Inhibition of Neutrophil Function by Two Tick Salivary Proteins

Guo, Ximing; Booth, Carmen J.; Paley, Michael; Wang, Xiaomei; DePonte, Kathleen; Fikrig, Erol; Narasimhan, Sukanya; Montgomery, Ruth R.

doi:10.1128/iai.01507-08

Cited by 96 publications

(79 citation statements)

References 57 publications

(74 reference statements)

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“…In another example, Salp15 from tick saliva was able to directly interact with the surface of Borrelia burgdorferi and facilitated evasion from host B cell-mediated immunity (160), and immunization against Salp15 protected mice from Lyme disease (50). Another study identified two tick saliva proteins that functioned to inhibit polymorphonuclear leukocyte recruitment during infection of mice with Borrelia burgdorferi, likely increasing the spirochete burden and enhancing infection (77). Identification of proteins in mosquito saliva that are responsible for the enhancement of WNV transmission is under way, and these investigations may provide novel nonvirus targets for vaccine design.…”

Section: Mosquito Saliva Factorsmentioning

confidence: 99%

West Nile Virus: Biology, Transmission, and Human Infection

et al. 2012

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Section: Mosquito Saliva Factorsmentioning

confidence: 99%

West Nile Virus: Biology, Transmission, and Human Infection

et al. 2012

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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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“…The factors responsible for these processes were not identified. Recently, two proteins, ISL929 and 1373, were shown to downregulate neutrophil integrin expression and to reduce the production of superoxide anions (19). The member of the serpin superfamily, Iris (I. ricinus immunosuppressor), is a specific elastase inhibitor expressed in I. ricinus saliva (20).…”

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Neutrophil Extracellular Traps Entrap and KillBorrelia burgdorferiSensu Stricto Spirochetes and Are Not Affected byIxodes ricinusTick Saliva

Menten-Dedoyart

Faccinetto

Golovchenko

et al. 2012

The Journal of Immunology

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Lyme disease is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. They are transmitted mainly by Ixodes ricinus ticks. After a few hours of infestation, neutrophils massively infiltrate the bite site. They can kill Borrelia via phagocytosis, oxidative burst, and hydrolytic enzymes. However, factors in tick saliva promote propagation of the bacteria in the host even in the presence of a large number of neutrophils. The neutrophil extracellular trap (NET) consists in the extrusion of the neutrophil’s own DNA, forming traps that can retain and kill bacteria. The production of reactive oxygen species is apparently associated with the onset of NETs (NETosis). In this article, we describe NET formation at the tick bite site in vivo in mice. We show that Borrelia burgdorferi sensu stricto spirochetes become trapped and killed by NETs in humans and that the bacteria do not seem to release significant nucleases to evade this process. Saliva from I. ricinus did not affect NET formation by human neutrophils or its stability. However, it greatly decreased neutrophil reactive oxygen species production, suggesting that a strong decrease of hydrogen peroxide does not affect NET formation. Finally, round bodies trapped in NETs were observed, some of them staining as live bacteria. This observation could help contribute to a better understanding of the early steps of Borrelia invasion and erythema migrans formation after tick bite.

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Inhibition of Neutrophil Function by Two Tick Salivary Proteins

Cited by 96 publications

References 57 publications

West Nile Virus: Biology, Transmission, and Human Infection

West Nile Virus: Biology, Transmission, and Human Infection

Deconstructing Tick Saliva

Neutrophil Extracellular Traps Entrap and KillBorrelia burgdorferiSensu Stricto Spirochetes and Are Not Affected byIxodes ricinusTick Saliva

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