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1.  Characterization of Ixophilin, A Thrombin Inhibitor from the Gut of Ixodes scapularis 
PLoS ONE  2013;8(7):e68012.
Ixodes scapularis, the black-legged tick, vectors several human pathogens including Borrelia burgdorferi, the agent of Lyme disease in North America. Pathogen transmission to the vertebrate host occurs when infected ticks feed on the mammalian host to obtain a blood meal. Efforts to understand how the tick confronts host hemostatic mechanisms and imbibes a fluid blood meal have largely focused on the anticoagulation strategies of tick saliva. The blood meal that enters the tick gut remains in a fluid state for several days during the process of feeding, and the role of the tick gut in maintaining the blood-meal fluid is not understood. We now demonstrate that the tick gut produces a potent inhibitor of thrombin, a key enzyme in the mammalian coagulation cascade. Chromatographic fractionation of engorged tick gut proteins identified one predominant thrombin inhibitory activity associated with an approximately 18 kDa protein, henceforth referred to as Ixophilin. The ixophilin gene was preferentially transcribed in the guts of feeding nymphs. Expression began after 24 hours of feeding, coincident with the flow of host blood into the tick gut. Immunity against Ixophilin delayed tick feeding, and decreased feeding efficiency significantly. Surprisingly, immunity against Ixophilin resulted in increased Borrelia burgdorferi transmission to the host, possibly due to delayed feeding and increased transmission opportunity. These observations illuminate the potential drawbacks of targeting individual tick proteins in a functional suite. They also underscore the need to identify the “anticoagulome” of the tick gut, and to prioritize a critical subset of anticoagulants that could be targeted to efficiently thwart tick feeding, and block pathogen transmission to the vertebrate host.
doi:10.1371/journal.pone.0068012
PMCID: PMC3706618  PMID: 23874485
2.  Molecular Interactions that Enable Movement of the Lyme Disease Agent from the Tick Gut into the Hemolymph 
PLoS Pathogens  2011;7(6):e1002079.
Borrelia burgdorferi, the causative agent of Lyme disease, is transmitted to humans by bite of Ixodes scapularis ticks. The mechanisms by which the bacterium is transmitted from vector to host are poorly understood. In this study, we show that the F(ab)2 fragments of BBE31, a B.burgdorferi outer-surface lipoprotein, interfere with the migration of the spirochete from tick gut into the hemolymph during tick feeding. The decreased hemolymph infection results in lower salivary glands infection, and consequently attenuates mouse infection by tick-transmitted B. burgdorferi. Using a yeast surface display approach, a tick gut protein named TRE31 was identified to interact with BBE31. Silencing tre31 also decreased the B. burgdorferi burden in the tick hemolymph. Delineating the specific spirochete and arthropod ligands required for B. burgdorferi movement in the tick may lead to new strategies to interrupt the life cycle of the Lyme disease agent.
Author Summary
Lyme disease, the most common tick-borne illness in North America, is caused by Borrelia burgdorferi. Currently, spirochete and tick molecules that facilitate Borrelia migration within the vector, a key step for mammalian infection by tick-transmitted spirochetes, have not yet been identified. In this study, we show that F(ab)2 fragments of BBE31, a B.burgdorferi outer-surface lipoprotein, interfere with the spirochete migration from the tick gut into the hemolymph. Our results indicated that decreased hemolymph infection by blocking BBE31 resulted in lower salivary glands infection, which eventually attenuated murine infection by tick-transmitted B.burgdorferi. We also found that a tick gut protein TRE31 enables Borrelia movement by interacting with BBE31. This finding provides novel insights into the transmission of spirochete within the vector and provides potential vaccine targets to block the microbial life cycle within the vector.
doi:10.1371/journal.ppat.1002079
PMCID: PMC3111543  PMID: 21695244
3.  Immunity against Ixodes scapularis Salivary Proteins Expressed within 24 Hours of Attachment Thwarts Tick Feeding and Impairs Borrelia Transmission 
PLoS ONE  2007;2(5):e451.
In North America, the black-legged tick, Ixodes scapularis, an obligate haematophagus arthropod, is a vector of several human pathogens including Borrelia burgdorferi, the Lyme disease agent. In this report, we show that the tick salivary gland transcriptome and proteome is dynamic and changes during the process of engorgement. We demonstrate, using a guinea pig model of I. scapularis feeding and B. burgdorferi transmission, that immunity directed against salivary proteins expressed in the first 24 h of tick attachment — and not later — is sufficient to evoke all the hallmarks of acquired tick-immunity, to thwart tick feeding and also to impair Borrelia transmission. Defining this subset of proteins will promote a mechanistic understanding of novel I. scapularis proteins critical for the initiation of tick feeding and for Borrelia transmission.
doi:10.1371/journal.pone.0000451
PMCID: PMC1866177  PMID: 17505544
4.  Borrelia burgdorferi OspA is an arthropod-specific transmission- blocking Lyme disease vaccine 
Borrelia burgdorferi, the spirochetal agent of Lyme disease, is transmitted by Ixodes ticks. A vaccine based on B. burgdorferi outer surface protein (Osp) A protects mice from spirochete infection. Here we report on the expression of OspA on spirochetes inside engorging ticks and relate OspA expression to antispirochetal immunity. Spirochetes in the gut of unfed nymphal ticks were stained by an OspA antibody, whereas in feeding ticks, the majority of spirochetes in the gut and salivary glands did not stain with the antibody. Thus, OspA was not expressed on most spirochetes during transmission from the vector to the vertebrate host. To examine the mechanism of protection afforded by OspA antibody, mice were passively immunized with OspA antibody at different times relative to tick attachment. When OspA antibody was administered to mice before or at the time of tick attachment, spirochetal development events in the vector, such as growth and salivary gland invasion, were blocked and the mice were protected from B. burgdorferi infection. When OspA antibody was administered to mice 48 h after tick attachment, spirochetes persisted in the nymphs and the mice were not protected despite the presence of circulating antibodies in the host as well as in the tick blood meal. Thus, OspA immunity appears to be effective only during a narrow window time at the beginning of the blood meal when antibodies bind to OspA-expressing spirochetes in the tick gut and block transmission from the vector to the host.
PMCID: PMC2192397  PMID: 8551231
5.  A Tick Antioxidant Facilitates the Lyme Disease Agent’s Successful Migration from the Mammalian Host to the Arthropod Vector 
Cell host & microbe  2007;2(1):7-18.
SUMMARY
Lyme borreliosis serves as a model to understand strategies used by pathogens to migrate from mammals to arthropods. We show that a tick protein, Salp25D, plays a critical role - in the mammalian host - for acquisition of Borrelia burgdorferi by Ixodes scapularis. RNA interference-mediated silencing of salp25D in tick salivary glands impaired spirochete acquisition by ticks engorging on B. burgdorferi-infected mice. Immunization of mice with Salp25D also decreased Borrelia acquisition by I. scapularis. Salp25D detoxified reactive oxygen species at the vector-pathogen-host interface, thereby providing a survival advantage to B. burgdorferi at the tick feeding site in mice. These data demonstrate that a pathogen can exploit an arthropod molecule to defuse mammalian responses in order to successfully enter the vector from the reservoir host.
doi:10.1016/j.chom.2007.06.001
PMCID: PMC2699493  PMID: 18005713
6.  Acquisition of Coinfection and Simultaneous Transmission of Borrelia burgdorferi and Ehrlichia phagocytophila by Ixodes scapularis Ticks 
Infection and Immunity  2000;68(4):2183-2186.
The agents of Lyme disease (Borrelia burgdorferi) and human granulocytic ehrlichiosis (Ehrlichia phagocytophila) are both transmitted by the tick Ixodes scapularis. In nature, ticks are often infected with both agents simultaneously. We studied whether previous infection with either Borrelia or Ehrlichia in ticks would affect acquisition and transmission of a second pathogen. Ehrlichia-infected I. scapularis nymphs were fed upon Borrelia-infected mice, and Borrelia-infected I. scapularis nymphs were fed upon Ehrlichia-infected mice. The efficiency with which previously infected nymphal ticks acquired a second pathogen from infected hosts was compared to that of uninfected ticks. An average of 51% ± 15% of ticks acquired Ehrlichia from infected mice regardless of their prior infection status with Borrelia. An average of 85% ± 10% of ticks acquired Borrelia from infected mice regardless of their prior infection status with Ehrlichia. Also, we assessed the efficiency with which individual nymphs could transmit either agent alone, or both agents simultaneously, to individual susceptible hosts. An average of 76% ± 9% of Borrelia-infected ticks and 84% ± 10% of Ehrlichia-infected ticks transmitted these agents to mice regardless of the presence of the other pathogen. There was no evidence of interaction between the agents of Lyme disease and human granulocytic ehrlichiosis in I. scapularis ticks. The presence of either agent in the ticks did not affect acquisition of the other agent from an infected host. Transmission of the agents of Lyme disease and human granulocytic ehrlichiosis by individual ticks was equally efficient and independent. Dually infected ticks transmitted each pathogen to susceptible hosts as efficiently as ticks infected with only one pathogen.
PMCID: PMC97402  PMID: 10722618
7.  Impact of Climate Trends on Tick-Borne Pathogen Transmission 
Recent advances in climate research together with a better understanding of tick–pathogen interactions, the distribution of ticks and the diagnosis of tick-borne pathogens raise questions about the impact of environmental factors on tick abundance and spread and the prevalence and transmission of tick-borne pathogens. While undoubtedly climate plays a role in the changes in distribution and seasonal abundance of ticks, it is always difficult to disentangle factors impacting on the abundance of tick hosts from those exerted by human habits. All together, climate, host abundance, and social factors may explain the upsurge of epidemics transmitted by ticks to humans. Herein we focused on tick-borne pathogens that affect humans with epidemic potential. Borrelia burgdorferi s.l. (Lyme disease), Anaplasma phagocytophilum (human granulocytic anaplasmosis), and tick-borne encephalitis virus (tick-borne encephalitis) are transmitted by Ixodes spp. Crimean–Congo hemorrhagic fever virus (Crimean–Congo hemorrhagic fever) is transmitted by Hyalomma spp. In this review, we discussed how vector tick species occupy the habitat as a function of different climatic factors, and how these factors impact on tick survival and seasonality. How molecular events at the tick–pathogen interface impact on pathogen transmission is also discussed. Results from statistically and biologically derived models are compared to show that while statistical models are able to outline basic information about tick distributions, biologically derived models are necessary to evaluate pathogen transmission rates and understand the effect of climatic variables and host abundance patterns on pathogen transmission. The results of these studies could be used to build early alert systems able to identify the main factors driving the subtle changes in tick distribution and seasonality and the prevalence of tick-borne pathogens.
doi:10.3389/fphys.2012.00064
PMCID: PMC3313475  PMID: 22470348
tick; model; genetics; climate; Borrelia; Anaplasma; virus
8.  A tick mannose-binding lectin inhibits the vertebrate complement cascade to enhance transmission of the Lyme disease agent 
Cell host & microbe  2011;10(2):136-146.
Summary
The Lyme disease agent, Borrelia burgdorferi, is primarily transmitted to vertebrates by Ixodes ticks. The classical and alternative complement pathways are important in Borrelia eradication by the vertebrate host. We recently identified a tick salivary protein, designated P8 that reduced complement-mediated killing of Borrelia. We now discover that P8 interferes with the human lectin complement cascade resulting in impaired neutrophil phagocytosis and chemotaxis, and diminished Borrelia lysis. Therefore, P8 was renamed the lectin complement pathway inhibitor (TSLPI). TSLPI-silenced ticks, or ticks exposed to TSLPI-immune mice, were hampered in Borrelia transmission. Moreover, Borrelia acquisition and persistence in tick midguts was impaired in ticks feeding on TSLPI-immunized B. burgdorferi-infected mice. Together, our findings suggest an essential role for the lectin complement cascade in Borrelia eradication and demonstrate how a vector-borne pathogen co-opts a vector protein to facilitate early mammalian infection and vector colonization.
doi:10.1016/j.chom.2011.06.010
PMCID: PMC3170916  PMID: 21843870
MBL; lectin; ficolin; tick immunity; Borrelia burgdorferi; complement; vaccine
9.  Ixodes ricinus ticks removed from humans in Northern Europe: seasonal pattern of infestation, attachment sites and duration of feeding 
Parasites & Vectors  2013;6:362.
Background
The common tick Ixodes ricinus is the main vector in Europe of the tick-borne encephalitis virus and of several species of the Borrelia burgdorferi sensu lato complex, which are the etiological agents of Lyme borreliosis. The risk to contract bites of I. ricinus is dependent on many factors including the behaviour of both ticks and people. The tick’s site of attachment on the human body and the duration of tick attachment may be of clinical importance. Data on I. ricinus ticks, which were found attached to the skin of people, were analysed regarding potentially stage-specific differences in location of attachment sites, duration of tick attachment (= feeding duration), seasonal and geographical distribution of tick infestation in relation to age and gender of the tick-infested hosts.
Methods
During 2008–2009, 1770 tick-bitten persons from Sweden and the Åland Islands removed 2110 I. ricinus ticks. Participants provided information about the date of tick detection and location on their body of each attached tick. Ticks were identified to species and developmental stage. The feeding duration of each nymph and adult female tick was microscopically estimated based on the scutal and the coxal index.
Results
In 2008, participants were tick-bitten from mid-May to mid-October and in 2009 from early April to early November. The infestation pattern of the nymphs was bimodal whereas that of the adult female ticks was unimodal with a peak in late summer. Tick attachment site on the human body was associated with stage of the tick and gender of the human host. Site of attachment seemed to influence the duration of tick feeding. Overall, 63% of nymphs and adult female ticks were detected and removed more than 24 hours after attachment. Older persons, compared to younger ones, and men, compared to women, removed “their” ticks after a longer period of tick attachment.
Conclusions
The infestation behaviour of the different tick stages concerning where on the host’s body the ticks generally will attach and when such ticks generally will be detected and removed in relation to host age and gender, should be of value for the development of prophylactic methods against tick infestation and to provide relevant advice to people on how to avoid or reduce the risk of tick infestation.
doi:10.1186/1756-3305-6-362
PMCID: PMC3880168  PMID: 24360096
Ixodes ricinus; Tick infestation; Tick bite; Attachment site; Feeding behaviour; Feeding duration; Host-seeking behaviour; Seasonal activity; Sweden; Åland
10.  Passage through Ixodes scapularis Ticks Enhances the Virulence of a Weakly Pathogenic Isolate of Borrelia burgdorferi▿  
Infection and Immunity  2009;78(1):138-144.
Lyme disease is the most common tick-borne illness in the United States. In this paper we explore the contribution of Ixodes scapularis ticks to the pathogenicity of Borrelia burgdorferi in mice. Previously we demonstrated that an isolate of B. burgdorferi sensu stricto (designated N40), passaged 75 times in vitro (N40-75), was infectious but was no longer able to cause arthritis and carditis in C3H mice. We now show that N40-75 spirochetes can readily colonize I. scapularis and multiply during tick engorgement. Remarkably, tick-transmitted N40-75 spirochetes cause disease in mice. N40-75 spirochetes isolated from these animals also retained their pathogenicity when subsequently administered to mice via syringe inoculation. Array analysis revealed that several genes associated with virulence, including bba25, bba65, bba66, bbj09, and bbk32, had higher expression levels in the tick-passaged N40-75 spirochete. These data suggest that transmission of a high-passage attenuated isolate of B. burgdorferi by the arthropod vector results in the generation of spirochetes that have enhanced pathogenesis in mice.
doi:10.1128/IAI.00470-09
PMCID: PMC2798202  PMID: 19822652
11.  Vector Interactions and Molecular Adaptations of Lyme Disease and Relapsing Fever Spirochetes Associated with Transmission by Ticks 
Emerging Infectious Diseases  2002;8(2):115-121.
Pathogenic spirochetes in the genus Borrelia are transmitted primarily by two families of ticks. The Lyme disease spirochete, Borrelia burgdorferi, is transmitted by the slow-feeding ixodid tick Ixodes scapularis, whereas the relapsing fever spirochete, B. hermsii, is transmitted by Ornithodoros hermsi, a fast-feeding argasid tick. Lyme disease spirochetes are generally restricted to the midgut in unfed I. scapularis. When nymphal ticks feed, the bacteria pass through the hemocoel to the salivary glands and are transmitted to a new host in the saliva after 2 days. Relapsing fever spirochetes infect the midgut in unfed O. hermsi but persist in other sites including the salivary glands. Thus, relapsing fever spirochetes are efficiently transmitted in saliva by these fast-feeding ticks within minutes of their attachment to a mammalian host. We describe how B. burgdorferi and B. hermsii change their outer surface during their alternating infections in ticks and mammals, which in turn suggests biological functions for a few surface-exposed lipoproteins.
doi:10.3201/eid0802.010198
PMCID: PMC2732444  PMID: 11897061
Lyme disease; relapsing fever; ticks; surface proteins; Borrelia
12.  The Tick Salivary Protein Salp15 Inhibits the Killing of Serum-Sensitive Borrelia burgdorferi Sensu Lato Isolates▿  
Infection and Immunity  2008;76(7):2888-2894.
Borrelia burgdorferi, the agent of Lyme disease, is transmitted by ticks. During transmission from the tick to the host, spirochetes are delivered with tick saliva, which contains the salivary protein Salp15. Salp15 has been shown to protect spirochetes against B. burgdorferi-specific antibodies. We now show that Salp15 from both Ixodes ricinus and Ixodes scapularis protects serum-sensitive isolates of Borrelia burgdorferi sensu lato against complement-mediated killing. I. ricinus Salp15 showed strong protective effects compared to those of I. scapularis Salp15. Deposition of terminal C5b to C9 (one molecule each of C5b, C6, C7, and C8 and one or more molecules of C9) complement complexes, part of the membrane attack complex, on the surface of B. burgdorferi was inhibited in the presence of Salp15. In the presence of normal human serum, serum-sensitive Borrelia burgdorferi requires protection against complement-mediated killing, which is provided, at least in part, by the binding to the tick salivary protein Salp15.
doi:10.1128/IAI.00232-08
PMCID: PMC2446733  PMID: 18426890
13.  Functional Analysis of the Borrelia burgdorferi bba64 Gene Product in Murine Infection via Tick Infestation 
PLoS ONE  2011;6(5):e19536.
Borrelia burgdorferi, the causative agent of Lyme borreliosis, is transmitted to humans from the bite of Ixodes spp. ticks. During the borrelial tick-to-mammal life cycle, B. burgdorferi must adapt to many environmental changes by regulating several genes, including bba64. Our laboratory recently demonstrated that the bba64 gene product is necessary for mouse infectivity when B. burgdorferi is transmitted by an infected tick bite, but not via needle inoculation. In this study we investigated the phenotypic properties of a bba64 mutant strain, including 1) replication during tick engorgement, 2) migration into the nymphal salivary glands, 3) host transmission, and 4) susceptibility to the MyD88-dependent innate immune response. Results revealed that the bba64 mutant's attenuated infectivity by tick bite was not due to a growth defect inside an actively feeding nymphal tick, or failure to invade the salivary glands. These findings suggested there was either a lack of spirochete transmission to the host dermis or increased susceptibility to the host's innate immune response. Further experiments showed the bba64 mutant was not culturable from mouse skin taken at the nymphal bite site and was unable to establish infection in MyD88-deficient mice via tick infestation. Collectively, the results of this study indicate that BBA64 functions at the salivary gland-to-host delivery interface of vector transmission and is not involved in resistance to MyD88-mediated innate immunity.
doi:10.1371/journal.pone.0019536
PMCID: PMC3086921  PMID: 21559293
14.  Differential salivary gland transcript expression profile in Ixodes scapularis nymphs upon feeding or flavivirus infection 
Ticks and Tick-Borne Diseases  2012;3(1):18-26.
Ixodid ticks are vectors of human diseases such as Lyme disease, babesiosis, anaplasmosis, and tick-borne encephalitis. These diseases cause significant morbidity and mortality worldwide and are transmitted to humans during tick feeding. The tick-host-pathogen interface is a complex environment where host responses are modulated by the molecules in tick saliva to enable the acquisition of a blood meal. Disruption of host responses at the site of the tick bite may also provide an advantage for pathogens to survive and replicate. Thus, the molecules in tick saliva not only aid the tick in securing a nutrient-rich blood meal, but can also enhance the transmission and acquisition of pathogens. To investigate the effect of feeding and flavivirus infection on the salivary gland transcript expression profile in ticks, a first-generation microarray was developed using ESTs from a cDNA library derived from Ixodes scapularis salivary glands. When the salivary gland transcript profile in ticks feeding over the course of 3 days was compared to that in unfed ticks, a dramatic increase in transcripts related to metabolism was observed. Specifically, 578 transcripts were up-regulated compared to 151 down-regulated transcripts in fed ticks. When specific time points post attachment were analyzed, a temporal pattern of gene expression was observed. When Langat virus-infected ticks were compared to mock-infected ticks, transcript expression changes were observed at all 3 days of feeding. Differentially regulated transcripts include putative secreted proteins, lipocalins, Kunitz domain-containing proteins, anti-microbial peptides, and transcripts of unknown function. These studies identify salivary gland transcripts that are differentially regulated during feeding or in the context of flavivirus infection in Ixodes scapularis nymphs, a medically important disease vector. Further analysis of these transcripts may identify salivary factors that affect the transmission or replication of tick-borne flaviviruses.
doi:10.1016/j.ttbdis.2011.09.003
PMCID: PMC3275779  PMID: 22309855
Tick vector; Ixodes scapularis; Nymph; Salivary gland; Gene expression; Feeding; Flavivirus
15.  Langerhans Cell Deficiency Impairs Ixodes scapularis Suppression of Th1 Responses in Mice▿  
Infection and Immunity  2009;77(5):1881-1887.
Ixodes scapularis ticks transmit a number of human pathogens, including the Lyme disease spirochete Borrelia burgdorferi. I. scapularis suppresses host immunity in the skin to promote feeding and systemically skew T-helper (Th)-cell differentiation toward Th2 cells in secondary lymphoid organs. Although components of tick saliva are known to influence Th-cell polarization, the mechanism whereby tick feeding in the skin modulates regional and systemic Th-cell responses is unknown. In this study, the role of the epidermal Langerhans cell (LC) subset of skin dendritic cells in tick-mediated Th1/Th2-cell immunomodulation was assessed. Mice deficient in LCs (Langerin-DTA mice) exhibited enhanced lymph node (LN) concanavalin A (ConA)-induced Th1 responses after tick infestation in comparison to results for uninfested Langerin-DTA or wild-type (WT) mice, whereas effects on Th2-cell production of interleukin 4 were more variable. Nonetheless, the altered T-cell response did not impact tick feeding or refeeding. Gamma interferon production by ConA-stimulated LN cells of both WT and LC-deficient mice was enhanced by as much as fourfold after B. burgdorferi-infected-tick feeding, indicating that immunomodulatory effects of tick saliva were not able to attenuate the Th1 immune responses induced by this pathogen. Taken together, these findings show a requirement for LCs in the tick-mediated attenuation of Th1 responses in regional lymph nodes but not in the spleens of mice and show that the presence of a pathogen can overcome the Th1-inhibitory effects of tick feeding on the host.
doi:10.1128/IAI.00030-09
PMCID: PMC2681756  PMID: 19273564
16.  Isolation of Borrelia burgdorferi from saliva of the tick vector, Ixodes scapularis. 
Journal of Clinical Microbiology  1994;32(3):755-758.
A method for cultivating and isolating Lyme disease spirochetes, Borrelia burgdorferi, from the saliva of vector ticks, Ixodes scapularis (formerly known as Ixodes dammini), is described. Saliva was collected from partially engorged ticks after application of pilocarpine to induce salivation. B. burgdorferi was isolated from 8 of 14 (57%) of the saliva samples derived from ticks infected with the bacteria, as determined by direct immunofluorescent-antibody assay of tick hemolymph. A comparison of the protein profiles of the salivary isolates and a highly passaged strain (B31) showed that the salivary isolates all lacked a 22-kDa protein known to increase with continuous passage, but exhibited larger amounts of the OspA and OspB proteins than did the highly passaged B31 strain.
Images
PMCID: PMC263120  PMID: 8195390
17.  An Antivector Vaccine Protects against a Lethal Vector-Borne Pathogen 
PLoS Pathogens  2006;2(4):e27.
Vaccines that target blood-feeding disease vectors, such as mosquitoes and ticks, have the potential to protect against the many diseases caused by vector-borne pathogens. We tested the ability of an anti-tick vaccine derived from a tick cement protein (64TRP) of Rhipicephalus appendiculatus to protect mice against tick-borne encephalitis virus (TBEV) transmitted by infected Ixodes ricinus ticks. The vaccine has a “dual action” in immunized animals: when infested with ticks, the inflammatory and immune responses first disrupt the skin feeding site, resulting in impaired blood feeding, and then specific anti-64TRP antibodies cross-react with midgut antigenic epitopes, causing rupture of the tick midgut and death of engorged ticks. Three parameters were measured: “transmission,” number of uninfected nymphal ticks that became infected when cofeeding with an infected adult female tick; “support,” number of mice supporting virus transmission from the infected tick to cofeeding uninfected nymphs; and “survival,” number of mice that survived infection by tick bite and subsequent challenge by intraperitoneal inoculation of a lethal dose of TBEV. We show that one dose of the 64TRP vaccine protects mice against lethal challenge by infected ticks; control animals developed a fatal viral encephalitis. The protective effect of the 64TRP vaccine was comparable to that of a single dose of a commercial TBEV vaccine, while the transmission-blocking effect of 64TRP was better than that of the antiviral vaccine in reducing the number of animals supporting virus transmission. By contrast, the commercial antitick vaccine (TickGARD) that targets only the tick's midgut showed transmission-blocking activity but was not protective. The 64TRP vaccine demonstrates the potential to control vector-borne disease by interfering with pathogen transmission, apparently by mediating a local cutaneous inflammatory immune response at the tick-feeding site.
Synopsis
Blood-sucking vectors such as mosquitoes and ticks transmit hundreds of micro-organisms that cause diseases like malaria and Lyme disease. Controlling so many diseases is an enormous challenge. A new idea is to make vaccines against the vectors rather than against all the individual disease agents they carry. The authors examined this hypothesis using a vaccine prepared from tick cement. This cement is secreted by ticks to help them attach to a human or animal to feed. A mouse model was used in which mice were infested with ticks infected with tick-borne encephalitis virus (TBEV), the most important vector-borne virus in Europe and northern Asia. The control mice developed fatal encephalitis and died about a week after being bitten by the infected tick. By contrast, the tick cement vaccine gave protection similar to the level seen in mice immunized with a single shot of the commercial TBEV vaccine for humans. However, a commercial tick vaccine used to control cattle ticks did not protect the mice. The authors' tick cement vaccine appeared to work by causing a cellular immune response in the skin where ticks were feeding. These results show that it is feasible to produce a vaccine against a tick that protects against the disease agent it transmits.
doi:10.1371/journal.ppat.0020027
PMCID: PMC1424664  PMID: 16604154
18.  Influence of Outer Surface Protein A Antibody on Borrelia burgdorferi within Feeding Ticks 
Infection and Immunity  1999;67(1):30-35.
Borrelia burgdorferi, the spirochetal agent of Lyme disease, is transmitted by Ixodes ticks. When an infected nymphal tick feeds on a host, the bacteria increase in number within the tick, after which they invade the tick’s salivary glands and infect the host. Antibodies directed against outer surface protein A (OspA) of B. burgdorferi kill spirochetes within feeding ticks and block transmission to the host. In the studies presented here, passive antibody transfer experiments were carried out to determine the OspA antibody titer required to block transmission to the rodent host. OspA antibody levels were determined by using a competitive enzyme-linked immunosorbent assay that measured antibody binding to a protective epitope defined by monoclonal antibody C3.78. The C3.78 OspA antibody titer (>213 μg/ml) required to eradicate spirochetes from feeding ticks was considerably higher than the titer (>6 μg/ml) required to block transmission to the host. Although spirochetes were not eradicated from ticks at lower antibody levels, the antibodies reduced the number of spirochetes within the feeding ticks and interfered with the ability of spirochetes to induce ospC and invade the salivary glands of the vector. OspA antibodies may directly interfere with the ability of B. burgdorferi to invade the salivary glands of the vector; alternately, OspA antibodies may lower the density of spirochetes within feeding ticks below a critical threshold required for initiating events linked to transmission.
PMCID: PMC96273  PMID: 9864192
19.  A Chitin Deacetylase-Like Protein Is a Predominant Constituent of Tick Peritrophic Membrane That Influences the Persistence of Lyme Disease Pathogens within the Vector 
PLoS ONE  2013;8(10):e78376.
Ixodes scapularis is the specific arthropod vector for a number of globally prevalent infections, including Lyme disease caused by the bacterium Borrelia burgdorferi. A feeding-induced and acellular epithelial barrier, known as the peritrophic membrane (PM) is detectable in I. scapularis. However, whether or how the PM influences the persistence of major tick-borne pathogens, such as B. burgdorferi, remains largely unknown. Mass spectrometry-based proteome analyses of isolated PM from fed ticks revealed that the membrane contains a few detectable proteins, including a predominant and immunogenic 60 kDa protein with homology to arthropod chitin deacetylase (CDA), herein termed I. scapularis CDA-like protein or IsCDA. Although IsCDA is primarily expressed in the gut and induced early during tick feeding, its silencing via RNA interference failed to influence either the occurrence of the PM or spirochete persistence, suggesting a redundant role of IsCDA in tick biology and host-pathogen interaction. However, treatment of ticks with antibodies against IsCDA, one of the most predominant protein components of PM, affected B. burgdorferi survival, significantly augmenting pathogen levels within ticks but without influencing the levels of total gut bacteria. These studies suggested a preferential role of tick PM in limiting persistence of B. burgdorferi within the vector. Further understanding of the mechanisms by which vector components contribute to pathogen survival may help the development of new strategies to interfere with the infection.
doi:10.1371/journal.pone.0078376
PMCID: PMC3798397  PMID: 24147133
20.  Borrelia burgdorferi sensu lato in Ixodes ricinus ticks collected from migratory birds in Southern Norway 
Background
Borrelia burgdorferi sensu lato (s.l.) are the causative agent for Lyme borreliosis (LB), the most common tick-borne disease in the northern hemisphere. Birds are considered important in the global dispersal of ticks and tick-borne pathogens through their migration. The present study is the first description of B. burgdorferi prevalence and genotypes in Ixodes ricinus ticks feeding on birds during spring and autumn migration in Norway.
Methods
6538 migratory birds were captured and examined for ticks at Lista Bird Observatory during the spring and the autumn migration in 2008. 822 immature I. ricinus ticks were collected from 215 infested birds. Ticks were investigated for infection with B. burgdorferi s.l. by real-time PCR amplification of the 16S rRNA gene, and B. burgdorferi s.l. were thereafter genotyped by melting curve analysis after real-time PCR amplification of the hbb gene, or by direct sequencing of the PCR amplicon generated from the rrs (16S)-rrl (23S) intergenetic spacer.
Results
B. burgdorferi s.l. were detected in 4.4% of the ticks. The most prevalent B. burgdorferi genospecies identified were B. garinii (77.8%), followed by B.valaisiana (11.1%), B. afzelii (8.3%) and B. burgdorferi sensu stricto (2.8%).
Conclusion
Infection rate in ticks and genospecies composition were similar in spring and autumn migration, however, the prevalence of ticks on birds was higher during spring migration. The study supports the notion that birds are important in the dispersal of ticks, and that they may be partly responsible for the heterogeneous distribution of B. burgdorferi s.l. in Europe.
doi:10.1186/1751-0147-52-59
PMCID: PMC2988791  PMID: 21054890
21.  Attachment of Borrelia burgdorferi within Ixodes scapularis mediated by outer surface protein A 
Journal of Clinical Investigation  2000;106(4):561-569.
Borrelia burgdorferi outer surface protein (Osp) A has been used as a Lyme disease vaccine that blocks transmission: OspA antibodies of immune hosts enter ticks during blood feeding and destroy spirochetes before transmission to the host can occur. B. burgdorferi produce OspA in the gut of unfed Ixodes scapularis ticks, and many spirochetes repress OspA production during the feeding process. This preferential expression suggests that OspA may have an important function in the vector. Here we show that OspA mediates spirochete attachment to the tick gut by binding to an I. scapularis protein. The binding domains reside in the central region and COOH-terminus of OspA. OspA also binds to itself, suggesting that spirochete-spirochete interactions may further facilitate adherence in the gut. OspA-mediated attachment in the tick provides a possible mechanism for how stage-specific protein expression can contribute to pathogenesis during the B. burgdorferi natural cycle.
PMCID: PMC380253  PMID: 10953031
22.  Salp15 Binding to DC-SIGN Inhibits Cytokine Expression by Impairing both Nucleosome Remodeling and mRNA Stabilization  
PLoS Pathogens  2008;4(2):e31.
Ixodes ticks are major vectors for human pathogens, such as Borrelia burgdorferi, the causative agent of Lyme disease. Tick saliva contains immunosuppressive molecules that facilitate tick feeding and B. burgdorferi infection. We here demonstrate, to our knowledge for the first time, that the Ixodes scapularis salivary protein Salp15 inhibits adaptive immune responses by suppressing human dendritic cell (DC) functions. Salp15 inhibits both Toll-like receptor- and B. burgdorferi–induced production of pro-inflammatory cytokines by DCs and DC-induced T cell activation. Salp15 interacts with DC-SIGN on DCs, which results in activation of the serine/threonine kinase Raf-1. Strikingly, Raf-1 activation by Salp15 leads to mitogen-activated protein kinase kinase (MEK)-dependent decrease of IL-6 and TNF-α mRNA stability and impaired nucleosome remodeling at the IL-12p35 promoter. These data demonstrate that Salp15 binding to DC-SIGN triggers a novel Raf-1/MEK-dependent signaling pathway acting at both cytokine transcriptional and post-transcriptional level to modulate Toll-like receptor–induced DC activation, which might be instrumental to tick feeding and B. burgdorferi infection, and an important factor in the pathogenesis of Lyme disease. Insight into the molecular mechanism of immunosuppression by tick salivary proteins might provide innovative strategies to combat Lyme disease and could lead to the development of novel anti-inflammatory or immunosuppressive agents.
Author Summary
Upon attachment of the tick, the host elicits both innate and adaptive immune responses directed against the vector. In turn, ticks have developed countermeasures to withstand and evade host immune responses. In the current paper we demonstrate how a tick salivary protein induces immunosuppression of human dendritic cells and how this could facilitate infection with B. burgdorferi, the causative agent of Lyme disease. Insight into the molecular mechanism of immunosuppression by tick salivary proteins might provide innovative strategies to combat Lyme disease or other tick-borne illnesses and could lead to the development of novel anti-inflammatory or immunosuppressive drugs.
doi:10.1371/journal.ppat.0040031
PMCID: PMC2242833  PMID: 18282094
23.  Feeding of Ticks on Animals for Transmission and Xenodiagnosis in Lyme Disease Research 
Transmission of the etiologic agent of Lyme disease, Borrelia burgdorferi, occurs by the attachment and blood feeding of Ixodes species ticks on mammalian hosts. In nature, this zoonotic bacterial pathogen may use a variety of reservoir hosts, but the white-footed mouse (Peromyscus leucopus) is the primary reservoir for larval and nymphal ticks in North America. Humans are incidental hosts most frequently infected with B. burgdorferi by the bite of ticks in the nymphal stage. B. burgdorferi adapts to its hosts throughout the enzootic cycle, so the ability to explore the functions of these spirochetes and their effects on mammalian hosts requires the use of tick feeding. In addition, the technique of xenodiagnosis (using the natural vector for detection and recovery of an infectious agent) has been useful in studies of cryptic infection. In order to obtain nymphal ticks that harbor B. burgdorferi, ticks are fed live spirochetes in culture through capillary tubes. Two animal models, mice and nonhuman primates, are most commonly used for Lyme disease studies involving tick feeding. We demonstrate the methods by which these ticks can be fed upon, and recovered from animals for either infection or xenodiagnosis.
doi:10.3791/50617
PMCID: PMC3857350  PMID: 24022694
Infection; Issue 78; Medicine; Immunology; Infectious Diseases; Biomedical Engineering; Primates; Muridae; Ticks; Borrelia; Borrelia Infections; Ixodes; ticks; Lyme disease; xenodiagnosis; Borrelia; burgdorferi; mice; nonhuman primates; animal model
24.  Prevalence of tick-borne pathogens in Ixodes scapularis in a rural New Jersey County. 
Emerging Infectious Diseases  1998;4(1):97-99.
To assess the potential risk for other tick-borne diseases, we collected 100 adult Ixodes scapularis in Hunterdon County, a rapidly developing rural county in Lyme disease endemic western New Jersey. We tested the ticks by polymerase chain reaction for Borrelia burgdorferi, Babesia microti, and the rickettsial agent of human granulocytic ehrlichiosis (HGE). Fifty-five ticks were infected with at least one of the three pathogens: 43 with B. burgdorferi, five with B. microti, and 17 with the HGE agent. Ten ticks were coinfected with two of the pathogens. The results suggest that county residents are at considerable risk for infection by a tick-borne pathogen after an I. scapularis bite.
PMCID: PMC2627663  PMID: 9452402
25.  Protective efficacy of an oral vaccine to reduce carriage of Borrelia burgdorferi (strain N40) in mouse and tick reservoirs 
Vaccine  2005;24(11):1949-1957.
Lyme disease is caused by the spirochete Borrelia burgdorferi, which is transmitted through the bite of infected Ixodes ticks. Vaccination of mice with outer surface protein A (OspA) of B. burgdorferi has been shown to both protect mice against B. burgdorferi infection and reduce carriage of the organism in feeding ticks. Here we report the development of a murine-targeted OspA vaccine utilizing Vaccinia virus to interrupt transmission of disease in the reservoir hosts, thus reducing incidence of human disease. Oral vaccination of mice with a single dose of Vaccinia expressing OspA resulted in high antibody titers to OspA, 100% protection of vaccinated mice from infection with B. burgdorferi, and significant clearance of B. burgdorferi from infected ticks fed on vaccinated animals. The results indicate the vaccine is effective and may provide a manner to reduce incidence of Lyme disease.
doi:10.1016/j.vaccine.2005.10.044
PMCID: PMC1388312  PMID: 16300863
Lyme disease; Vaccinia virus; OspA

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