, Sohail M, Sakhon OS, Wikel SK, Kotsyfakis M, et al. Ixodes scapularis saliva mitigates inflammatory cytokine secretion during Anaplasma phagocytophilum stimulation of immune cells. Parasit Vectors. 2012;5:229. PubMed PMC

Sukumaran B, Ogura Y, Pedra JHF, Kobayashi KS, Flavell RA, Fikrig E. Receptor interacting protein-2 contributes to host defense against Anaplasma phagocytophilum infection. FEMS Immunol Med Microbiol. 2012;66:211–9. PubMed PMC

Chen G, Wang X, Severo MS, Sakhon OS, Sohail M, Brown LJ, et al. The Tick Salivary Protein Sialostatin L2 Inhibits Caspase-1-Mediated Inflammation during Anaplasma phagocytophilum Infection. Infect Immun. 2014;82:2553–64. Seminal work addressing the role of inflammasomes in Anaplasma phagocytophilum infection and the immunosuppressive effects of the tick saliva protein, SL2, in this context. PubMed PMC

Mansueto P, Vitale G, Cascio A, Seidita A, Pepe I, Carroccio A, et al. New Insight into Immunity and Immunopathology of Rickettsial Diseases, New Insight into Immunity and Immunopathology of Rickettsial Diseases. J Immunol Res J Immunol Res. 2012;2012:e967852. PubMed PMC

Chattoraj P, Yang Q, Khandai A, Al-Hendy O, Ismail N. TLR2 and Nod2 Mediate Resistance or Susceptibility to Fatal Intracellular Ehrlichia Infection in Murine Models of Ehrlichiosis. PLoS ONE. 2013;8:e58514. This study demonstrates that while both TLR and inflammasome-associated genes are upregulated in response to Ehrlichia infection, Nod2 (and not TLR2) contributes to an inflammatory response that leads to Ehrlichia-induced toxic shock. PubMed PMC

Yang Q, Stevenson HL, Scott MJ, Ismail N. Type I Interferon Contributes to Noncanonical Inflammasome Activation, Mediates Immunopathology, and Impairs Protective Immunity during Fatal Infection with Lipopolysaccharide-Negative Ehrlichiae. Am J Pathol. 2015;185:446–61. PubMed PMC

Radulovic S, Price PW, Beier MS, Gaywee J, Macaluso JA, Azad A. Rickettsia-macrophage interactions: host cell responses to Rickettsia akari and Rickettsia typhi. Infect Immun. 2002;70:2576–82. PubMed PMC

Jordan JM, Woods ME, Soong L, Walker DH. Rickettsiae stimulate dendritic cells through toll-like receptor 4, leading to enhanced NK cell activation in vivo. J Infect Dis. 2009;199:236–42. PubMed PMC

Sahni SK, Narra HP, Sahni A, Walker DH. Recent molecular insights into rickettsial pathogenesis and immunity. Future Microbiol. 2013;8:1265–88. A comprehensive review discussing what is known regarding rickettsial disease and the recent advances in understanding rickettsial pathogenesis and associated immune responses. PubMed PMC

Milhano N, Saito TB, Bechelli J, Fang R, Vilhena M, De Sousa R, et al. The role of Rhipicephalus sanguineus sensu lato saliva in the dissemination of Rickettsia conorii in C3H/HeJ mice. Med Vet Entomol. 2015;29:225–9. PubMed

Alexopoulou L, Thomas V, Schnare M, Lobet Y, Anguita J, Schoen RT, et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med. 2002;8:878–84. PubMed

Lieskovska J, Kopecky J. Effect of tick saliva on signalling pathways activated by TLR-2 ligand and Borrelia afzelii in dendritic cells. Parasite Immunol. 2012;34:421–9. PubMed

Oliveira CJF, Sá-Nunes A, Francischetti IMB, Carregaro V, Anatriello E, Silva JS, et al. Deconstructing Tick Saliva Non-Protein Molecules With Potent Immunomodulatory Properties. J Biol Chem. 2011;286:10960–9. PubMed PMC

Lieskovská J, Páleníková J, Širmarová J, Elsterová J, Kotsyfakis M, Campos Chagas A, et al. Tick salivary cystatin sialostatin L2 suppresses IFN responses in mouse dendritic cells. Parasite Immunol. 2015;37:70–8. PubMed

Klein M, Brühl T-J, Staudt V, Reuter S, Grebe N, Gerlitzki B, et al. Tick Salivary Sialostatin L Represses the Initiation of Immune Responses by Targeting IRF4-Dependent Transcription in Murine Mast Cells. J Immunol. 2015;195:621–31. This study demonstrates that the tick saliva protein, SL, suppresses inflammation at the RNA level by inhibiting production of the transcription factor, IRF4. PubMed PMC

Carvalho-Costa TM, Mendes MT, da Silva MV, da Costa TA, Tiburcio MGS, Anhê ACBM, et al. Immunosuppressive effects of Amblyomma cajennense tick saliva on murine bone marrow-derived dendritic cells. Parasit Vectors. 2015;8:22. PubMed PMC

Steere AC, Coburn J, Glickstein L. The emergence of Lyme disease. J Clin Invest. 2004;113:1093–101. PubMed PMC

Radolf JD, Caimano MJ, Stevenson B, Hu LT. Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat Rev Microbiol. 2012;10:87–99. PubMed PMC

de Silva AM, Fikrig E. Arthropod- and host-specific gene expression by Borrelia burgdorferi. J Clin Invest. 1997;99:377–9. PubMed PMC

Dunham-Ems SM, Caimano MJ, Pal U, Wolgemuth CW, Eggers CH, Balic A, et al. Live imaging reveals a biphasic mode of dissemination of Borrelia burgdorferi within ticks. J Clin Invest. 2009;119:3652–65. PubMed PMC

Steere AC, Schoen RT, Taylor E. The clinical evolution of Lyme arthritis. Ann Intern Med. 1987;107:725–31. PubMed

Steere AC, Levin RE, Molloy PJ, Kalish RA, Abraham JH, Liu NY, et al. Treatment of Lyme arthritis. Arthritis Rheum. 1994;37:878–88. PubMed

Silva MJB, Carneiro MBH, dos Anjos Pultz B, Pereira Silva D, de Lopes MEM, dos Santos LM. The multifaceted role of commensal microbiota in homeostasis and gastrointestinal diseases. J Immunol Res. 2015;2015:321241. PubMed PMC

Frosali S, Pagliari D, Gambassi G, Landolfi R, Pandolfi F, Cianci R. How the Intricate Interaction among Toll-Like Receptors, Microbiota, and Intestinal Immunity Can Influence Gastrointestinal Pathology. J Immunol Res. 2015;2015:489821. PubMed PMC

Sousa ACP, Szabó MPJ, Oliveira CJF, Silva MJB. Exploring the anti-tumoral effects of tick saliva and derived components. Toxicon. 2015;102:69–73. PubMed

Horka H, Staudt V, Klein M, Taube C, Reuter S, Dehzad N, et al. The Tick Salivary Protein Sialostatin L Inhibits the Th9-Derived Production of the Asthma-Promoting Cytokine IL-9 and Is Effective in the Prevention of Experimental Asthma. J Immunol. 2012;188:2669–76. PubMed PMC

Sun M, He C, Cong Y, Liu Z. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 2015;8:969–78. PubMed PMC

Chen GY, Nuñez G. Sterile inflammation: sensing and reacting to damage. Nat Rev Immunol. 2010;10:826–37. PubMed PMC

Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, et al. Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab. 2012;32:1659–76. PubMed PMC

Sá-Nunes A, Bafica A, Antonelli LR, Choi EY, Francischetti IMB, Andersen JF, et al. The immunomodulatory action of sialostatin L on dendritic cells reveals its potential to interfere with autoimmunity. J Immunol. 2009;182:7422–9. PubMed PMC

Fukunaga M, Takahashi Y, Tsuruta Y, Matsushita O, Ralph D, McClelland M, et al. Genetic and phenotypic analysis of Borrelia miyamotoi sp. nov., isolated from the ixodid tick Ixodes persulcatus, the vector for Lyme disease in Japan. Int J Syst Bacteriol. 1995;45:804–10. PubMed

Scoles GA, Papero M, Beati L, Fish D. A Relapsing Fever Group Spirochete Transmitted by Ixodes scapularis Ticks. Vector-Borne Zoonotic Dis. 2001;1:21–34. PubMed

Platonov AE, Karan LS, Kolyasnikova NM, Makhneva NA, Toporkova MG, Maleev VV, et al. Humans Infected with Relapsing Fever Spirochete Borrelia miyamotoi, Russia. Emerg Infect Dis. 2011;17:1816–23. PubMed PMC

Gugliotta JL, Goethert HK, Berardi VP, Telford SR. Meningoencephalitis from Borrelia miyamotoi in an immunocompromised patient. N Engl J Med. 2013;368:240–5. PubMed PMC

Krause PJ, Narasimhan S, Wormser GP, Rollend L, Fikrig E, Lepore T, et al. Human Borrelia miyamotoi infection in the United States. N Engl J Med. 2013;368:291–3. PubMed PMC

Krause PJ, Fish D, Narasimhan S, Barbour AG. Borrelia miyamotoi infection in nature and in humans. Clin Microbiol Infect. 2015;21:631–9. PubMed PMC

Schwan TG, Raffel SJ, Schrumpf ME, Porcella SF. Diversity and Distribution of Borrelia hermsii. Emerg Infect Dis. 2007;13:436–42. PubMed PMC

Schwan TG, Policastro PF, Miller Z, Thompson RL, Damrow T, Keirans JE. Tick-borne Relapsing Fever Caused by Borrelia hermsii. Emerg Infect Dis. 2003;9:1151–4. PubMed PMC

Schwan TG. Vector Interactions and Molecular Adaptations of Lyme Disease and Relapsing Fever Spirochetes Associated with Transmission by Ticks. Emerg Infect Dis. 2002;8:115–21. PubMed PMC

Dugat T, Lagrée A-C, Maillard R, Boulouis H-J, Haddad N. Opening the black box of Anaplasma phagocytophilum diversity: current situation and future perspectives. Front Cell Infect Microbiol. 2015;5:61. PubMed PMC

Lani R, Moghaddam E, Haghani A, Chang L-Y, AbuBakar S, Zandi K. Tick-borne viruses: A review from the perspective of therapeutic approaches. Ticks Tick-Borne Dis. 2014;5:457–65. PubMed

Message in a vesicle - trans-kingdom intercommunication at the vector-host interface