The Tick Salivary Protein Salp15 Inhibits the Killing of Serum-Sensitive Borrelia burgdorferi Sensu Lato Isolates

Abstract

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.The Lyme disease agent Borrelia burgdorferi survives in a tick-mouse cycle. In the United States, B. burgdorferi sensu stricto is maintained primarily in Ixodes scapularis ticks, while the European vector of B. burgdorferi sensu stricto, B. garinii, and B. afzelii strains are generally Ixodes ricinus ticks. Feeding of ixodid ticks normally takes several days (2), which gives the host immune system time to react to the arthropod. The ticks have developed several mechanisms to evade both the innate and adaptive host responses, which enable them to take an effective blood meal. Tick saliva possesses proteins with immunosuppressive (14, 18), anticomplement (5,19,27), and antihemostatic (21, 22) activity. Salp15, a feeding-induced tick salivary protein, is known to inhibit CD4 ϩ T-cell activation and proliferation by specifically binding to the CD4 coreceptor of the T cells (1, 6, 13). Also, Salp15 appeared to enhance the survival of B. burgdorferi in the host after transmission by the tick by specifically interacting with B. burgdorferi outer surface protein C (OspC) and providing protection against borreliacidal antibodies (25). Recently we found three Salp15 homologues in I. ricinus ticks (12), and one of these homologues, Salp15 Iric-1, showed 80% similarity to I. scapularis Salp15 (Iscap Salp15) at the DNA level.The innate response, the complement system in particular, plays a crucial role in the eradication of invading pathogens. The complement system is important in the initiation of attack against B. burgdorferi. The spirochetes are opsonized and also directly killed by the formation of the lytic pore-forming membrane attack complex (MAC) (3, 23). B. burgdorferi sensu stricto, B. garinii, and B. afzelii isolates are able to activate complement both by the classical pathway and by the alternative pathway in nonimmune human serum (NHS) in the absence of specific antibodies, but they differ in susceptibility to complement-mediated killing (28). Serum-resistant Borrelia strains are able to evade comple...

Outer Surface Protein OspC Is an Antiphagocytic Factor That Protects Borrelia burgdorferi from Phagocytosis by Macrophages

“…OspC also has been proposed to play roles in promoting survival and/or dissemination of spirochetes within the mammalian host. For example, OspC binds to a tick salivary protein, Salp15, which can protect spirochetes from complementand antibody-mediated killing (23,24). OspC was shown to bind host plasminogen (25,26), and this phenotype correlates with invasiveness of spirochetes in mice (27).…”

Tick saliva affects both proliferation and distribution of Borrelia burgdorferi spirochetes in mouse organs and increases transmission of spirochetes to ticks

“…This protein protected serum-sensitive B. burgdorferi s.l. isolates against complement-mediated killing (Schuijt et al, 2008), inhibited production of proinflammatory cytokines TNF-a, IL-6, and IL-12 by dendritic cells and impaired CD4+ T cell activation (Anguita et al, 2002).…”

“…The only SAT factor identified so far is Salp15 (Ramamoorthi et al, 2005). This protein is upregulated in the salivary glands of Borrelia-infected ticks, binds on the spirochete surface lipoprotein OspC, protects bacteria from the killing effect of complement and inhibits adaptive immune response against Borrelia antigens (Schuijt et al, 2008;Hovius et al, 2008). While many of the SAT studies are based on the effect of tick salivary gland extract (SGE) or saliva on the infectivity of the pathogen for ticks (Labuda et al, 1993), very few report on the effect of tick saliva on the proliferation and spreading of the pathogen in the host (Kročova´et al, 2003).…”

Lyme disease

“…117,162 OspC binds to a tick salivary protein, Salp15, which promotes efficient transit and early colonization by inhibiting complementmediated destruction, dendritic cell function, and humoral and cellular host immunity. [163][164][165] In early infection, the attachment of decorin-binding protein A to collagen-rich tissues like skin may instigate the dysregulation of inflammation, impairing immunologic clearance. 52 Similarly, a fibronectin-binding surface protein, BBK32, may contribute to the virulence and tissue specificity of B burgdorferi, 55,166 although this has been debated.…”