A Tick Mannose-Binding Lectin Inhibitor Interferes with the Vertebrate Complement Cascade to Enhance Transmission of the Lyme Disease Agent

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06420, USA.
Cell host & microbe (Impact Factor: 12.33). 08/2011; 10(2):136-46. DOI: 10.1016/j.chom.2011.06.010
Source: PubMed


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, which 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 tick salivary lectin 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.

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Available from: Jianfeng Dai, Jan 21, 2014
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    • "An indirect assay to measure complement-mediated killing was also employed, adapted from the method described by Kraiczy et al. (2000) and described previously (Schuijt et al., 2011; Wagemakers et al., 2014). A 1.5 × 10 7 spirochaetes of each isolate including the serum sensitive control isolate, A87S, were incubated with NHS or HIS in BSK-II medium with 240 ␮g/ml phenol red (Merck, Darmstadt , Germany) at 33 • C for 10 days. "
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    ABSTRACT: Borrelia burgdorferi can be categorized based on restriction fragment length polymorphism analysis into ribosomal spacer type (RST) 1, 2 and 3. A correlation between RST type and invasiveness of Borrelia isolates has been demonstrated in clinical studies and experimental models, and RST 1 isolates are more likely to cause disseminated disease than RST 3 isolates. We hypothesized that this could partially be due to increased susceptibility of RST 3 isolates to killing by the innate immune system early in infection. Thus, we investigated the interaction of five RST 1 and five RST 3 isolates with various components of the human innate immune system in vitro. RST 3 isolates induced significantly greater upregulation of activation markers in monocyte-derived dendritic cells compared to RST 1 isolates at a low multiplicity of infection. However, RST 1 isolates stimulated greater interleukin-6 production. At a high multiplicity of infection no differences in dendritic cell activation or cytokine production were observed. In addition, we observed no differences in the ability of RST 1 and RST 3 isolates to activate monocytes or neutrophils and all strains were phagocytosed at a comparable rate. Finally, all isolates tested were equally resistant to complement-mediated killing, as determined by dark-field microscopy and a growth inhibition assay. In conclusion, we demonstrate that the RST 1 and 3 isolates showed no distinction in their susceptibility to the various components of the human immune system studied here, suggesting that other factors are responsible for their differential invasiveness. Copyright © 2015. Published by Elsevier GmbH.
    Immunobiology 06/2015; 220(10). DOI:10.1016/j.imbio.2015.06.006 · 3.04 Impact Factor
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    • "I. scapularis and I. ricinus saliva inhibit alternative pathway C3 convertase activity by causing dissociation of C3b from Bb (Valenzuela et al., 2000; Daix et al., 2007; Tyson et al., 2007). Tick salivary lectin pathway inhibitor (TSPLI) present in saliva of I. scapularis reduces spirochete killing by inhibiting lectin pathway complement mediated activation on the surface of B. burgdorferi (Schuijt et al., 2011). In concert with tick modulation of host complement defenses, B. burgdorferi itself inhibits innate immune defenses, including complement activation (Singh and Girschick, 2004; Hovius, 2009). "
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    ABSTRACT: Ticks are unique among hematophagous arthropods by continuous attachment to host skin and blood feeding for days; complexity and diversity of biologically active molecules differentially expressed in saliva of tick species; their ability to modulate the host defenses of pain and itch, hemostasis, inflammation, innate and adaptive immunity, and wound healing; and, the diverse array of infectious agents they transmit. All of these interactions occur at the cutaneous interface in a complex sequence of carefully choreographed host defense responses and tick countermeasures resulting in an environment that facilitates successful blood feeding and establishment of tick-borne infectious agents within the host. Here, we examine diverse patterns of tick attachment to host skin, blood feeding mechanisms, salivary gland transcriptomes, bioactive molecules in tick saliva, timing of pathogen transmission, and host responses to tick bite. Ticks engage and modulate cutaneous and systemic immune defenses involving keratinocytes, natural killer cells, dendritic cells, T cell subpopulations (Th1, Th2, Th17, Treg), B cells, neutrophils, mast cells, basophils, endothelial cells, cytokines, chemokines, complement, and extracellular matrix. A framework is proposed that integrates tick induced changes of skin immune effectors with their ability to respond to tick-borne pathogens. Implications of these changes are addressed. What are the consequences of tick modulation of host cutaneous defenses? Does diversity of salivary gland transcriptomes determine differential modulation of host inflammation and immune defenses and therefore, in part, the clades of pathogens effectively transmitted by different tick species? Do ticks create an immunologically modified cutaneous environment that enhances specific pathogen establishment? Can tick saliva molecules be used to develop vaccines that block pathogen transmission?
    Frontiers in Microbiology 11/2013; 4:337. DOI:10.3389/fmicb.2013.00337 · 3.99 Impact Factor
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    • "For instance, ISAC, Salp20, IRAC I/II, TSLP1, and Salp15 inhibit complement through different mechanisms. ISAC, Salp20, and IRACI/II dissociate the crucial complement convertase molecule C3 (Paesen et al., 1999; Lögdberg and Wester, 2000; Valenzuela et al., 2000; Anguita et al., 2002; Leboulle et al., 2002; Sangamnatdej et al., 2002; Andersen et al., 2005; Garg et al., 2006; Daix et al., 2007; Schroeder et al., 2007; Tyson et al., 2007, 2008; Déruaz et al., 2008; Schuijt et al., 2011). However, TSLP1 and Salp15 target the complement pathway by inhibiting mannosebinding lectin and MAC, respectively (Schuijt et al., 2008). "
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    ABSTRACT: Arthropod saliva possesses anti-hemostatic, anesthetic, and anti-inflammatory properties that facilitate feeding and, inadvertently, dissemination of pathogens. Vector-borne diseases caused by these pathogens affect millions of people each year. Many studies address the impact of arthropod salivary proteins on various immunological components. However, whether and how arthropod saliva counters Nod-like (NLR) sensing remains elusive. NLRs are innate immune pattern recognition molecules involved in detecting microbial molecules and danger signals. Nod1/2 signaling results in activation of the nuclear factor-κB and the mitogen-activated protein kinase pathways. Caspase-1 NLRs regulate the inflammasome~- a protein scaffold that governs the maturation of interleukin (IL)-1β and IL-18. Recently, several vector-borne pathogens have been shown to induce NLR activation in immune cells. Here, we provide a brief overview of NLR signaling and discuss clinically relevant vector-borne pathogens recognized by NLR pathways. We also elaborate on possible anti-inflammatory effects of arthropod saliva on NLR signaling and microbial pathogenesis for the purpose of exchanging research perspectives.
    Frontiers in Microbiology 10/2013; 4:308. DOI:10.3389/fmicb.2013.00308 · 3.99 Impact Factor
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