Ticks and the pathogens they transmit constitute a growing burden for human and animal health worldwide. Vector competence is a component of vectorial capacity and depends on genetic determinants affecting the ability of a vector to transmit a pathogen. These determinants affect traits such as tick-host-pathogen and susceptibility to pathogen infection. Therefore, the elucidation of the mechanisms involved in tick-pathogen interactions that affect vector competence is essential for the identification of molecular drivers for tick-borne diseases. In this review, we provide a comprehensive overview of tick-pathogen molecular interactions for bacteria, viruses, and protozoa affecting human and animal health. Additionally, the impact of tick microbiome on these interactions was considered. Results show that different pathogens evolved similar strategies such as manipulation of the immune response to infect vectors and facilitate multiplication and transmission. Furthermore, some of these strategies may be used by pathogens to infect both tick and mammalian hosts. Identification of interactions that promote tick survival, spread, and pathogen transmission provides the opportunity to disrupt these interactions and lead to a reduction in tick burden and the prevalence of tick-borne diseases. Targeting some of the similar mechanisms used by the pathogens for infection and transmission by ticks may assist in development of preventative strategies against multiple tick-borne diseases.

Animal and Plant Health AgencySurrey UK

Biology Centre Czech Academy of Sciences Institute of ParasitologyCeske Budejovice Czechia

Department of Microbiology Medical School Aristotle University of ThessalonikiThessaloniki Greece

Department of Veterinary Pathobiology Center for Veterinary Health Sciences Oklahoma State UniversityStillwater OK USA

Facultad de Veterinaria Universidad de ZaragozaZaragoza Spain

Faculty of Health and Medicine University of SurreyGuildford UK

Faculty of Science University of South BohemiaČeské Budějovice Czechia

Global Health and Tropical Medicine Instituto de Higiene e Medicina Tropical Universidade Nova de LisboaLisboa Portugal

Institute for Parasitology and Tropical Veterinary Medicine Freie Universität BerlinBerlin Germany

Institute of Infection and Global Health University of LiverpoolLiverpool UK

National Center of Reference for Anaplasma Babesia Rickettsia and Theileria Intituto Zooprofilattico Sperimentale della SiciliaSicily Italy

SaBio Instituto de Investigación en Recursos Cinegéticos CSIC UCLM JCCMCiudad Real Spain

UMR BIPAR INRA ANSES ENVAMaisons Alfort France

Zobrazit více v PubMed

Abraham N. M., Liu L., Jutras B. L., Yadav A. K., Narasimhan S., Gopalakrishnan V., et al. . (2017). Pathogen-mediated manipulation of arthropod microbiota to promote infection. Proc. Natl. Acad. Sci. U.S.A. 114, E781–E790. 10.1073/pnas.1613422114 PubMed DOI PMC

Ahantarig A., Trinachartvanit W., Baimai V., Grubhoffer L. (2013). Hard ticks and their bacterial endosymbionts (or would be pathogens). Folia. Microbiol. 58, 419–428. 10.1007/s12223-013-0222-1 PubMed DOI

Alberdi P., Mansfield K. L., Manzano-Román R., Cook C., Ayllón N., Villar M., et al. . (2016). Tissue-specific signatures in the transcriptional response to Anaplasma phagocytophilum infection of Ixodes scapularis and Ixodes ricinus tick cell lines. Front. Cell. Infect. Microbiol. 6:20. 10.3389/fcimb.2016.00020 PubMed DOI PMC

Almazán C., Kocan K. M., Blouin E. F., de la Fuente J. (2005). Vaccination with recombinant tick antigens for the control of Ixodes scapularis adult infestations. Vaccine 23, 5294–5298. 10.1016/j.vaccine.2005.08.004 PubMed DOI

Andreotti R., Perez de Leon A. A., Dowd S. E., Guerrero F. D., Bendele K. G., Scoles G. A. (2011). Assessment of bacterial diversity in the cattle tick Rhipicephalus (Boophilus) microplus through tag-encoded pyrosequencing. BMC. Microbiol. 11:6. 10.1186/1471-2180-11-6 PubMed DOI PMC

Antunes S., Galindo R. C., Almazán C., Rudenko N., Golovchenko M., Grubhoffer L., et al. . (2012). Functional genomics studies of Rhipicephalus (Boophilus) annulatus ticks in response to infection with the cattle protozoan parasite, Babesia bigemina. Int. J. Parasitol. 42, 187–195. 10.1016/j.ijpara.2011.12.003 PubMed DOI

Ashida H., Mimuro H., Ogawa M., Kobayashi T., Sanada T., Kim M., et al. . (2011). Host-pathogen interactions cell death and infection: a double-edged sword for host and pathogen survival. J. Cell. Biol. 195, 931–942. 10.1083/jcb.201108081 PubMed DOI PMC

Ayllón N., Naranjo V., Hajdušek O., Villar M., Galindo R. C., Kocan K. M., et al. . (2015b). Nuclease Tudor-SN is involved in tick dsRNA-mediated RNA interference and feeding but not in defense against flaviviral or Anaplasma phagocytophilum rickettsial infection. PLoS ONE 10:e0133038. 10.1371/journal.pone.0133038 PubMed DOI PMC

Ayllón N., Villar M., Busby A. T., Kocan K. M., Blouin E., Bonzón-Kulichenko E. F., et al. . (2013). Anaplasma phagocytophilum inhibits apoptosis and promotes cytoskeleton rearrangement for infection of tick cells. Infect. Immun. 81, 2415–2425. 10.1128/IAI.00194-13 PubMed DOI PMC

Ayllón N., Villar M., Galindo R. C., Kocan K. M., Šíma R., López J. A., et al. . (2015a). Systems biology of tissue-specific response to Anaplasma phagocytophilum reveals differentiated apoptosis in the tick vector Ixodes scapularis. PLoS Genet. 11:e1005120. 10.1371/journal.pgen.1005120 PubMed DOI PMC

Baldridge G. D., Burkhardt N. Y., Simser J. A., Kurtti T. J., Munderloh U. G. (2004). Sequence and expression analysis of the ompA gene of Rickettsia peacockii, an endosymbiont of the Rocky Mountain wood tick, Dermacentor andersoni. Appl. Environ. Microbiol. 70, 6628–6636. 10.1128/AEM.70.11.6628-6636.2004 PubMed DOI PMC

Baxter R. H., Contet A., Krueger K. (2017). Arthropod innate immune systems and vector-borne diseases. Biochemistry. 56, 907–918. 10.1021/acs.biochem.6b00870 PubMed DOI PMC

Beerntsen B. T., James A. A., Christensen B. M. (2000). Genetics of mosquito vector competence. Microbiol. Mol. Biol. Rev. 64, 115–137. 10.1128/MMBR.64.1.115-137.2000 PubMed DOI PMC

Bell-Sakyi L., Zweygarth E., Blouin E. F., Gould E. A., Jongejan F. (2007). Tick cell lines: tools for tick and tick-borne disease research. Trends. Parasitol. 23, 450–457. 10.1016/j.pt.2007.07.009 PubMed DOI

Bernasconi M. V., Casati S., Peter O., Piffaretti J. C. (2002). Rhipicephalus ticks infected with Rickettsia and Coxiella in Southern Switzerland (Canton Ticino). Infect. Genet. Evol. 2, 111–120. 10.1016/S1567-1348(02)00092-8 PubMed DOI

Bohacsova M., Mediannikov O., Kazimirova M., Raoult D., Sekeyova Z. (2016). Arsenophonus nasoniae and Rickettsiae infection of Ixodes ricinus due to parasitic wasp Ixodiphagus hookeri. PLoS ONE 11:e0149950. 10.1371/journal.pone.0149950 PubMed DOI PMC

Bonnet S., de la Fuente J., Nicollet P., Liu X., Madani N., Blanchard B., et al. . (2013). Prevalence of tick-borne pathogens in adult Dermacentor spp. ticks from nine collection sites in France. Vector Borne Zoonotic Dis. 13, 226–236. 10.1089/vbz.2011.0933 PubMed DOI

Burgdorfer W., Hayes S., Mavros A. (1981). Non-pathogenic rickettsiae in Dermacentor andersoni: a limiting factor for the distribution of Rickettsia rickettsia, in Rickettsia and Rickettsial Disease, ed Burgdorfer W. (New York, NY: Academic Press; ), 585–594.

Busby A. T., Ayllón N., Kocan K. M., Blouin E. F., de la Fuente G., Galindo R. C., et al. . (2012). Expression of heat-shock proteins and subolesin affects stress responses, Anaplasma phagocytophilum infection and questing behavior in the tick, Ixodes scapularis. Med. Vet. Entomol. 26, 92–102. 10.1111/j.1365-2915.2011.00973.x PubMed DOI

Cabezas-Cruz A., Alberdi P., Ayllón N., Valdés J. J., Pierce R., Villar M., et al. . (2016). Anaplasma phagocytophilum increases the levels of histone modifying enzymes to inhibit cell apoptosis and facilitate pathogen infection in the tick vector, Ixodes scapularis. Epigenetics 11, 303–319. 10.1080/15592294.2016.1163460 PubMed DOI PMC

Cabezas-Cruz A., Estrada-Peña A., Rego R. O. M., De la Fuente J. (2017). Tick-pathogen ensembles: do molecular interactions lead ecological innovation? Front. Cell. Infect. Microbiol. 7:74. 10.3389/fcimb.2017.00074 PubMed DOI PMC

Chauvin A., Moreau E., Bonnet S., Plantard O., Malandrin L. (2009). Babesia and its hosts: adaptation to long-lasting interactions as a way to achieve efficient transmission. Vet. Res. 40, 37. 10.1051/vetres/2009020 PubMed DOI PMC

Clay K., Klyachko O., Grindle N., Civitello D., Oleske D., Fuqua C. (2008). Microbial communities and interactions in the lone star tick, Amblyomma americanum. Mol. Ecol. 17, 4371–4381. 10.1111/j.1365-294X.2008.03914.x PubMed DOI

Cooper A., Stephens J., Ketheesan N., Govan B. (2013). Detection of Coxiella burnetii DNA in wildlife and ticks in northern Queensland, Australia. Vector Borne Zoonotic Dis. 13, 12–16. 10.1089/vbz.2011.0853 PubMed DOI

Cotté V., Sabatier L., Schnell G., Carmi-Leroy A., Rousselle J. C., Arsène-Ploetze F., et al. . (2014). Differential expression of Ixodes ricinus salivary gland proteins in the presence of the Borrelia burgdorferi sensu lato complex. J. Proteomics. 96, 29–43. 10.1016/j.jprot.2013.10.033 PubMed DOI

Coumou J., Narasimhan S., Trentelman J. J., Wagemakers A., Koetsveld J., Ersoz J. I., et al. . (2016). Ixodes scapularis dystroglycan-like protein promotes Borrelia burgdorferi migration from the gut. J. Mol. Med. 94, 361–370. 10.1007/s00109-015-1365-0 PubMed DOI PMC

Cramaro W. J., Revets D., Hunewald O. E., Sinner R., Reye A. L., Muller C. P. (2015). Integration of Ixodes ricinus genome sequencing with transcriptome and proteome annotation of the naive midgut. BMC Genomics 16:871. 10.1186/s12864-015-1981-7 PubMed DOI PMC

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 Pathog. 6:e1001205. 10.1371/journal.ppat.1001205 PubMed DOI PMC

de Castro M. H., de Klerk D., Pienaar R., Latif A. A., Rees D. J., Mans B. J. (2016). De novo assembly and annotation of the salivary gland transcriptome of Rhipicephalus appendiculatus male and female ticks during blood feeding. Ticks Tick Borne Dis. 7, 536–548. 10.1016/j.ttbdis.2016.01.014 PubMed DOI

de la Fuente J., Blouin E. F., Kocan K. M. (2003). Infection exclusion of the rickettsial pathogen Anaplasma marginale in the tick vector Dermacentor variabilis. Clin. Diagn. Lab. Immunol. 10, 182–184. 10.1128/cdli.10.1.182-184.2003 PubMed DOI PMC

de la Fuente J., Contreras M. (2015). Tick vaccines: current status and future directions. Expert Rev. Vaccines 14, 1367–1376. 10.1586/14760584.2015.1076339 PubMed DOI

de la Fuente J., Estrada-Peña A., Cabezas-Cruz A., Brey R. (2015). Flying ticks: anciently evolved associations that constitute a risk of infectious disease spread. Parasit Vectors 8, 538. 10.1186/s13071-015-1154-1 PubMed DOI PMC

de la Fuente J., Estrada-Peña A., Cabezas-Cruz A., Kocan K. M. (2016). Anaplasma phagocytophilum uses common strategies for infection of ticks and vertebrate hosts. Trends Microbiol. 24, 173–180. 10.1186/s13071-015-1154-1 PubMed DOI

de la Fuente J., Estrada-Peña A., Venzal J. M., Kocan K. M., Sonenshine D. E. (2008). Overview: ticks as vectors of pathogens that cause disease in humans and animals. Front. Biosci. 13, 6938–6946. 10.2741/3200 PubMed DOI

de la Fuente J., Garcia-Garcia J. C., Blouin E. F., McEwen B. R., Clawson D., Kocan K. M. (2001). Major surface protein 1a effects tick infection and transmission of Anaplasma marginale. Int. J. Parasitol. 31, 1705–1714. 10.1016/S0020-7519(01)00287-9 PubMed DOI

de la Fuente J., Kocan K. M. (2014). Development of vaccines for control of tick infestations and interruption of pathogen transmission, in Biology of Ticks, 2nd Edn., ed Sonenshine D., Roe M. (New York, NY: Oxford University Press; ), 333–352.

de la Fuente J., Kocan K. M., Almazán C., Blouin E. F. (2007). RNA interference for the study and genetic manipulation of ticks. Trends Parasitol. 23, 427–433. 10.1016/j.pt.2007.07.002 PubMed DOI

Dergousoff S. J., Chilton N. B. (2010). Detection of a new Arsenophonus-type bacterium in Canadian populations of the Rocky Mountain wood tick, Dermacentor andersoni. Exp. Appl. Acarol. 52, 85–91. 10.1007/s10493-010-9340-5 PubMed DOI

Dickson D. L., Turell M. J. (1992). Replication and tissue tropisms of Crimean-Congo hemorrhagic fever virus in experimentally infected adult Hyalomma truncatum (Acari: Ixodidae). J. Med. Entomol. 29, 767–773. 10.1093/jmedent/29.5.767 PubMed DOI

Doherty P. C., Reid H. W. (1971). Experimental louping ill in the sheep. II, Neuropathology. J. Comp. Pathol. 81, 331–337. 10.1016/0021-9975(71)90020-X PubMed DOI

Eng M. W., van Zuylen M. N., Severson D. W. (2016). Apoptosis-related genes control autophagy and influence DENV-2 infection in the mosquito vector, Aedes aegypti. Insect Biochem. Mol. Biol. 76, 70–83. 10.1016/j.ibmb.2016.07.004 PubMed DOI PMC

Engelstadter J., Hurst G. D. (2007). The impact of male-killing bacteria on host evolutionary processes. Genetics 175, 245–254. 10.1534/genetics.106.060921 PubMed DOI PMC

Estrada-Peña A., de la Fuente J., Ostfeld R. S., Cabezas-Cruz A. (2015). Interactions between tick and transmitted pathogens evolved to minimise competition through nested and coherent networks. Sci. Rep. 5:10361. 10.1038/srep10361 PubMed DOI PMC

Estrada-Peña A., Ortega C., Sánchez N., Desimone L., Sudre B., Suk J. E., et al. . (2011). Correlation of Borrelia burgdorferi sensu lato prevalence in questing Ixodes ricinus ticks with specific abiotic traits in the western Palearctic. Appl. Environ. Microbiol. 77, 3838–3845. 10.1128/AEM.00067-11 PubMed DOI PMC

Florin-Christensen M., Schnittger L. (2009). Piroplasmids and ticks: a long-lasting intimate relationship. Front. Biosci. 14, 3064–3073. 10.2741/3435 PubMed DOI

Garcia-Garcia J. C., Barat N. C., Trembley S. J., Dumler J. S. (2009a). Epigenetic silencing of host cell defense genes enhances intracellular survival of the rickettsial pathogen Anaplasma phagocytophilum. PLoS Pathog. 5:e1000488. 10.1371/journal.ppat.1000488 PubMed DOI PMC

Garcia-Garcia J. C., Rennoll-Bankert K. E., Pelly S., Milstone A. M., Dumler J. S. (2009b). Silencing of host cell CYBB gene expression by the nuclear effector AnkA of the intracellular pathogen Anaplasma phagocytophilum. Infect Immun. 77, 2385–2391. 10.1128/IAI.00023-09 PubMed DOI PMC

Garg R., Juncadella I. J., Ramamoorthi N., Ananthanarayanan S. K., Thomas V., Rincón M., et al. . (2006). Cutting edge: CD4 is the receptor for the tick saliva immunosuppressor, Salp15. J. Immunol. 177, 6579–6583. 10.4049/jimmunol.177.10.6579 PubMed DOI PMC

Garrison A. R., Radoshitzky S. R., Kota K. P., Pegoraro G., Ruthel G., et al. . (2013). Crimean-Congo hemorrhagic fever virus utilizes a clathrin- and early endosome-dependent entry pathway. Virology 444, 45–54. 10.1016/j.virol.2013.05.030 PubMed DOI

Gerold G., Bruening J., Weigel B., Pietschmann T. (2017). Protein interactions during the flavivirus and hepacivirus life cycle. Mol. Cell. Proteomics 16(4 Suppl. 1), S75–S91. 10.1074/mcp.r116.065649 PubMed DOI PMC

Gomes-Solecki M. (2014). Blocking pathogen transmission at the source: reservoir targeted OspA-based vaccines against Borrelia burgdorferi. Front. Cell Infect Microbiol. 4:136. 10.3389/fcimb.2014.00136 PubMed DOI PMC

Gómez-Díaz E., Jordà M., Peinado M. A., Rivero A. (2012). Epigenetics of host-pathogen interactions: the road ahead and the road behind. PLoS Pathog. 8:e1003007. 10.1371/journal.ppat.1003007 PubMed DOI PMC

Gulia-Nuss M., Nuss A. B., Meyer J. M., Sonenshine D. E., Roe R. M., Waterhouse R. M., et al. . (2016). Genomic insights into the Ixodes scapularis tick vector of Lyme disease. Nat. Commun. 7:10507. 10.1038/ncomms10507 PubMed DOI PMC

Hajdušek O., Síma R., Ayllón N., Jalovecká M., Perner J., de la Fuente J., et al. . (2013). Interaction of the tick immune system with transmitted pathogens. Front. Cell Infect Microbiol. 3:26. 10.3389/fcimb.2013.00026 PubMed DOI PMC

Harrus S., Perlman-Avrahami A., Mumcuoglu K. Y., Morick D., Eyal O., Baneth G. (2011). Molecular detection of Ehrlichia canis, Anaplasma bovis, Anaplasma platys, Candidatus Midichloria mitochondrii and Babesia canis vogeli in ticks from Israel. Clin. Microbiol. Infect 17, 459–463. 10.1111/j.1469-0691.2010.03316.x PubMed DOI

Heekin A. M., Guerrero F. D., Bendele K. G., Saldivar L., Scoles G. A., Dowd S. E., et al. . (2013). The ovarian transcriptome of the cattle tick, Rhipicephalus (Boophilus) microplus, feeding upon a bovine host infected with Babesia bovis. Parasit. Vectors 6:276. 10.1186/1756-3305-6-276 PubMed DOI PMC

Heekin A. M., Guerrero F. D., Bendele K. G., Saldivar L., Scoles G. A., Gondro C., et al. . (2012). Analysis of Babesia bovis infection-induced gene expression changes in larvae from the cattle tick, Rhipicephalus (Boophilus) microplus. Parasit. Vectors 5:162. 10.1186/1756-3305-5-162 PubMed DOI PMC

Hermann C., Gern L. (2010). Survival of Ixodes ricinus (Acri: Ixodidae) under challenging conditions of temperature and humidity is influenced by Borrelia burgdorferi sensu laro infection. J. Med. Entomol. 47, 1196–1204. 10.1603/ME10111 PubMed DOI

Herrmann C., Gern L. (2012). Do the level of energy reserves, hydration status and Borrelia infection influence walking by Ixodes ricinus (Acari: Ixodidae) ticks? Parasitology 139, 330–337. 10.1017/S0031182011002095 PubMed DOI

Hourcade D. E., Akk A. M., Mitchell L. M., Zhou H. F., Hauhart R., et al. . (2016). Anti-complement activity of the Ixodes scapularis salivary protein Salp20. Mol. Immunol. 69, 62–69. 10.1016/j.molimm.2015.11.008 PubMed DOI PMC

Ireton K. (2013). Molecular mechanisms of cell-cell spread of intracellular bacterial pathogens. Open Biol. 3:130079. 10.1098/rsob.130079 PubMed DOI PMC

Ivanov I. N., Mitkova N., Reye A. L., Hübschen J. M., Vatcheva-Dobrevska R. S., Dobreva E. G., et al. . (2011). Detection of new Francisella-like tick endosymbionts in Hyalomma spp. and Rhipicephalus spp. (Acari: Ixodidae) from Bulgaria. Appl. Environ. Microbiol. 77, 5562–5565. 10.1128/AEM.02934-10 PubMed DOI PMC

Johnson N., Voller K., Phipps L. P., Mansfield K. L., Fooks A. R. (2012). Rapid molecular detection methods for arboviruses of livestock of importance to Northern Europe. J. Biomed. Biotechnol. 2012:719402. 10.1155/2012/719402 PubMed DOI PMC

Jongejan F., Uilenberg G. (2004). The global importance of ticks. Parasitology 129(Suppl.), S3–S14. 10.1017/S0031182004005967 PubMed DOI

Kagemann J., Clay K. (2013). Effects of infection by Arsenophonus and Rickettsia bacteria on the locomotive ability of the ticks Amblyomma americanum, Dermacentor variabilis, and Ixodes scapularis. J. Med. Entomol. 50, 155–162. 10.1603/ME12086 PubMed DOI

Kleiboeker S., Scoles G. A., Burrage T. G., Sur J. (1999). African swine fever virus replication in the midgut epithelium is required for infection of Ornithodoros ticks. J. Virol. 73, 8587–8598. PubMed PMC

Klyachko O., Stein B. D., Grindle N., Clay K., Fuqua C. (2007). Localization and visualization of a coxiella-type symbiont within the lone star tick, Amblyomma americanum. Appl. Environ. Microbiol. 73, 6584–6594. 10.1128/AEM.00537-07 PubMed DOI PMC

Kotsyfakis M., Schwarz A., Erhart J., Ribeiro J. M. (2015). Tissue-and time-dependent transcription in Ixodes ricinus salivary glands and midguts when blood feeding on the vertebrate host. Sci. Rep. 5:9103. 10.1038/srep09103 PubMed DOI PMC

Kung F., Anguita J., Pal U. (2013). Borrelia burgdorferi and tick proteins supporting pathogen persistence in the vector. Future Microbiol. 8, 41–56. 10.2217/fmb.12.121 PubMed DOI PMC

Labuda M., Nuttall P. A. (2003). Tick-borne viruses. Parasitology 129, S221–S245. 10.1017/S0031182004005220 PubMed DOI

Lee J. H., Park H. S., Jang W. J., Koh S. E., Park T. K., Kang S. S., et al. . (2004). Identification of the Coxiella sp. detected from Haemaphysalis longicornis ticks in Korea. Microbiol. Immunol. 48, 125–130. 10.1111/j.1348-0421.2004.tb03498.x PubMed DOI

Liu L. M., Liu J. N., Liu Z., Yu Z. J., Xu S. Q., Yang X. H., et al. . (2013). Microbial communities and symbionts in the hard tick Haemaphysalis longicornis (Acari: Ixodidae) from north China. Parasit. Vectors 6:310. 10.1186/1756-3305-6-310 PubMed DOI PMC

Lo N., Beninati T., Sassera D., Bouman E. A., Santagati S., Gern L., et al. . (2006). Widespread distribution and high prevalence of an alpha-proteobacterial symbiont in the tick Ixodes ricinus. Environ. Microbiol. 8, 1280–1287. 10.1111/j.1462-2920.2006.01024.x PubMed DOI

Lu P., Zhou Y., Yu Y., Cao J., Zhang H., Gong H., et al. . (2016). RNA interference and the vaccine effect of a subolesin homolog from the tick Rhipicephalus haemaphysaloides. Exp. Appl. Acarol. 68, 113–126. 10.1007/s10493-015-9987-z PubMed DOI

Macaluso K. R., Sonenshine D. E., Ceraul S. M., Azad A. F. (2002). Rickettsial infection in Dermacentor variabilis (Acari: Ixodidae) inhibits transovarial transmission of a second Rickettsia. J. Med. Entomol. 39, 809–813. 10.1603/0022-2585-39.6.809 PubMed DOI

Mansfield K. L., Cook C., Ellis R., Bell-Sakyi L., Johnson N., Alberdi P., et al. . (2017). Tick-borne pathogens induce differential expression of genes promoting cell survival and host resistence in Ixodes ricinus cells. Parasit. Vectors 10:81. 10.1186/s13071-017-2011-1 PubMed DOI PMC

Mansfield K. L., Johnson N., Banyard A. C., Núñez A., Baylis M., Solomon T., et al. . (2016). Innate and adaptive immune responses to tick-borne flavivirus infection in sheep. Vet. Microbiol. 185, 20–28. 10.1016/j.vetmic.2016.01.015 PubMed DOI

Martinez J., Longdon B., Bauer S., Chan Y. S., Miller W. J., Bourtzis K., et al. . (2014). Symbionts commonly provide broad spectrum resistance to viruses in insects: a comparative analysis of Wolbachia strains. PLoS Pathog. 10:e1004369. 10.1371/journal.ppat.1004369 PubMed DOI PMC

Mather T. N., Ribeiro J. M., Spielman A. (1987). Lyme disease and babesiosis: acaricide focused on potentially infected ticks. Am. J. Trop. Med. Hyg. 36, 609–614. PubMed

Merino O., Antunes S., Mosqueda J., Moreno-Cid J. A., Pérez de la Lastra J. M., et al. . (2013). Vaccination with proteins involved in tick-pathogen interactions reduces vector infestations and pathogen infection. Vaccine 31, 5889–5896. 10.1016/j.vaccine.2013.09.037 PubMed DOI

Michelet L., Bonnet S., Madani N., Moutailler S. (2013). Discriminating Francisella tularensis and Francisella-like endosymbionts in Dermacentor reticulatus ticks: evaluation of current molecular techniques. Vet. Microbiol. 163, 399–403. 10.1016/j.vetmic.2013.01.014 PubMed DOI

Montagna M., Sassera D., Epis S., Bazzocchi C., Vannini C., Lo N., et al. . (2013). Candidatus Midichloriaceae” fam. nov. (Rickettsiales), an ecologically widespread clade of intracellular alphaproteobacteria. Appl. Environ. Microbiol. 79, 3241–3248. 10.1128/AEM.03971-12 PubMed DOI PMC

Naranjo V., Ayllón N., Pérez de la Lastra J. M., Galindo R. C., Kocan K. M., Blouin E. F., et al. . (2013). Reciprocal regulation of NF-kB (Relish) and Subolesin in the tick vector, Ixodes scapularis. PLoS ONE 8:e65915. 10.1371/journal.pone.0065915 PubMed DOI PMC

Narasimhan S., Rajeevan N., Liu L., Zhao Y. O., Heisig J., Pan J., et al. . (2014). Gut microbiota of the tick vector Ixodes scapularis modulate colonization of the Lyme disease spirochete. Cell. Host. Microbe. 15, 58–71. 10.1016/j.chom.2013.12.001 PubMed DOI PMC

Neelakanta G., Sultana H., Fish D., Anderson J. F., Fikrig E. (2010). Anaplasma phagocytophilum induces Ixodes scapularis ticks to express an antifreeze glycoprotein gene that enhances their survival in the cold. J. Clin. Invest. 120, 3179–3190. 10.1172/JCI42868 PubMed DOI PMC

Nene V., Lee D., Kang'a S., Skilton R., Shah T., de Villiers E., et al. . (2004). Genes transcribed in the salivary glands of female Rhipicephalus appendiculatus ticks infected with Theileria parva. Insect. Biochem. Mol. Biol. 34, 1117–1128. 10.1016/j.ibmb.2004.07.002 PubMed DOI

Nuttall P. A. (2014). Tick-borne viruses, in Biology of Ticks, ed Sonenshine D. E., Roe R. M. (Oxford: Oxford University Press; ), 180–210.

Pal U., Li X., Wang T., Montgomery R. R., Ramamoorthi N., Desilva A. M., et al. . (2004). TROSPA, an Ixodes scapularis receptor for Borrelia burgdorferi. Cell 119, 457–468. 10.1016/j.cell.2004.10.027 PubMed DOI

Papa A. (2010). Crimean-Congo hemorrhagic fever and hantavirus infections, in Tropical and Emerging Infectious Diseases, ed Maltezou H., Gikas A. (Kerala: Research Signpost; ), 49–73.

Plantard O., Bouju-Albert A., Malard M. A., Hermouet A., Capron G., Verheyden H. (2012). Detection of Wolbachia in the tick Ixodes ricinus is due to the presence of the hymenoptera endoparasitoid Ixodiphagus hookeri. PLoS ONE 7:e30692. 10.1371/journal.pone.0030692 PubMed DOI PMC

Qiu Y., Nakao R., Ohnuma A., Kawamori F., Sugimoto C. (2014). Microbial population analysis of the salivary glands of ticks; a possible strategy for the surveillance of bacterial pathogens. PLoS ONE 9:e103961. 10.1371/journal.pone.0103961 PubMed DOI PMC

Rachinsky A., Guerrero F. D., Scoles G. A. (2007). Differential protein expression in ovaries of uninfected and Babesia-infected southern cattle ticks Rhipicephalus (Boophilus) microplus. Insect Biochem. Mol. Biol. 37, 1291–1308. 10.1016/j.ibmb.2007.08.001 PubMed DOI

Radolf J. D., Caimano M. J., Stevenson B., Hu L. T. (2012). Of ticks, mice and men: understanding the dual-host lifestyle of Lyme disease spirochaetes. Nat. Rev. Microbiol. 10, 87–99. 10.1038/nrmicro2714 PubMed DOI PMC

Ramamoorthi N., Narasimhan S., Pal U., Bao F., Yang X. F., Fish D., et al. . (2005). The Lyme disease agent exploits a tick protein to infect the mammalian host. Nature 436, 573–577. 10.1038/nature03812 PubMed DOI PMC

Ramphul U. N., Garver L. S., Molina-Cruz A., Canepa G. E., Barillas-Mury C. (2015). Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells. Proc. Natl. Acad. Sci. U.S.A. 112, 1273–1280. 10.1073/pnas.1423586112 PubMed DOI PMC

Reis C., Cote M., Paul R. E., Bonnet S. (2011). Questing ticks in suburban forest are infected by at least six tick-borne pathogens. Vector Borne Zoonotic Dis. 11, 907–916. 10.1089/vbz.2010.0103 PubMed DOI

Rennoll-Bankert K. E., Garcia-Garcia J. C., Sinclair S. H., Dumler J. S. (2015). Chromatin-bound bacterial effector ankyrin A recruits histone deacetylase 1 and modifies host gene expression. Cell Microbiol. 17, 1640–1652. 10.1111/cmi.12461 PubMed DOI PMC

Rollend L., Fish D., Childs J. E. (2013). Transovarial transmission of Borrelia spirochetes by Ixodes scapularis: a summary of the literature and recent observations. Ticks Tick Borne Dis. 4, 46–51. 10.1016/j.ttbdis.2012.06.008 PubMed DOI

Rosa P. A., Tilly K., Stewart P. E. (2005). The burgeoning molecular genetics of the Lyme disease spirochaete. Nat. Rev. Microbiol. 3, 129–143. 10.1038/nrmicro1086 PubMed DOI

Rudenko N., Golovchenko M., Edwards M. J., Grubhoffer L. (2005). Differential expression of Ixodes ricinus tick genes induced by blood feeding or Borrelia burgdorferi infection. J. Med. Entomol. 42, 36–41. 10.1093/jmedent/42.1.36 PubMed DOI

Rynkiewicz E. C., Hemmerich C., Rusch D. B., Fuqua C., Clay K. (2015). Concordance of bacterial communities of two tick species and blood of their shared rodent host. Mol. Ecol. 24, 2566–2579. 10.1111/mec.13187 PubMed DOI

Sabin L. R., Zheng Q., Thekkat P., Yang J., Hannon G. J., Gregory B. D., et al. . (2013). Dicer-2 processes diverse viral RNA species. PLoS ONE 8:e55458. 10.1371/journal.pone.0055458 PubMed DOI PMC

Sassera D., Beninati T., Bandi C., Bouman E. A., Sacchi L., Fabbi M., et al. . (2006). Candidatus Midichloria mitochondrii,” an endosymbiont of the tick Ixodes ricinus with a unique intramitochondrial lifestyle. Int. J. Syst. Evol. Microbiol. 56, 2535–2540. 10.1099/ijs.0.64386-0 PubMed DOI

Schnittger L., Rodriguez A. E., Florin-Christensen M., Morrison D. A. (2012). Babesia: a world emerging. Infect Genet. Evol. 12, 1788–1809. 10.1016/j.meegid.2012.07.004 PubMed DOI

Schuijt T. J., Coumou J., Narasimhan S., Dai J., Deponte K., Wouters D., et al. . (2011b). A tick mannose-binding lectin inhibitor interferes with the vertebrate complement cascade to enhance transmission of the Lyme disease agent. Cell Host Microbe. 10, 136–146. 10.1016/j.chom.2011.06.010 PubMed DOI PMC

Schuijt T. J., Narasimhan S., Daffre S., DePonte K., Hovius J. W., Van't Veer C., et al. . (2011a). Identification and characterization of Ixodes scapularis antigens that elicit tick immunity using yeast surface display. PLoS ONE 6:e15926. 10.1371/journal.pone.0015926 PubMed DOI PMC

Severo M. S., Choy A., Stephens K. D., Sakhon O. S., Chen G., Chung D. W., et al. . (2013). The E3 ubiquitin ligase XIAP restricts Anaplasma phagocytophilum colonization of Ixodes scapularis ticks. J. Infect Dis. 208, 1830–1840. 10.1093/infdis/jit380 PubMed DOI PMC

Severo M. S., Pedra J. H. F., Ayllón N., Kocan K. M., de la Fuente J. (2015). Anaplasma, in Molecular Medical Microbiology, 2nd Edn., ed Tang Y. W., Sussman M., Liu D., Poxton I., Schwartzman J. (New York, NY: Academic Press; Elsevier; ), 2033–2042.

Shaw D. K., Wang X., Brown L. J., Oliva C. A. S., Reif K. E., Smith A. A., et al. . (2017). Infection-derived lipids elicit an immune deficiency circuit in arthropods. Nat. Commun. 8:14401. 10.1038/ncomms14401 PubMed DOI PMC

Shih C. M., Telford S. R., III., Spielman A. (1995). Effect of ambient temperature on competence of deer ticks as hosts for Lyme disease spirochetes. J. Clin. Microbiol. 33, 958–961. PubMed PMC

Shtanko O., Nikitina R. A., Altuntas C. Z., Chepurnov A. A., Davey R. A. (2014). Crimean-Congo hemorrhagic fever virus entry into host cells occurs through the multivesicular body and requires ESCRT regulators. PLoS Pathog. 10:e1004390. 10.1371/journal.ppat.1004390 PubMed DOI PMC

Simon M., Johansson C., Mirazimi A. (2009). Crimean-Congo hemorrhagic fever virus entry and replication is clathrin-, pH- and cholesterol-dependent. J. Gen. Virol. 90(Pt 1), 210–215. 10.1099/vir.0.006387-0 PubMed DOI

Smith A. A., Navasa N., Yang X., Wilder C. N., Buyuktanir O., Marques A., et al. . (2016). Cross-Species Interferon signaling boosts microbicidal activity within the tick vector. Cell Host Microbe 20, 91–98. 10.1016/j.chom.2016.06.001 PubMed DOI PMC

Steiner F. E., Pinger R. R., Vann C. N., Grindle N., Civitello D., Clay K., et al. . (2008). Infection and co-infection rates of Anaplasma phagocytophilum variants, Babesia spp., Borrelia burgdorferi, and the rickettsial endosymbiont in Ixodes scapularis (Acari: Ixodidae) from sites in Indiana, Maine, Pennsylvania, and Wisconsin. J. Med. Entomol. 45, 289–297. 10.1093/jmedent/45.2.289 PubMed DOI

Suda Y., Fukushi S., Tani H., Murakami S., Saijo M., Horimoto T., et al. . (2016). Analysis of the entry mechanism of Crimean-Congo hemorrhagic fever virus, using a vesicular stomatitis virus pseudotyping system. Arch. Virol. 161, 1447–1454. 10.1007/s00705-016-2803-1 PubMed DOI PMC

Sultana H., Neelakanta G., Kantor F. S., Malawista S. E., Fish D., Montgomery R. R., et al. . (2010). Anaplasma phagocytophilum induces actin phosphorylation to selectively regulate gene transcription in Ixodes scapularis ticks. J. Exp. Med. 207, 1727–1743. 10.1084/jem.20100276 PubMed DOI PMC

Tabata J., Hattori Y., Sakamoto H., Yukuhiro F., Fujii T., Kugimiya S., et al. . (2011). Male killing and incomplete inheritance of a novel spiroplasma in the moth Ostrinia zaguliaevi. Microb. Ecol. 61, 254–263. 10.1007/s00248-010-9799-y PubMed DOI

Taylor M., Mediannikov O., Raoult D., Greub G. (2012). Endosymbiotic bacteria associated with nematodes, ticks and amoebae. FEMS Immunol. Med. Microbiol. 64, 21–31. 10.1111/j.1574-695X.2011.00916.x PubMed DOI

Tully J. G., Rose D. L., Yunker C. E., Carle P., Bové J. M., Williamson D. L., et al. . (1995). Spiroplasma ixodetis sp. nov., a new species from Ixodes pacificus ticks collected in Oregon. Int. J. Syst. Bacteriol. 45, 23–28. 10.1099/00207713-45-1-23 PubMed DOI

Turell M. J. (2007). Role of ticks in the transmission of Crimean-Congo hemorrhagic fever virus, in Crimean-Congo Hemorrhagic Fever: A Global Perspective, ed Ergonul O., Whitehouse C. A. (Dordrecht: Springer Press; ), 143–154.

Uilenberg G. (2006). Babesia-a historical overview. Vet. Parasitol. 138, 3–10. 10.1016/j.vetpar.2006.01.035 PubMed DOI

Vayssier-Taussat M., Kazimirova M., Hubalek Z., Hornok S., Farkas R., Cosson J. F., et al. . (2015). Emerging horizons for tick-borne pathogens: from the “one pathogen-one disease” vision to the pathobiome paradigm. Future Microbiol. 10, 2033–2043. 10.2217/fmb.15.114 PubMed DOI PMC

Venzal J. M., Estrada-Peña A., Castro O., de Souza C. G., Félix M. L., Nava S., et al. . (2008). Amblyomma triste Koch, 1844 (Acari: Ixodidae): hosts and seasonality of the vector of Rickettsia parkeri in Uruguay. Vet. Parasitol. 155, 104–109. 10.1016/j.vetpar.2008.04.017 PubMed DOI

Villar M., Ayllón N., Alberdi P., Moreno A., Moreno M., Tobes R., et al. . (2015a). Integrated metabolomics, transcriptomics and proteomics identifies metabolic pathways affected by Anaplasma phagocytophilum infection in tick cells. Mol. Cell Proteomics. 14, 3154–3172. 10.1074/mcp.M115.051938 PubMed DOI PMC

Villar M., Ayllón N., Kocan K. M., Bonzón-Kulichenko E., Alberdi P., et al. . (2015b). Identification and characterization of Anaplasma phagocytophilum proteins involved in infection of the tick vector, Ixodes scapularis. PLoS ONE 10:e0137237. 10.1371/journal.pone.0137237 PubMed DOI PMC

Vlachou D., Schlegelmilch T., Christophides G. K., Kafatos F. C. (2005). Functional genomic analysis of midgut epithelial responses in Anopheles during Plasmodium invasion. Curr. Biol. 15, 1185–1195. 10.1016/j.cub.2005.06.044 PubMed DOI

Wagemakers A., Coumou J., Schuijt T. J., Oei A., Nijhof A. M., van 't Veer C., et al. . (2016). An Ixodes ricinus tick salivary lectin pathway inhibitor protects Borrelia burgdorferi sensu lato from human complement. Vector Borne Zoonotic Dis. 16, 223–228. 10.1089/vbz.2015.1901 PubMed DOI

Wang J. L., Zhang J. L., Chen W., Xu X. F., Gao N., Fan D. Y., et al. . (2010). Roles of small GTPase Rac1 in the regulation of actin cytoskeleton during dengue virus infection. PLoS Negl. Trop. Dis. 4:e809. 10.1371/journal.pntd.0000809 PubMed DOI PMC

Weisheit S., Villar M., Tykalová H., Popara M., Loecherbach J., Watson M., et al. . (2015). Ixodes scapularis and Ixodes ricinus tick cell lines respond to infection with tick-borne encephalitis virus: transcriptomic and proteomic analysis. Parasit. Vectors 8, 599. 10.1186/s13071-015-1210-x PubMed DOI PMC

Williams-Newkirk A. J., Rowe L. A., Mixson-Hayden T. R., Dasch G. A. (2012). Presence, genetic variability, and potential significance of “Candidatus Midichloria mitochondrii” in the lone star tick Amblyomma americanum”. Exp. Appl. Acarol. 58, 291–300. 10.1007/s10493-012-9582-5 PubMed DOI PMC

Yokoyama N., Okamura M., Igarashi I. (2006). Erythrocyte invasion by Babesia parasites: current advances in the elucidation of the molecular interactions between the protozoan ligands and host receptors in the invasion stage. Vet. Parasitol. 138, 22–32. 10.1016/j.vetpar.2006.01.037 PubMed DOI

Zchori-Fein E., Bourtzis K. (2011). Manipulative Tenants: Bacteria Associated with Arthropods. New York, NY: CRC Press.

Zhang L., Zhang Y., Adusumilli S., Liu L., Narasimhan S., Dai J., et al. . (2011). Molecular interactions that enable movement of the Lyme disease agent from the tick gut into the hemolymph. PLoS Pathog. 7:e1002079. 10.1371/journal.ppat.1002079 PubMed DOI PMC

Zhang X., Norris D. E., Rasgon J. L. (2011). Distribution and molecular characterization of Wolbachia endosymbionts and filarial nematodes in Maryland populations of the lone star tick (Amblyomma americanum). FEMS Microbiol. Ecol. 77, 50–56. 10.1111/j.1574-6941.2011.01089.x PubMed DOI PMC

Zhong J., Jasinskas A., Barbour A. G. (2007). Antibiotic treatment of the tick vector Amblyomma americanum reduced reproductive fitness. PLoS ONE 2:e405. 10.1371/journal.pone.0000405 PubMed DOI PMC

Experimental Infection of Mice and Ticks with the Human Isolate of Anaplasma phagocytophilum NY-18

Evaluation of two artificial infection methods of live ticks as tools for studying interactions between tick-borne viruses and their tick vectors

Tick defensin γ-core reduces Fusarium graminearum growth and abrogates mycotoxins production with high efficiency

Enlisting the Ixodes scapularis Embryonic ISE6 Cell Line to Investigate the Neuronal Basis of Tick-Pathogen Interactions

The bacterial community of the lone star tick (Amblyomma americanum)

Editorial: Biological Drivers of Vector-Pathogen Interactions

Comparative proteomics of the vector Dermacentor reticulatus revealed differentially regulated proteins associated with pathogen transmission in response to laboratory infection with Rickettsia slovaca

Environmental and Molecular Drivers of the α-Gal Syndrome

Counterattacking the tick bite: towards a rational design of anti-tick vaccines targeting pathogen transmission

A bite so sweet: the glycobiology interface of tick-host-pathogen interactions

Functional Evolution of Subolesin/Akirin

Use of Graph Theory to Characterize Human and Arthropod Vector Cell Protein Response to Infection With Anaplasma phagocytophilum

The Complexity of Piroplasms Life Cycles

Reptile-associated Borrelia species in the goanna tick (Bothriocroton undatum) from Sydney, Australia

Ticks and Tick-Borne Pathogens of the Caribbean: Current Understanding and Future Directions for More Comprehensive Surveillance

Anaplasma phagocytophilum MSP4 and HSP70 Proteins Are Involved in Interactions with Host Cells during Pathogen Infection

Combination of RT-PCR and proteomics for the identification of Crimean-Congo hemorrhagic fever virus in ticks

Functional Redundancy and Ecological Innovation Shape the Circulation of Tick-Transmitted Pathogens