Modulation of the Host Immune System by Ectoparasitic Arthropods

This is the authors' abstract. We don't add key points for this paper.

The first things that come to mind when people think about ectoparasitic arthropods are the nuisance they cause, the irritation induced by their bites, and the disease-causing agents they transmit. Ectoparasitic insects and arachnids are often thought of as crawling or flying hypodermic needles and syringes that merely suck blood and inject disease-causing agents. However, the relationships between ectoparasitic arthropods and their hosts are far more complex. The saliva of blood-feeding arthropods contains a complex array of pharmacologically active molecules that help them evade host antihemostatic defenses. These compounds include inhibitors of platelet aggregation, blockers of both the intrinsic and extrinsic blood coagulation cascades, and vasodilators (Ribeiro 1995, Champagne and Valenzuela 1996). Such antihemostatic compounds have been identified in mosquitoes, sand flies, black flies, biting midges, stable flies, horseflies, tsetse flies, kissing bugs, fleas, argasid ticks, and ixodid ticks (Ribeiro 1995). Ectoparasitic arthropods also contain compounds that help them evade the effects of host grooming, a process that represents a significant threat to ectoparasitic arthropods, especially long-term blood feeders. For example, saliva of the tick Ixodes dammini (= Ixodes scapularis;Figure 1) contains a kininase. This enzyme is capable of destroying bradykinin (Ribeiro et al. 1985), a mediator involved in the sensation of itch (Alexander 1986). The likelihood of successful parasitism is increased by reducing host awareness of the arthropod at the cutaneous surface. Arthropod-mediated host immunosuppression provides a favorable environment for the establishment of vector-borne pathogens Feeding larvae of the tick Ixodes scapularis on mouse skin. This tick is a vector of Lyme disease in the eastern and central United States. Electron micrograph: George B. Schoeler. Molecules that inhibit host antihemostatic defenses and cutaneous irritation are only two examples of pharmacological activities associated with the saliva of ectoparasitic arthropods. Undoubtedly, many additional molecules that facilitate survival and feeding remain to be discovered. However, sufficient evidence is already available to support the assertion that blood-feeding arthropods are indeed “smart” pharmacologists (Ribeiro 1995). Ectoparasitic arthropods also do not act merely as needles in transmitting disease. In fact, vector transmission of a disease-causing agent can result in the development of different host responses than those induced by needle inoculation of the same pathogen. For example, the hamster antibody response to the spirochete that causes Lyme disease, Borrelia burgdorferi, differs depending on whether the spirochetes are transmitted by tick bite or needle inoculation (Roehrig et al. 1992). Tick-transmitted B. burgdorferi do not induce the development of antibodies to the spirochete outer surface protein Osp A. By contrast, needle-inoculated spirochetes grown in culture induce anti-Osp A antibodies. The basis for this difference is that spirochete expression of Osp A is down-regulated when an infected tick takes a blood meal; consequently, the spirochetes transmitted to the host have little, if any, Osp A (Schwan et al. 1995, Schwan 1996). In this situation, the host response reflects a change in immunogen expression by the disease-causing agent in the feeding vector. Furthermore, mice infected with B. burgdorferi by feeding of the tick Ixodes ricinus are more likely to transmit the spirochete back to the tick than mice infected by needle inoculation of spirochetes (Gern et al. 1993). The complexity of host immune responses to disease-causing agents is increased by the fact that infectious agents have themselves developed strategies for evading host defenses (Dessaint and Capron 1993, Marrack and Kapler 1994, Kotwal 1996). Viruses, prokaryotic microorganisms, and eukaryotic endopara-sites are able to modulate host immunity, both innate and acquired (Dessaint and Capron 1993, Marrack and Kapler 1994, Kotwal 1996). Innate immunity comprises those nonspecific factors that represent rapid, preprogrammed first lines of defense. By contrast, specific acquired immunity requires the stimulation, expansion, and differentiation of B and/or T lymphocytes with receptors that are specific for the inducing substance. Infectious agents modulate both nonspecific innate and specific acquired immune defenses by varying surface antigens, engaging in molecular mimicry of host immunogens, residing within cells or tissues that render them inaccessible to immune attack, inducing tolerance, impairing antigen processing, diverting host immune responses toward molecules that are not essential for survival, modulating complement function, altering expression of surface molecules on cells of the immune system, covering themselves with host molecules, and altering cytokine responses. Rather than totally eliminating the infectious agent, the immune responses induced by endoparasitic protozoa and helminths often result in a balance between a level of persistent infection (after elimination of most of the initial infection) and resistance to reinfection (Dessaint and Capron 1993). This phenomenon is known as concomitant immunity (Sher and Scott 1993). The balance between continued stimulation of immune defenses by the persistent infectious agent and resistance to additional infection (i.e., in an environment in which exposure to the infectious agent might be frequent over time) provides a biological advantage to the host. The spectrum of immune interactions between blood-feeding arthropods and hosts therefore becomes more complex when vector-borne pathogens are added to the mix. Both vector-borne disease-causing agents and blood-feeding arthropods interact in complex ways with host immune defenses (Wikel 1996, Wikel et al. 1996, Wikel and Bergman 1997). Ectoparasitic arthropods are vectors of a variety of viruses, rickettsiae, bacteria, protozoa, and helminths, and each of these pathogens has complex interactions with the host and vector (Beaty and Marquardt 1996). In light of the fact that infectious agents from viruses to eukaryotic parasites modulate host defenses, it is not surprising that ectoparasitic arthropods can immunosuppress their hosts in the same way that infectious agents do (Wikel 1996, Wikel et al. 1996, Wikel and Bergman 1997). However, the relationship between arthropods and the host immune system is more complicated. At the same time as they down-regulate host innate and specific acquired immune defenses, ectoparasitic arthropods induce host responses that impair their ability to feed and infest (Wikel 1982a, 1982b, 1996, Arlian 1996, Sandeman 1996, Wikel et al. 1996). Successful ectoparasitic arthropods appear to achieve a balance between host immunity, which prevents an overwhelming infestation, and down-regulation of host defenses. Ectoparasitic arthropod suppression of host immunity almost certainly evolved to facilitate blood feeding and survival within host tissues (Arlian 1996, Sandeman 1996, Wikel et al. 1996). Coincidentally, arthropod-mediated host immunosuppression provides a favorable environment for the establishment of vector-borne pathogens (Wikel et al. 1996, Zeidner et al. 1996, Wikel and Bergman 1997). This favorable environment reflects the fact that the host immune regulatory and effector responses that are suppressed by arthropods are the same ones that are needed to respond effectively to vector-borne disease-causing agents (Playfair 1993, Wikel et al. 1996). In this article, I show that ectoparasitic arthropod suppression of host immune defenses is, indeed, an important factor for both successful infestation and successful pathogen transmission. In addition, I discuss how an understanding of the modulation of host immune responses by vector arthropods will change the way in which biologists study the transmission, establishment, and pathogenesis of vector-borne pathogens and the immune responses to these pathogens. Before examining how ectoparasitic arthropods modulate host immunity, it is necessary to comment briefly on anti-arthropod immune responses induced by infestation. (Comprehensive reviews have been published on host immune responses induced by infestation with bugs, fleas, and sucking lice [Jones 1996]; mosquitoes and flies [Sandeman 1996]; scabies mites [Arlian 1996]; mange mites and chiggers [Wrenn 1996]; and ticks [Wikel 1996].) Host responses to ectoparasitic arthropods vary greatly, depending on the host-parasite relationship. However, in most cases ectoparasitic insects and arachnids stimulate host immunoregulatory and effector responses involving antigen-presenting cells, T lymphocytes, B lymphocytes, antibodies, complement, mast cells, circulating granulocytes, cytokines, and other biologically active molecules (Arlian 1996, Jones 1996, Sandeman 1996, Wikel 1996, Wrenn 1996). In general, ectoparasitic arthropod-host relationships are characterized by the development of immunological resistance to reinfestation after some initial level of exposure. As stated above, in addition to inducing anti-arthropod immunity, both insects, which feed rapidly, and arachnids, which engorge slowly, modulate host immune responses (Wikel et al. 1996, Wikel and Bergman 1997). At first glance, the ability of ectoparasitic arthropods to suppress host immune defenses while eliciting antiarthropod immune responses appears paradoxical. However, the relationship of anti-arthropod immunity and arthropod modulation of host defenses is a clever balancing act that assures survival of both ectoparasite and host. Ectoparasitic arthropods only partially suppress host immune defenses (Wikel et al. 1996, Wikel and Bergman 1997). Consequently, the host can still defend against the multitude of pathogens and insults that it normally encounters. Keeping the host alive is to the advantage of the ectoparasitic arthropod. Furthermore, partial suppression of host immune defenses provides a more favorable environment for blood-feeding and tissue-migrating ectoparasitic arthropods. Although most research on arthropod modulation of host immunity focuses on ticks, which require days to feed, blood-feeding mosquitoes and biting flies, which feed in minutes, also modulate host immune responses (Bissonnette et al. 1993, Cross et al. 1993a, 1993b, 1994a, 1994b, Hall and Titus 1995). Why would an insect that takes a blood meal in minutes need to immunosuppress the host? Damage might be inflicted by the “pre-programmed” components of the innate immune defenses, which include complement, mast cells, and phagocytic cells. In addition, arthropod-specific circulating antibodies and effector T lymphocytes could be damaging if consumed in the blood meal. Homocytotropic antibodies bound to mast cells or basophils could release mediators that would damage the feeding arthropod. Furthermore, the ability to immunosuppress the host might allow large numbers of insects to attack a host over a period of days, weeks, or months. For example, infestations of a single cow with 4000 horn flies, Haematobia irritans, was reported to be a common level of infestation in Texas (Bruce 1940). The black fly, Simulium is a feeding insect that host defenses. The of the antibody response to of was by the responses of mice by flies with those of mice with et al. by developed antibodies to molecules than This that molecules in the for from the saliva with the bite or in the of to known pharmacologically active molecules in black saliva not induced in the molecules that are essential for feeding do not induce host antibodies, the likelihood of a blood meal from a host over time will be by mice with black of the and which that both circulating antibodies and immune responses. Both and developed antibodies, which would to responses to The of is et al. with this have cells complex surface than do These molecules are for the of to T lymphocytes by and other antigen-presenting cells. The of this to bite modulation of cutaneous immune the of the black on the antigen-presenting cells cells and at the bite cells are antigen-presenting cells in the et al. In addition, the of the can molecules and are reported to be able to act as antigen-presenting cells and 1993). The same the ability of B and T lymphocytes to in in the of et al. act specific immunogens, they the of T lymphocytes not those with an immunogen This of B and T lymphocytes to was not to of the to biological on the ability to lymphocytes from mice to black the same as mice et al. However, lymphocytes from black bite not it was to whether the more response the bite was additional of mice with blood cells with black in a more antibody response than with blood cells et al. This that the black contains factors that can immune responses. the basis for black on et al. are that development and effector of the immune response and the response to an infectious agent et al. 1997). is, a way to immune responses to ectoparasitic arthropods and to how the arthropods, in modulate host innate and specific acquired defenses (Wikel et al. 1996, Wikel and Bergman 1997). how might the immune mice with or an of et al. is an antigen that an immune response only in with T from mice with black with of the and in than lymphocytes from et al. of mice lymphocytes with not the of other and these that a feeding of can down-regulate host defenses. are evidence that blood-feeding flies are capable of modulating host it is that the suppression of host immunity could be a factor in the ability of these insects to effectively transmit disease-causing agents. of the sand flies and of the agent of cutaneous in the and Hall and Titus 1995). both sand are capable of modulating specific of host defenses. of the ability of to to specific T lymphocytes and Titus and saliva of as as their of and Titus 1995). These are significant in light of the that antigen-presenting cells, of T lymphocytes, can host resistance to infection and Titus 1995). flies additional host of mice with blood cells with of suppressed the ability of T lymphocytes from the mice after to in when with blood cells Furthermore, the addition of sand to mouse cells the ability of cells to when in the of A a Both that sand the immune responses of T lymphocytes to a These will have important the ability of to immune responses to disease-causing agents that are transmitted by sand In of host by the sand to the effects of infestation on the host response to both feeding and development within the of the and The of sand flies a blood meal the of host and increased the of saliva antibodies on of and the development within the fly, was to in blood with from that been by sand flies and an immune response and The of hamster antibodies to sand saliva both the infection of flies and the of parasites the of the These support the that antibodies to immunogens, when to sand flies the development of disease-causing agents within the A blood meal in a of minutes from a or from a by 1996). mosquitoes do not a blood meal. A of not the release of the cytokine from mast cells (Bissonnette et al. 1993). This which has a molecular of at is by which that it is a of this cytokine to that it host responses to cells are in the and they contain molecules that could feeding from the stimulation of in of T lymphocytes by the or et al. Furthermore, the ability of the A to induce T of and not ability to induce the release of and et al. This a on the of T which is associated with responses. is the of the of with larvae provides an for the host immune system to stimulate and interact with the arthropod. In larvae that to their with of the host innate and specific acquired defenses, be to have developed strategies to host larvae of the fly, the A and which complement comprises a of that can be by different to a variety of molecules with biological activities in and these activities include mediators from mast cells, of and et al. The of complement is by an of the pathogen or other substance. of by larvae the larvae the and of complement at for of the attack complex which could of the larvae et al. A also the ability of T lymphocytes to in when with the and A and and it the ability of T lymphocytes to which could to the in of these cells to et al. 1995). A expression of the surface and while the expression of I of the complex et al. 1997). larvae of the the agent of cutaneous in or that inhibit the of host antibody responses and 1992). larvae host defenses by that complement et al. and et al. 1995). these show that blood feeding and tissue-migrating larvae of insects are capable of modulating the immune system by a variety of ways are needed to the ability of insects to suppress host immunity, to the of to and the molecules, and to the of host immunosuppression on the transmission of disease-causing agents. examples of ectoparasitic arthropod-mediated host In to insects that a blood meal within minutes, ixodid ticks host blood over a period of days to than a them to stimulate a host immune response and interact with of that response (Wikel 1982a, 1996). tick change the of hosts are likely to be to a array of and pharmacologically active molecules (Wikel 1996). The interactions molecules and host immune defenses can result in the development of acquired host immunity to tick infestation that is as numbers and of and of feeding ticks (Wikel 1996). In light of the of feeding and the for immune by the it is not surprising that ixodid ticks have developed that suppress both innate and acquired specific host immune defenses (Wikel 1996, Wikel et al. 1996, Wikel and Bergman 1997). A balance between host immune defenses and in a in host immunity that tick feeding reducing the ability of the host to (Wikel and Bergman 1997). immunosuppression evolved to facilitate it is as an important factor in the successful transmission and establishment of host infection with disease-causing agents (Wikel 1996, Zeidner et al. 1996, Wikel and Bergman 1997). of a tick Electron micrograph: George B. Schoeler. immunosuppression host immune regulatory and effector involved in the and expression of acquired resistance to infestation (Wikel and Bergman 1997). to host innate and specific acquired defenses include the of the complement active of molecules of the complement host of complement components and reducing the of by host the of T lymphocytes, reducing cytokine by lymphocytes, and antibody responses (Wikel 1996, Wikel and Bergman 1997). of immunosuppression is cells. cells are lymphocytes, B that are tissues of the to respond to and cells surface of or infectious agents The evidence for this surprising from the that an from of partially ticks of the the ability of cells to cells in et al. A from ticks was not cells have not been to be of However, these cells have been to have important regulatory for both innate and specific acquired immune defenses 1995). For example, of is important in the response 1995). cytokine in the of tick is tick feeding to impair function, host defenses against infectious viruses, would be of complement a in the expression of immunity (Wikel of dammini the of complement factors and on that normally complement, of the complement components and reducing which the of by (Ribeiro Furthermore, dammini saliva the of the impairing the release of mast of of to and is to a saliva (Ribeiro In addition, the of dammini saliva is to a (Ribeiro and 1986). of these complement components many of the associated with and infestation also the of antibodies that can be circulating as as in the of that to mast cells and basophils by the of their (Wikel 1982a, 1996). that with antibodies bound to mast cells or basophils will those cells to release mediators of Host antibodies are an important of acquired resistance to infestation (Wikel 1982a, 1996). As a tick feeding in the of molecules that the ability of the host to an antibody response (Wikel 1996, Wikel and Bergman 1997). For example, with larvae of the tick are able than to an antibody response when with blood cells (Wikel The ability to an antibody response is infestation and after tick feeding with the tick show antibody responses the period of tick feeding of host antibody responses tick infestation could facilitate tick by reducing that might be against pharmacologically active molecules by the tick that are essential for successful A of tick immunosuppression appears to be T T lymphocytes have both and effector that are essential to the of the immune T lymphocytes are a of immunosuppression and from a host have a ability to in when in the of the and A (Wikel Although tick infestation to in the a is (Wikel In addition, suppression of responses to is a than a infestation (Wikel that the host the ability to partially the factors that are tick evidence that T lymphocytes are of immunosuppression from the that from of inhibit of T lymphocytes of mice and Wikel 1992). of with ricinus show in when with A and 1993). Host responses appear to be suppressed by a variety of tick (Wikel 1996, Wikel and Bergman 1997). In addition to the examples saliva of dammini the in responses of mouse T lymphocytes to A or et al. infestation of of with the tick in responses of blood lymphocytes to et al. 1993). is the molecular basis by which tick or saliva suppress host in saliva contains which is known to have for the immune system (Ribeiro et al. 1992). is little, if any, evidence to support an for B. was reported to suppress induced by in et al. However, the of protein in suppression could not be the saliva not only also an of evidence the of in tick of by dammini saliva is to a protein with a molecular of at et al. A protein in the of of lymphocytes in et al. 1995, are not the of immune system they are certainly the in light of their in et al. 1997). of host is a by which the innate and specific acquired immune defenses of their hosts and 1994, Kotwal 1996). The that ticks modulate host is therefore not surprising and Wikel Wikel and Bergman 1997). from the of inhibit of the and and Wikel 1992). The same of and not that of and Wikel 1992). of dammini also of et al. The and by lymphocytes, is by lymphocytes and These that ticks the of and lymphocytes, both of which are central in specific when blood with a of the and of partially they for many and et al. 1995). do ectoparasitic arthropods by host of can the of T immunoregulatory and effector for the of antibodies, of infectious and of infected cells by T can of B and T lymphocytes and nonspecific resistance to of which normally provides stimulation of and and and effector as as antibody responses. At differentiation and and surface expression of I and of impair both innate and specific acquired immunosuppression therefore those of the host immune defenses that are essential for the and expression of immunity Wikel 1996, Wikel et al. 1996, Wikel and Bergman 1997). that arthropods can suppress the immune system of their a is whether host immunosuppression the transmission and establishment of infectious agents. The is Zeidner et al. that of the host by tick feeding against tick transmission of B. These mice with the and in or infestation with scapularis infected with the spirochete B. with in a infection of to feeding of B. The infection of on by infected ticks by contrast, Furthermore, to the culture not inhibit spirochete of or in the of and with the of host immunosuppression in infectious disease transmission have come from of mice with scapularis (Wikel et al. 1997). with to tick transmission of B. burgdorferi a infestation, an infection of mice that only the infected tick infestation an infection of that are Wikel and George B. is whether the host immune response that from infestation with ticks the ability of the tick to immunosuppress the host. The about the of tick infestation on disease transmission a with for the of transmitted by arthropods that suppress host immune a be developed that would the of host molecules arthropod Such a could it to the essential for the transmission and establishment of a of pathogens by a arthropod vector. on from each disease-causing agent, could be against infectious agents. The immunological relationships blood-feeding arthropods, their and the disease-causing agents the arthropods transmit are complex. are in understanding of these have only to Ectoparasitic arthropod modulation of host immunity, which likely evolved to facilitate blood feeding or is by infectious agents for their transmission. The fact that blood feeding arthropods can suppress host innate and specific acquired immune defenses be However, think in of the of feeding arthropods a host over time than the of The numbers of over a period of time can be research on the and of the molecules that modulate host immune defenses. The and molecular basis for host immune suppression to be receptors on cells of the immune system do do these molecules within cells of the immune do they these molecules have in the modulation of host The of vector molecules in pathogen transmission important for the study of host responses to vector-borne pathogens. these on needle inoculation the as is often almost certainly not an of the associated with the transmission establishment of this fact in of how study and the many other to be this is in the of arthropod-mediated host immunosuppression will from the study of the suppression in this to the of specific at the bite will likely from of the cells, T cells, and in the of which have important in this research can be to the of whether of this can be to as a in the of against arthropod vectors and the they transmit. The research is in by the for and of the the of the for of and and the