Tick modulation of host immunity: an important factor in pathogen transmission

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Abstract

Immunological interactions at the tick–host interface involve innate and specific acquired host immune defenses and immunomodulatory countermeasures by the tick. Tick feeding stimulates host immune response pathways involving antigen-presenting cells, cytokines, B-cells, T-cells, circulating and homocytotropic antibodies, granulocytes, and an array of biologically active molecules. In response to host immune defenses, tick-mediated host immunosuppressive countermeasures inhibit: host antibody responses; complement activation; T-cell proliferation; and cytokine elaboration by macrophages and Th1-lymphocytes. Immunosuppressive proteins identified in tick salivary glands and saliva have been partially characterised. Tick-induced host immunosuppression facilitates blood meal acquisition and is an important factor in the transmission/establishment of the tick-borne disease-causing agent, Borrelia burgdorferi. A novel strategy for control of tick-borne pathogens is proposed.

Introduction

Disease-causing agents transmitted by blood-feeding arthropods are significant public health concerns[1]. In addition to the emergence of new diseases, many well-recognised vector-borne diseases are occurring more frequently and are increasing the range over which they occur. Many factors contribute to the emergence and re-emergence of arthropod-borne diseases: insecticide/acaricide resistance; drug resistance; economic and social factors; environmental change; and genetic changes in the vector-borne pathogens1, 2.

On a global basis, ticks are second only to mosquitoes as vectors of disease-causing agents to humans, and they are the most important arthropod transmitting pathogens to other animal species[3]. The public health importance of ticks is not diminishing. Furthermore, new tick-borne disease causing agents are being discovered. Lyme borreliosis, caused by Borrelia burgdorferi, occurs in regions with temperate climates, and it is the most frequently reported vector-borne disease in the United States[4]. In the United States, the vectors of B. burgdorferi are Ixodes scapularis in the east and midwest and Ixodes pacificus in the west[5]. In addition to B. burgdorferi, I. scapularis is a vector of the human pathogens: Babesia microti[6]; the causative agent of human granulocytic ehrlichiosis[7]; and a recently described encephalitis-like virus[8]. In addition, Ehrlichia chaffeensis, transmitted by Amblyomma americanum, causes human monocytic ehrlichiosis[7], which was described as a new species in 1991[9]. Furthermore, E. chaffeensis infections have been reported from Europe and Africa[7]. Throughout the world, it would be surprising if new emerging and re-emerging tick-borne diseases are not encountered in the coming years.

The tick is clearly not just a crawling hypodermic needle and syringe with regard to the transmission of tick-borne pathogens. Tick-transmitted infectious agents undergo developmental cycles within the vector. The microorganisms can express molecules during the vector phase that are not evident during infection of the mammalian host. The outer surface lipoprotein OspA is expressed by B. burgdorferi within the unfed tick, but it is down regulated upon initiation of blood-feeding[10]. As OspA expression is being reduced, expression of the lipoprotein OspC is being upregulated. Likewise, the 6.6 kDa outer membrane associated lipoprotein of B. burgdorferi is expressed during the tick phase of the spirochete life cycle[11]. Recently, Borrelia hermsii was shown to undergo phenotypic changes between the mammalian host and the tick vector, Ornithodoros hermsi[12]. Additional factors of great importance in tick feeding and pathogen transmission are the number and diversity of pharmacologically active molecules in tick saliva. Those activities include anti-coagulants; inhibitors of platelet aggregation; vasodilators; and suppressants of host immune defenses13, 14. Ticks, as well as blood-feeding arthropods in general, are indeed `smart pharmacologists'[13]. The factors of vector specific phenotype of tick-borne pathogens and the pharmacological activities of tick saliva change the way in which we think about and study tick-borne disease-causing agents. The vector environment and pharmacological properties of vector saliva establish the fact that the arthropod is not a passive partner in the vector–host–pathogen relationship.

This report focusses on the ability of ticks to modulate host immune responses and the potential consequences of that immunosuppression for pathogen transmission. Furthermore, the inhibition of the action of tick-derived host immunosuppressants might provide a powerful, novel, strategy for the control of tick-transmitted pathogens. Rather than targeting each individual tick-borne pathogen for vaccine development, develop a vector-blocking vaccine to those tick factors essential for successful transmission and establishment of disease-causing agents.

Section snippets

Immune responses to infestation

Due to the fact that ixodid ticks acquire a blood meal over a period of days, it is easy to understand how they induce host immune responses to salivary gland derived molecules[15]. Although not the topic of this report, short-term blood feeding insects induce host immune responses to their bites. Recent reviews have been published regarding host immunity to bugs, fleas and sucking lice[16], as well as mosquitoes and flies[17]. Indeed, ectoparasitic insects stimulate an array of host innate and

Modulation of host immunity

Disease-causing microorganisms, ranging from viruses to metazoan endoparasites, are able to suppress or deviate host innate and specific acquired immune responses39, 40, 41. Some of the immunomodulatory strategies employed include: impairing the function of antigen presenting cells; reducing T-lymphocyte function; suppressing and deviating cytokine production and action; diminishing antibody responses; enzymatic cleavage of immunoglobulins; and blocking complement activation. Most infectious

Consequences for pathogen transmission

Does tick-mediated host immunosuppression have an impact upon transmission and establishment of tick-borne disease-causing agents? The evidence being accumulated indicates that tick modulation of host immunity is an important factor in pathogen transmission. The most compelling work in this regard is that of Zeidener et al.[62]in which reconstitution of cytokines reduced by tick feeding provided protection against tick transmission of B. burgdorferi. Ramachandra and Wikel[60]reported that D.

Implications for control of tick-borne diseases

Tick-mediated host immunosuppression is an important factor in tick feeding and the transmission of tick-borne disease-causing agents. The observations regarding repeated infestation with pathogen-free ticks and the subsequent development of resistance to tick-transmitted infection is intriguing. Could a control strategy be developed that would target the factors in tick saliva that are essential for host immunosuppression and the transmission of infectious agents? Such a vector-blocking

Acknowledgements

The author's research described in this report resulted in part from support from The Centers for Disease Control and Prevention of the U.S. Public Health Service; the U.S. Department of Agriculture; the Oklahoma Center for Advancement of Science and Technology; and Oklahoma Agricultural Experiment Station Project OKL02174.

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