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Tick-borne disease systems emerge from the shadows: the beauty lies in molecular detail, the message in epidemiology

  • S. E. RANDOLPH (a1)


This review focuses on some of the more ground-shifting advances of recent decades, particularly those at the molecular and cellular level that illuminate mechanisms underpinning the natural ecology of tick-host-pathogen interactions and the consequent epidemiology of zoonotic infections in humans. Knowledge of components of tick saliva, now recognized as the central pillar in the tick's ability to complete its blood meal and the pathogen's differential ability to use particular hosts for transmission, has burgeoned with new molecular techniques. Functional studies have linked a few of them to saliva-assisted transmission of non-systemic infections between co-feeding ticks, the quantitative key to persistent cycles of the most significant tick-borne pathogen in Europe. Human activities, however, may be equally important in determining dynamic patterns of infection incidence in humans.


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Alekseev, A. N. and Chunikhin, S. P. (1990). Exchange of tick-borne encephalitis virus between Ixodidae simultaneously feeding on the animals with sub-threshold levels of viraemia. Meditsinskaya Parazitologiya i Parazitarnye Bolezni 2, 4850.
Alekseev, A. N., Chunikhin, S. P., Rukhkyan, M. Y. and Stefutkina, L. F. (1991). Possible role of Ixodidae salivary gland substrate as an adjuvant enhancing arbovirus transmission. Meditsinskaya Parazitologiya i Parazitarnye Bolezni 1, 2831.
Anderson, J. F. and Valenzuela, J. G. (2008). Tick saliva: from pharmacology and biochemistry to transcriptome analysis and functional genomes. In Ticks: Biology, Disease and Control (ed. Bowman, A. S. and Nuttall, P. A.), pp. 92–107. Cambridge University Press, Cambridge, UK.
Barbour, A. G. and Fish, D. (1993). The biological and social phenomenon of Lyme disease. Science 260, 16101616.
Barnard, C. J., Behnke, J. M. and Sewell, J. (1994). Social behaviour and susceptibility to infection in house mice (Mus musculus): effects of group size, aggressive behaviour and status-related hormonal responses prior to infection on susceptibility to Babesia microti. Parasitology 108, 487496.
Brossard, M. and Wikel, S. K. (2008). Tick immunobiology. In Ticks: Biology, Disease and Control (ed. Bowman, A. S. and Nuttall, P. A.), pp. 186204. Cambridge University Press, Cambridge, UK.
Bubeck-Martinez, S. (2005). Immune evasion of the Lyme disease spirochetes. Frontiers of Biosciences 10, 873878.
Burgdorfer, W., Barbour, A. G., Hayes, S. F., Benach, J. L., Grunwaldt, E. and Davies, J. P. (1982). Lyme disease – a tick-borne spirochetosis? Science 220, 321322.
Cadenas, F. M., Rais, O., Humair, P.-F., Douet, V., Moret, J. and Gern, L. (2007). Identification of host bloodmeal source and Borrelia burgdorferi sensu lato in field-collected Ixodes ricinus ticks in Chaumont (Switzerland). Journal of Medical Entomology 44, 11091117.
Cumming, G. S. (1998). Host preference in African ticks (Acari: Ixodidae): a quantitative data set. Bulletin of Entomological Research 88, 379406.
Dawkins, R. and Krebs, J. R. (1979). Arms races between and within species. Proceedings of the Royal Society of London, B 205, 489511.
Derdakova, M., Dudioak, V., Brei, B., Brownstein, J. S., Schwartz, I. and Fish, D. (2008). Interaction and transmission of two Borrelia burgdorferi sensu stricto strains in a tick-rodent maintenance system. Applied and Environmental Microbiology 70, 67836788.
Diekmann, O. and Heesterbeek, J. A. P. (2000). Mathematical Epidemiology of Infectious Diseases: Model Building, Analysis and Interpretation, John Wiley and Sons, Ltd, New York, USA.
Diekmann, O., Heesterbeek, J. A. P. and Metz, J. A. (1990). On the definition and the computation of the basic reproduction ratio R0 in models for infectious diseases in heterogeneous populations. Journal of Mathematical Biology 28, 365382.
Dizij, A. and Kurtenbach, K. (1995). Clethrionomys glareolus, but not Apodemus flavicollis, acquires resistance to Ixodes ricinus L., the main European vector of Borrelia burgdorferi. Parasite Immunology 17, 177183.
Dumler, J. S. and Walker, D. H. (2001). Tick-borne ehrlichiosis. Lancet (Suppl. S), 2128.
Gern, L. and Rais, O. (1996). Efficient transmission of Borrelia burgdorferi between cofeeding Ixodes ricinus ticks (Acari: Ixodidae). Journal of Medical Entomology 33, 189192.
Gilbert, L., Norman, R., Laurenson, M. K., Reid, H. W. and Hudson, P. J. (2001). Disease persistence and apparent competition in a three-host community: an empirical and analytical study of large-scale, wild populations. Journal of Animal Ecology 70, 10531061.
Gilmore, R. D., Mbow, M. L. and Stevenson, B. (2001). Analysis of Borrelia burgdorferi gene expression during life cycle phases of the tick Ixodes scapularis. Microbes and Infection 3, 799808.
Grossman, C. J. (1985). Interaction between the gonadal steroids and the immune system. Science 227, 257261.
Hanincova, K., Ogden, N. H., Diuk-Wasser, M., Pappas, C. J., Iyer, R., Fish, D., Schwartz, I. and Kurtenbach, K. (2008). Fitness variation of Borrelia burgdorferi sensu stricto strains in mice. Applied and Environmental Microbiology 74, 153157.
Hannier, S., Liversidge, J., Sternberg, J. M. and Bowman, A. S. (2004). Characterization of the B-cell inhibitory protein factor in Ixodes ricinus tick saliva: a potential role in enhanced Borrelia burgdorferi transmission. Immunology 113, 401408.
Hartemink, N. A., Randolph, S. E., Davis, S. A. and Heesterbeek, J. A. P. (2008). The basic reproduction number for complex disease systems: defining R 0 for tick-borne infections. The American Naturalist 171, 743754.
Horak, I. G., Fourie, L. J., Novelle, P. A. and Williams, E. J. (1991). Parasites of domestic and wild animals in South Africa. XXVI. The mosaic of Ixodid tick infestations on birds and mammals in the Mountain Zebra National Park. Onderstepoort Journal of Veterinary Research 58, 125136.
Hu, C. M., Cheminade, Y., Perret, J.-L., Weynants, V., Lobet, Y. and Gern, L. (2003). Early detection of Borrelia burgdorferi sensu lato infection in Balb/c mice by co-feeding Ixodes ricinus ticks. International Journal of Medical Microbiology 293, 421426.
Huegli, D., Hu, C. M., Humair, P.-F., Wilske, B. and Gern, L. (2002). Apodemus species mice, reservoir hosts of Borrelia garinii OspA serotype 4 in Switzerland. Journal of Clinical Microbiology 40, 47354737.
Hughes, V. L. and Randolph, S. E. (2001 a). Testosterone depresses innate and acquired resistance to ticks in natural rodent hosts: a force for aggregated distributions of parasites. Journal of Parasitology 87, 4954.
Hughes, V. L. and Randolph, S. E. (2001 b). Testosterone increases the transmission potential of tick-borne parasites. Parasitology 123, 365371.
Humair, P.-F., Peter, O., Wallich, B. and Gern, L. (1995). Strain variation of Lyme disease spirochetes isolated from Ixodes ricinus ticks and rodents collected in two endemic areas in Switzerland. Journal of Medical Entomology 32, 433438.
Humair, P.-F., Postic, D., Wallich, R. and Gern, L. (1998). An avian reservoir (Turdus merula) of the Lyme borreliosis spirochetes. Zentralblatt für Bakteriologie 287, 521538.
Humair, P.-F., Rais, O. and Gern, L. (1999). Transmission of Borrelia afzelii from Apodemus mice and Clethrionomys voles to Ixodes ricinus ticks: differential transmission pattern and overwintering maintenance. Parasitology 118, 3342.
Jones, L. D., Davies, C. R., Steele, G. M. and Nuttall, P. A. (1987). A novel mode of arbovirus transmission involving a nonviraemic host. Science 237, 775777.
Jones, L. D., Hodgson, E. and Nuttall, P. A. (1989). Enhancement of virus transmission by tick salivary glands. Journal of General Virology 70, 18951898.
Kimura, K., Isogal, E., Isogal, H., Kamewaka, Y., Nishikawa, T., Ishii, N. and Fujii, N. (1995). Detection of Lyme disease spirochetes in the skin of naturally infected wild sika deer (Cervus nippon yesoensis) by PCR. Applied and Environmental Microbiology 61, 16411642.
Kirstein, F. and Gray, J. S. (1996). A molecular marker for the identification of the zoonotic reservoirs of the Lyme borreliosis by analysis of the blood meal in its European vector Ixodes ricinus. Applied and Environmental Microbiology 62, 40604065.
Kjemtrup, A. M. and Conrad, P. A. (2000). Human babesiosis: an emerging tick-borne disease. International Journal for Parasitology 30, 13231337.
Krocova, Z., Macela, A., Hernychova, I., Kroca, M., Pechova, J. and Kopecky, J. (2003). Tick salivary gland extract accelerates proliferation of Franciscella tularensis in the host. Journal of Parasitology 89, 1420.
Kurtenbach, K., Carey, D., Hoodless, A. N., Nuttall, P. A. and Randolph, S. E. (1998 a). Competence of pheasants as reservoirs for Lyme disease spirochetes. Journal of Medical Entomology 35, 7781.
Kurtenbach, K., De Michelis, S., Etti, S., Schäfer, S. M., Sewell, H.-S., Vbrade, V. and Kraiczy, P. (2002 a). Host association of Borrelia burgdorferi sensu lato – the key role of host complement. Trends in Microbiology 10, 7479.
Kurtenbach, K., De Michelis, S., Sewell, H.-S., Etti, S., Schäfer, S. M., Hails, R., Collares-Pereira, M., Santos-Reis, M., Hanincova, K., Labuda, M., Bormane, A. and Donaghy, M. (2001). Distinct combinations of Borrelia burgdorferi sensu lato genospecies found in individual questing ticks from Europe. Applied and Environmental Microbiology 67, 49264929.
Kurtenbach, K., Dizij, A., Seitz, H. M., Margos, G., Moter, S. E., Kramer, M. D., Wallich, R., Schaible, U. E. and Simon, M. M. (1994). Differential immune responses to Borrelia burgdorferi in European wild rodent species influence spirochete transmission to Ixodes ricinus L. (Acari: Ixodidae). Infection and Immunity 62, 53445352.
Kurtenbach, K., Peacey, M. F., Rijpkema, S. G. T., Hoodless, A. N., Nuttall, P. A. and Randolph, S. E. (1998 b). Differential transmission of the genospecies of Borrelia burgdorferi sensu lato by game birds and small rodents in England. Applied and Environmental Microbiology 64, 11691174.
Kurtenbach, K., Schäfer, S. M., Sewell, H.-S., Peacey, M. F., Hoodless, A. N., Nuttall, P. A. and Randolph, S. E. (2002 b). Differential survival of Lyme borreliosis spirochetes in ticks feeding on birds. Infection and Immunity 70, 58935895.
Kurtenbach, K., Sewell, H., Ogden, N. H., Randolph, S. E. and Nuttall, P. A. (1998 c). Serum complement as a key factor in Lyme disease ecology. Infection and Immunity 66, 12481251.
Kyckova, K. and Kopecky, J. (2006). Effect of tick saliva on mechanisms of innate immune response against Borrelia afzelii. Journal of Medical Entomology 43, 12081214.
Labuda, M., Austyn, J. M., Zuffova, E., Kozuch, O., Fuchsberger, N., Lysy, J. and Nuttall, P. A. (1996). Importance of localized skin infection in tick-borne encephalitis virus transmission. Virology 219, 357366.
Labuda, M., Jones, L. D., Williams, T., Danielová, V. and Nuttall, P. A. (1993 a). Efficient transmission of tick-borne encephalitis virus between cofeeding ticks. Journal of Medical Entomology 30, 295299.
Labuda, M., Jones, L. D., Williams, T. and Nuttall, P. A. (1993 b). Enhancement of tick-borne encephalitis virus transmission by tick salivary gland extracts. Medical and Veterinary Entomology 7, 193196.
Labuda, M., Nuttall, P. A., Kozuch, O., Eleckova, E., Williams, T., Zuffova, E. and Sabo, A. (1993 c). Non-viraemic transmission of tick-borne encephalitis virus: a mechanism for arbovirus survival in nature. Experientia 49, 802805.
Labuda, M., Trimnell, A. R., Lickova, M., Kazimirova, M., Davies, G. M., Lissina, O., Hails, R. S. and Nuttall, P. A. (2006). An antivector vaccine protects against a lethal vector-borne pathogen. PLoS Pathogens 2, 02510259.
Lawrie, C. H., Randolph, S. E. and Nuttall, P. A. (1999). Ixodes ticks: serum species sensitivity of anti-complement activity. Experimental Parasitology 93, 207214.
Lawrie, C. H., Sim, R. B. and Nuttall, P. A. (2005). Investigation of the mechanisms of anti-complement activity in Ixodes ricinus ticks. Molecular Immunology 42, 3138.
LoGiudice, K., Ostfeld, R. S., Schmidt, K. A. and Keesing, F. (2003). The ecology of infectious disease: Effects of host diversity and community composition on Lyme disease risk. Proceedings of the National Academy of Sciences, USA 100, 567571.
Machackova, M., Obornik, M. and Kopecky, J. (2006). Effect of salivary gland extract from Ixodes ricinus ticks on the proliferation of Borrelia burgdorferi sensu stricto in vivo. Folia Parasitologica 53, 153158.
Norval, R. A. I. and Rechav, Y. (1979). An assembly pheromone and its perception in the tick Amblyomma variegatum (Acarina: Ixodidae). Journal of Medical Entomology 16, 507511.
Nuttall, P. A. (1998). Displaced tick-parasite interactions at the host interface. Parasitology 116, S65S72.
Nuttall, P. A. and Labuda, M. (2008). Saliva-assisted transmission of tick-borne pathogens. In Ticks: Biology, Disease and Control (ed. Bowman, A. S. and Nuttall, P. A.), pp. 205219. Cambridge University Press, Cambridge, UK.
Ogden, N. H., Bigras-Poulin, M., Hanincova, K., Maarouf, A., O'Callaghan, C. J. and Kurtenbach, K. (2008). Projected effects of climate change on tick phenology and fitness of pathogens transmitted by the North American tick Ixodes scapularis. Journal of Theoretical Biology 254, 621632.
Ogden, N. H., Nuttall, P. A. and Randolph, S. E. (1997). Natural Lyme disease cycles maintained via sheep by co-feeding ticks. Parasitology 115, 591599.
Parola, P., Paddock, C. D. and Raoult, D. (2005). Tick-borne rickettsiosis around the world: emerging diseases challenging old concepts. Clinical Microbiology Reviews 18, 719756.
Parola, P., Socolovschi, C., Jeanjean, L., Bitam, I., Fournier, P.-E., Sotto, A., Labauge, P. and Raoult, D. (2008). Warmer weather linked to tick attack and emergence of severe rickettsiosis. PLoS Neglected Tropical Diseases 2, e338.
Pechová, J., Stepánová, G., Kovár, L. and Kopecky, J. (2002). Tick salivary gland extract-activated transmission of Borrelia afzelii spirochaetes. Folia Parasitologica 49, 153159.
Pichon, B., Egan, D., Rogers, M. and Gray, J. S. (2003). Detection and identification of pathogens and host DNA in unfed host-seeking Ixodes ricinus L. (Acari: Ixodidae). Journal of Medical Entomology 40, 723731.
Piesman, J. and Gern, L. (2008). Lyme borreliosis in Europe and North America. In Ticks: Biology, Disease and Control (ed. Bowman, A. S. and Nuttall, P. A.), pp. 220252. Cambridge University Press, Cambridge, UK.
Ramamoorthi, N., Narasimhan, S. and Pal, U. (2005). The Lyme disease agent exploits a tick protein to infect the mammalian host. Nature, London 436, 573577.
Randolph, S. E. (1977). Changing spatial relationships in a population of Apodemus sylvaticus with the onset of breeding. Journal of Animal Ecology 46, 653676.
Randolph, S. E. (1979). Population regulation in ticks: the role of acquired resistance in natural and unnatural hosts. Parasitology 79, 141156.
Randolph, S. E. (1994). Density-dependent acquired resistance to ticks in natural hosts, independent of concurrent infection with Babesia microti. Parasitology 108, 413419.
Randolph, S. E. (1995). Quantifying parameters in the transmission of Babesia microti by the tick Ixodes trianguliceps amongst voles (Clethrionomys glareolus). Parasitology 110, 287295.
Randolph, S. E. (2000). Ticks and tick-borne disease systems in space and from space. Advances in Parasitology 47, 217243.
Randolph, S. E. (2001). Tick-borne encephalitis in Europe. Lancet 358, 17311732.
Randolph, S. E. (2004). Tick ecology: processes and patterns behind the epidemiological risk posed by ixodid ticks as vectors. Parasitology 129, S37S66.
Randolph, S. E., Asokliene, L., Avsic-Zupanc, T., Bormane, A., Burri, C., Golovljova, I., Hubalek, Z., Knap, N., Kondrusik, M., Kupca, A., Pejcoch, M., Vasilenko, V. and Žygutiene, M. (2008). Variable spikes in TBE incidence in 2006: independent of variable tick abundance but related to weather. Parasites & Vectors 1, e44.
Randolph, S. E., Gern, L. and Nuttall, P. A. (1996). Co-feeding ticks: epidemiological significance for tick-borne pathogen transmission. Parasitology Today 12, 472479.
Randolph, S. E., Green, R. M., Hoodless, A. N. and Peacey, M. F. (2002). An empirical quantitative framework for the seasonal population dynamics of the tick Ixodes ricinus. International Journal for Parasitology 32, 979989.
Randolph, S. E., Green, R. M., Peacey, M. F. and Rogers, D. J. (2000). Seasonal synchrony: the key to tick-borne encephalitis foci identified by satellite data. Parasitology 121, 1523.
Randolph, S. E., Miklisová, D., Lysy, J., Rogers, D. J. and Labuda, M. (1999). Incidence from coincidence: patterns of tick infestations on rodents facilitate transmission of tick-borne encephalitis virus. Parasitology 118, 177186.
Randolph, S. E. and Šumilo, D. (2007). Tick-borne encephalitis in Europe: dynamics of changing risk. In Emerging Pests and Vector-borne Disease in Europe (ed. Takken, W. and Knols, B. G. J.), pp. 187206. Wageningen Academic Publishers, The Netherlands.
Ribeiro, J. M. C. (1989). Role of saliva in tick/host interactions. Experimental and Applied Acarology 7, 1520.
Ribeiro, J. M. C., Alarcon-Chaidez, F., Francishetti, I. M. B., Mans, B. J., Mather, T. N., Valenzuela, J. G. and Wikel, S. K. (2006). An annotated catalog of salivary gland transcripts from Ixodes scapularis ticks. Insect Biochemistry and Molecular Biology 36, 111129.
Rosa, R., Pugliese, A., Norman, R. and Hudson, P. J. (2003). Thresholds for disease persistence in models for tick-borne infections including non-viraemic transmission, extended feeding and tick aggregation. Journal of Theoretical Biology 224, 359376.
Spielman, A., Wilson, M. L., Levine, J. F. and Piesman, J. (1985). Ecology of Ixodes dammini-borne human babesiosis and Lyme disease. Annual Review of Entomology 30, 439460.
Steere, A. C., Malawista, S. E., Snydman, D. R., Shope, R. E., Andiman, W. A., Ross, M. R. and Steele, F. M. (1977). Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three Connecticut communities. Arthritis and Rheumatism 20, 7–17.
Stevenson, B., El-Hage, N., Hines, M. A., Miller, J. C. and Babb, K. (2002). Differential binding of host complement inhibitor factor H by Borrelia burgdorferi Erp surface proteins: a possible mechanism underlying the expansive host range of Lyme disease spirochetes. Infection and Immunity 70, 491497.
Šumilo, D., Asokliene, L., Avsic-Zupanc, T., Bormane, A., Vasilenko, V., Lucenko, I., Golovljova, I. and Randolph, S. E. (2008 a). Behavioural responses to perceived risk of tick-borne encephalitis: vaccination and avoidance in the Baltics and Slovenia. Vaccine 26, 25802588.
Šumilo, D., Asokliene, L., Bormane, A., Vasilenko, V., Golovljova, I. and Randolph, S. E. (2007). Climate change cannot explain the upsurge of tick-borne encephalitis in the Baltics. PLoS ONE, 2, e500.
Šumilo, D., Bormane, A., Asokliene, L., Vasilenko, V., Golovljova, I., Avsic-Zupanc, T., Hubalek, Z. and Randolph, S. E. (2008 b). Socio-economic factors in the differential upsurge of tick-borne encephalitis in Central and Eastern Europe. Reviews in Medical Virology 18, 8195.
Trager, W. (1939). Acquired immunity to ticks. Journal of Parasitology 25, 5781.
Wang, G. and Nuttall, P. A. (1995). Immunoglobulin-G binding proteins in the ixodid ticks, Rhipicephalus appendiculatus, Amblyomma variegatum and Ixodes hexagonus. Parasitology 111, 161165.
Wang, H., Paesen, G. C. and Nuttall, P. A. (1998). Male ticks help their mates to feed. Nature, London 391, 753754.
Wikel, S. K. (1996). Host immunity to ticks. Annual Review of Entomology 41, 122.
Wikel, S. K. and Allen, J. R. (1977). Acquired resistance to ticks. III. Cobra venom factor and the resistance response. Immunology 32, 457465.
Woolhouse, M. E. J., Dye, C., Etard, J. F., Smith, T., Charlwood, J. D., Garnett, G. P., Hagan, P., Hii, J. L. K., Ndhlovu, P. D., Quinnell, R. J., Watts, C. H., Chandiwana, S. K. and Anderson, R. M. (1997). Heterogeneities in the transmission of infectious agents: Implications for the design of control programs. Proceedings of the National Academy of Sciences, USA 94, 338342.
Zeider, N. S., Schneider, B. S., Nuncio, M. S., Gern, L. and Piesman, J. (2002). Coinoculation of Borrelia spp. with tick salivary gland lysate enhances spirochete load in mice and is tick species-specific. Journal of Parasitology 88, 12761278.


Tick-borne disease systems emerge from the shadows: the beauty lies in molecular detail, the message in epidemiology

  • S. E. RANDOLPH (a1)


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