A Novel Mechanism of Complement Inhibition Unmasked by a Tick Salivary Protein That Binds to Properdin

Tyson, Katharine R.; Elkins, Christopher A.; Silva, Aravinda M. de

doi:10.4049/jimmunol.180.6.3964

Cited by 66 publications

(63 citation statements)

References 33 publications

(40 reference statements)

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“…Ticks such as Ixodes scapularis and Ixodes ricinus express proteins preventing deposition of C3b, such as Isac (26) and IRACs/IxACs (31,32). IRACs and IxACs, along with Salp20, also have the ability to bind properdin (33). Interestingly, the SMIPPs analyzed in the current study combine the properties of many of the molecules described above, as they have the ability to bind C1q, MBL, and properdin.…”

Section: Discussionmentioning

confidence: 83%

“…The concentrations of SMIPPs in the mite gut are not known and the local concentrations of complement proteins at the sites of mite infection are also not determined. However, 33 SMIPPs have now been identified and, since both of the SMIPPs tested here show complement inhibitory functions, it is possible that many of these molecules inhibit complement. This makes it quite plausible that high concentrations of SMIPPs will be found in vivo.…”

Section: Discussionmentioning

confidence: 99%

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Scabies Mite Inactivated Serine Protease Paralogs Inhibit the Human Complement System

Bergström

Reynolds

Johnstone

et al. 2009

The Journal of Immunology

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Infestation of skin by the parasitic itch mite Sarcoptes scabiei afflicts 300 million people worldwide and there is a need for novel and efficient therapies. We have previously identified a multigene family of serine proteases comprising multiple catalytically inactive members (scabies mite-inactivated protease paralogs (SMIPPs)), which are secreted into the gut of S. scabiei. SMIPPs are located in the mite gut and in feces excreted into the upper epidermis. Scabies mites feed on epidermal protein, including host plasma; consequently, they are exposed to host defense mechanisms both internally and externally. We found that two recombinantly expressed SMIPPs inhibited all three pathways of the human complement system. Both SMIPPs exerted their inhibitory action due to binding of three molecules involved in the three different mechanisms which initiate complement: C1q, mannose-binding lectin, and properdin. Both SMIPPs bound to the stalk domains of C1q, possibly displacing or inhibiting C1r/C1s, which are associated with the same domain. Furthermore, we found that binding of both SMIPPs to properdin resulted in prevention of assembly of the alternative pathway convertases. However, the SMIPPs were not able to dissociate already formed convertases. Immunohistochemical staining demonstrated the presence of C1q in the gut of scabies mites in skin burrows. We propose that SMIPPs minimize complement-mediated gut damage and thus create a favorable environment for the scabies mites.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Scabies Mite Inactivated Serine Protease Paralogs Inhibit the Human Complement System

Bergström

Reynolds

Johnstone

et al. 2009

The Journal of Immunology

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“…I. scapularis saliva contains a protein, Isac, which uncouples factor Bb of the alternative pathway C3 convertase (Valenzuela et al 2000). Another I. scapularis salivary protein, Salp 20, directly binds to and displaces properdin from C3 convertase, accelerating the decay of the C3 convertase and leading to inhibition of the alternative complement pathway (Tyson et al 2008). Salivary gland transcriptome analyses also identified gene products such as I. scapularis sialostatins L and L2, which are cysteine protease inhibitors that target cathepsins and possess anti-inflammatory activity (Kotsyfakis et al 2006(Kotsyfakis et al , 2007.…”

Section: Discussionmentioning

confidence: 99%

Dermatologic Changes Induced by RepeatedIxodes scapularisBites and Implications for Prevention of Tick-Borne Infection

Krause

Grant‐Kels

Tahan

et al. 2009

Vector-Borne and Zoonotic Diseases

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Previous studies in rodents and people have demonstrated that repeated tick exposure is associated with reduced Borrelia burgdorferi transmission but the mechanism of prevention remains unclear. We examined the acute histopathologic reactions to initial and repeated Ixodes scapularis bites in BALB/c mice and in people. Skin biopsies of BALB/c mice infested for the first time by I. scapularis nymphs revealed vascular dilatation and an accumulation of inflammatory cells adjacent to the bite site but absent at the site of tick attachment. Such changes would enhance tick-borne pathogen transmission. Mice reexposed to I. scapularis nymphs experienced a decrease in vascular dilatation and a marked increase in inflammatory cells at the site of tick attachment. Skin biopsies of people with attached I. scapularis nymphs revealed similar histologic patterns. These results indicate that cellular changes at the tick-dermal interface following I. scapularis attachment are likely to allow for successful transmission of tick-borne pathogens in non-tick-immune hosts and to inhibit tick-borne pathogen transmission in hosts that have developed tick immunity.

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“…Regarding anti-tick immunity, molecules present in tick saliva have been associated with modulation of various steps of host immune responses. For example, sialostatin L and PGE 2 2 inhibit maturation of dendritic cells (DCs) and prevent antigen presentation (13,15); DAP-36 and SALP15 inhibit T cell proliferation and activation (16,17); ISL 929 and ISL 1373 reduce recruitment of neutrophils (18); IgG-binding proteins theoretically decrease antibody functions (3,19); ISAC, SALP-20, and OmCI inhibit alternative and/or classical pathways of the complement system (20,21); and EVASIN-1, -3, and -4 bind chemokines and hamper cell migration (22,23).…”

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confidence: 99%

Deconstructing Tick Saliva

Oliveira

Sá-Nunes

Francischetti

et al. 2011

Journal of Biological Chemistry

111

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Dendritic cells (DCs) are powerful initiators of innate and adaptive immune responses. Ticks are blood-sucking ectoparasite arthropods that suppress host immunity by secreting immunomodulatory molecules in their saliva. Here, compounds present in Rhipicephalus sanguineus tick saliva with immunomodulatory effects on DC differentiation, cytokine production, and costimulatory molecule expression were identified. R. sanguineus tick saliva inhibited IL-12p40 and TNF-␣ while potentiating IL-10 cytokine production by bone marrow-derived DCs stimulated by Toll-like receptor-2, -4, and -9 agonists. To identify the molecules responsible for these effects, we fractionated the saliva through microcon filtration and reversed-phase HPLC and tested each fraction for DC maturation. Fractions with proven effects were analyzed by micro-HPLC tandem mass spectrometry or competition ELISA. Thus, we identified for the first time in tick saliva the purine nucleoside adenosine (concentration of ϳ110 pmol/l) as a potent anti-inflammatory salivary inhibitor of DC cytokine production. We also found prostaglandin E 2 (PGE 2 ϳ100 nM) with comparable effects in modulating cytokine production by DCs. Both Ado and PGE 2 inhibited cytokine production by inducing cAMP-PKA signaling in DCs. Additionally, both Ado and PGE 2 were able to inhibit expression of CD40 in mature DCs. Finally, flow cytometry analysis revealed that PGE 2 , but not Ado, is the differentiation inhibitor of bone marrow-derived DCs. The presence of non-protein molecules adenosine and PGE 2 in tick saliva indicates an important evolutionary mechanism used by ticks to subvert host immune cells and allow them to successfully complete their blood meal and life cycle.Ticks are phylogenetically distant from their hosts, but in general, these ectoparasites have developed, through their evolution, measures for adapting to host defense strategies. The most well studied approaches that ticks employ to evade host responses are the refined mixtures of proteic and non-protein molecules present in their saliva with anticlotting, anti-inflammatory, or immunomodulatory activities. As a result, a number of authors have demonstrated the suppression of cell-mediated and humorally mediated immune responses upon in vitro assays and following experimental models of tick infestations or naturally infested hosts (1-8).In the last 4 decades, many of these proteic and non-protein molecules have been characterized and their specific functions identified. To date, a diversity of proteic (e.g. chitinases, mucins, ixostatins, cystatins, defensins, hyaluronidases, Kunitz, lectins, and lipocalins) and non-protein molecules (e.g. prostaglandins and endocannabinoids) have been characterized (9 -14). (18); IgG-binding proteins theoretically decrease antibody functions (3, 19); ISAC, SALP-20, and OmCI inhibit alternative and/or classical pathways of the complement system (20, 21); and EVASIN-1, -3, and -4 bind chemokines and hamper cell migration (22,23).Despite the characterization of these molecules, most co...

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A Novel Mechanism of Complement Inhibition Unmasked by a Tick Salivary Protein That Binds to Properdin

Cited by 66 publications

References 33 publications

Scabies Mite Inactivated Serine Protease Paralogs Inhibit the Human Complement System

Scabies Mite Inactivated Serine Protease Paralogs Inhibit the Human Complement System

Dermatologic Changes Induced by RepeatedIxodes scapularisBites and Implications for Prevention of Tick-Borne Infection

Deconstructing Tick Saliva

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