UvA-DARE (Digital Academic Repository) Tick-host-pathogen interactions in Lyme borreliosis Hovius, J.W.R. Link to publication

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1 UvA-DARE (Digital Academic Repository) Tick-host-pathogen interactions in Lyme borreliosis Hovius, J.W.R. Link to publication Citation for published version (APA): Hovius, J. W. R. (2009). Tick-host-pathogen interactions in Lyme borreliosis General rights It is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulations If you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. UvA-DARE is a service provided by the library of the University of Amsterdam ( Download date: 19 Jun 2018

2 Dit is Hovius geschenk, waaruit de heelkracht blijkt, die nog natuur bezit, wanneer de kunst bezwijkt. Jacobus Hovius ( ) Voor mijn ouders, Taco & Wendy en mijn lieve nichtjes

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6 Historical aspects of Lyme borreliosis Lyme borreliosis was first recognized as a distinct clinical entity in 1975 in Old Lyme, Connecticut, USA (Fig. 1A and B), in children attending the Yale-New Haven Hospital and initially thought to have juvenile rheumatoid arthritis [1], although certain clinical signs that were part of the disease were previously described in Europe [2,3]. In the early 1980s Burgdorfer and colleagues were the first to culture the causative spirochetal agent, Borrelia burgdorferi sensu stricto from ticks in an endemic area [4], and this spirochete was later cultured from patients with Lyme disease symptoms [5,6]. More than 30 years after the identification it has become clear that the causative agent of this emerging zoonosis belongs to a broader group of spirochetes referred to as the Borrelia burgdorferi sensu lato group, encompassing several pathogenic Borrelia species [7]. Their corkscrew-shaped appearance allows the bacterium to move through tick and host tissues (Fig. 1C). Ecological and biological aspects of the life cycle of Borrelia burgdorferi The obligate enzootic life cycle of the spirochetes involves ticks (Fig. 1D) and a variety of vertebrate hosts, including small rodents, large mammals and birds [8,9]. In general, uninfected tick larvae acquire the bacterium by feeding on infected animals. Ticks remain infected during their consecutive molting periods, enabling both nymphal and adult ticks to transmit spirochetes to other (larger) animals and humans. After their final bloodmeal adult female ticks, which have already mated, lay uninfected eggs; vertical transmission only rarely occurs. In the United States Borrelia burgdorferi sensu stricto [4], from here on referred to as B. burgdorferi, is the causative agent of Lyme borreliosis [5] and is mainly transmitted by the deer tick, Ixodes scapularis. By contrast, in Europe at least three major pathogenic Borrelia species, i.e. B. burgdorferi, Borrelia garinii and Borrelia afzelii are prevalent and able to cause Lyme borreliosis [10,11] and are primarily transmitted by the sheep tick, Ixodes ricinus. Both Ixodes species are capable of transmitting spirochetes while feeding. Importantly, during the course of the bloodmeal, ticks also introduce saliva into the host skin, containing a wide range of physiologically active components that interfere with host processes or interact with pathogens. The aim of this thesis was to elucidate tick-host-pathogen interactions that could directly or indirectly affect the ability of Borrelia burgdorferi sensu lato to survive in the host, since these could be important factors in the pathogenesis of Lyme borreliosis. Apart from the introduction (Chapter 1), we have divided the thesis in four sections: tick-host interactions (Part I), tick-pathogen interactions (Part II), host-pathogen interactions (Part III) and spin-off of research on tick-host-pathogen interactions (Part IV). Part I: Tick-host interactions Adult Ixodes ticks require five to seven days to feed to repletion [12]. In order to secure attachment of the tick and to ensure susceptibility of reservoir hosts for future tick infestations, tick saliva contains modulators of host immune responses. In the first section of the thesis we investigated 11

7 the immunosuppressive activity of a 15 kda feeding induced I. scapularis salivary protein, Salp15 (Chapter 2 and 3). Part II: Tick-pathogen interactions Salp15 was originally identified in I. scapularis [13,14]. In chapter 4, we determined whether I. ricinus, the major vector for Lyme borreliosis in Europe, express salp15 related genes (Chapter 4). Besides possessing immunosuppressive activity I. scapularis Salp15 has been shown to bind to B. burgdorferi Outer surface protein (Osp)C [15]. This interaction protects the spirochete from antibody-mediated complement dependent killing by the immune host. In this thesis we characterized the interaction of the three major pathogenic European Borrelia species with one of the Salp15-related proteins in I. ricinus saliva, Salp15 Iric-1 (Chapter 5). In addition, we investigated the binding capacity of the I. ricinus Salp15 homologue to OspC from other, complement-sensitive, Borrelia isolates and assessed the effect of this interaction on antibody-independent complementmediated killing in vitro (Chapter 6). Part III: Host-pathogen interactions The host immune response is crucially important in the pathogenesis of Lyme borreliosis [16]. Therefore, in a cohort of naturally Borrelia infected asymptomatic and symptomatic pet dogs we investigated the extent of the humoral immune response (Chapter 7). In humans, all three Borrelia species frequently cause an expanding migrating red skin lesion, classically accompanied by central clearing, and designated erythema migrans [17]. When untreated, the spirochete can disseminate and cause disease that affects various organs, however B. burgdorferi, B. garinii and B. afzelii are associated with different disease manifestations [11]. In this thesis we studied the effect of simultaneous infection with B. burgdorferi and B. garinii on the course of experimental murine Lyme borreliosis (Chapter 8). In in vitro studies B. burgdorferi has been shown to upregulate expression of the urokinase Plasminogen Activator Receptor (upar; CD87; Plaur) [18,19], a receptor expressed on a variety of immune cells and important in the instigation of both innate and adaptive immune responses. In this thesis we investigated the role upar in the course of experimental murine Lyme borreliosis in vivo (Chapter 9). Part IV: Spin-off of research on tick-host-pathogen interactions Tick saliva contains a wide range of physiologically active molecules that are crucial for attachment to the host or for the transmission of pathogens [15], and that interact with host processes, including coagulation and fibrinolysis, and immunity and inflammation [20,21]. In this chapter we speculate how immunologically targeting specific tick salivary proteins could prevent the transmission of tick-borne pathogens, such as Borrelia burgdorferi, from the tick to the host (Chapter 10). Importantly, we also discuss molecules in tick saliva that have been intensively studied in vitro 12

8 or in animal models for human diseases, and that, due to their specificity, are potential future anticoagulant or immunosuppressive agents (Chapter 10). Figure 1. Historical, ecological and biological aspects of Lyme borreliosis. (A) Lyme disease was named after the town Old Lyme, Connecticut, USA. (B) The Old Lyme public schoolbus. Picture: K.E. Hovius. (C) Borrelia burgdorferi visualized by microscopy. (D) Ixodes ticks are the main vector for Lyme borreliosis. Picture: G.A. Oei. For color figure see page

9 Reference List 1. Steere AC, Malawista SE, Snydman DR, Shope RE, Andiman WA, Ross MR, Steele FM (1977) Lyme arthritis: an epidemic of oligoarticular arthritis in children and adults in three connecticut communities. Arthritis Rheum 20: Afzelius A (1921) Erythema chronicum migrans. Acta Derm Venereol 2: Bannwarth A (1941) Chronische lymphocytare meningitis, entzundliche polyneuritis un Rheumatismus : ein betrag zum problem allergie und nervensystem. Arch Psych Nervenkrank 113: Burgdorfer W, Barbour AG, Hayes SF, Benach JL, Grunwaldt E, Davis JP (1982) Lyme disease-a tick-borne spirochetosis? Science 216: Steere AC, Grodzicki RL, Kornblatt AN, Craft JE, Barbour AG, Burgdorfer W, Schmid GP, Johnson E, Malawista SE (1983) The spirochetal etiology of Lyme disease. N Engl J Med 308: Steere AC (1989) Lyme disease. N Engl J Med 321: Wang G, van Dam AP, Le Fleche A, Postic D, Peter O, Baranton G, de Boer R, Spanjaard L, Dankert J (1997) Genetic and phenotypic analysis of Borrelia valaisiana sp. nov. (Borrelia genomic groups VS116 and M19). Int J Syst Bacteriol 47: Anderson JF, Magnarelli LA (1980) Vertebrate host relationships and distribution of ixodid ticks (Acari: Ixodidae) in Connecticut, USA. J Med Entomol 17: Anderson JF, Johnson RC, Magnarelli LA, Hyde FW (1986) Involvement of birds in the epidemiology of the Lyme disease agent Borrelia burgdorferi. Infect Immun 51: Busch U, Hizo-Teufel C, Boehmer R, Fingerle V, Nitschko H, Wilske B, Preac-Mursic V (1996) Three species of Borrelia burgdorferi sensu lato (B. burgdorferi sensu stricto, B. afzelii, and B. garinii) identified from cerebrospinal fluid isolates by pulsed-field gel electrophoresis and PCR. J Clin Microbiol 34: van Dam AP, Kuiper H, Vos K, Widjojokusumo A, de Jongh BM, Spanjaard L, Ramselaar AC, Kramer MD, Dankert J (1993) Different genospecies of Borrelia burgdorferi are associated with distinct clinical manifestations of Lyme borreliosis. Clin Infect Dis 17: Binnington KC, Kemp DH (1980) Role of tick salivary glands in feeding and disease transmission. Adv Parasitol 18: Das S, Marcantonio N, DePonte K, Telford SR, III, Anderson JF, Kantor FS, Fikrig E (2000) SALP16, a gene induced in Ixodes scapularis salivary glands during tick feeding. Am J Trop Med Hyg 62: Das S, Banerjee G, DePonte K, Marcantonio N, Kantor FS, Fikrig E (2001) Salp25D, an Ixodes scapularis antioxidant, is 1 of 14 immunodominant antigens in engorged tick salivary glands. J Infect Dis 184: Ramamoorthi N, Narasimhan S, Pal U, Bao F, Yang XF, Fish D, Anguita J, Norgard MV, Kantor FS, Anderson JF, Koski RA, Fikrig E (2005) The Lyme disease agent exploits a tick protein to infect the mammalian host. Nature 436: Weis JJ (2002) Host-pathogen interactions and the pathogenesis of murine Lyme disease. Curr Opin Rheumatol 14: Steere AC (2001) Lyme disease. N Engl J Med 345: Coleman JL, Gebbia JA, Benach JL (2001) Borrelia burgdorferi and other bacterial products induce expression and release of the urokinase receptor (CD87). J Immunol 166: Coleman JL, Benach JL (2003) The urokinase receptor can be induced by Borrelia burgdorferi through receptors of the innate immune system. Infect Immun 71: Brossard M, Wikel SK (2004) Tick immunobiology. Parasitology 129 Suppl: S161-S Maritz-Olivier C, Stutzer C, Jongejan F, Neitz AW, Gaspar AR (2007) Tick anti-hemostatics: targets for future vaccines and therapeutics. Trends Parasitol 23: