The Ixodes scapularis salivary protein, salp15, prevents the association of HIV-1 gp120 and CD4

Juncadella, Ignacio J.; Garg, Renu; Bates, Tonya C.; Olivera, Elı́as R.; Anguíta, Juan

doi:10.1016/j.bbrc.2007.12.104

Cited by 10 publications

(13 citation statements)

References 27 publications

(35 reference statements)

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“…For example, Salp15 facilitates transmission of the Lyme disease spirochete from the tick vector to the host [74]. However, it is unclear whether this is due to the binding of Salp15 to: (i) DC-SIGN on DCs, thus inhibiting the spirochete-induced production of pro-inflammatory cytokines by DCs and so modulating DC-induced T cell activation [27]; (ii) CD4, thereby inhibiting T cell activation [28], [75], [76]; and/or (iii) OspC, an outer surface protein on the spirochete, hence protecting the spirochete from antibody-mediated killing [77]. Likewise, Maxadilan promotes transmission of Leishmania parasites although the relative contribution of DC modulation to enhanced transmission is unresolved [78].…”

Section: Discussionmentioning

confidence: 99%

Novel Immunomodulators from Hard Ticks Selectively Reprogramme Human Dendritic Cell Responses

et al. 2013

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Hard ticks subvert the immune responses of their vertebrate hosts in order to feed for much longer periods than other blood-feeding ectoparasites; this may be one reason why they transmit perhaps the greatest diversity of pathogens of any arthropod vector. Tick-induced immunomodulation is mediated by salivary components, some of which neutralise elements of innate immunity or inhibit the development of adaptive immunity. As dendritic cells (DC) trigger and help to regulate adaptive immunity, they are an ideal target for immunomodulation. However, previously described immunoactive components of tick saliva are either highly promiscuous in their cellular and molecular targets or have limited effects on DC. Here we address the question of whether the largest and globally most important group of ticks (the ixodid metastriates) produce salivary molecules that specifically modulate DC activity. We used chromatography to isolate a salivary gland protein (Japanin) from Rhipicephalus appendiculatus ticks. Japanin was cloned, and recombinant protein was produced in a baculoviral expression system. We found that Japanin specifically reprogrammes DC responses to a wide variety of stimuli in vitro, radically altering their expression of co-stimulatory and co-inhibitory transmembrane molecules (measured by flow cytometry) and their secretion of pro-inflammatory, anti-inflammatory and T cell polarising cytokines (assessed by Luminex multiplex assays); it also inhibits the differentiation of DC from monocytes. Sequence alignments and enzymatic deglycosylation revealed Japanin to be a 17.7 kDa, N-glycosylated lipocalin. Using molecular cloning and database searches, we have identified a group of homologous proteins in R. appendiculatus and related species, three of which we have expressed and shown to possess DC-modulatory activity. All data were obtained using DC generated from at least four human blood donors, with rigorous statistical analysis. Our results suggest a previously unknown mechanism for parasite-induced subversion of adaptive immunity, one which may also facilitate pathogen transmission.

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Section: Discussionmentioning

confidence: 99%

Novel Immunomodulators from Hard Ticks Selectively Reprogramme Human Dendritic Cell Responses

et al. 2013

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“…, 2006). In addition, because Salp15 binds to the most extracellular domains of the CD4 in a region that may overlap with the binding residues of the human immunodeficiency virus (HIV)‐1 envelope protein gp120, it is suggested that the domain may be bound with glycoprotein (Juncadella et al. , 2008).…”

Section: Resultsmentioning

confidence: 99%

Two novel Salp15‐like immunosuppressant genes from salivary glands of Ixodes persulcatus Schulze tick

Mori

Konnai

Yamada

et al. 2010

Insect Molecular Biology

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Salp15, a 15-kDa tick salivary gland protein, is known for several suppressive activities against host immunity and critical functions for the transmission of Lyme borrelia in Ixodes scapularis and Ixodes ricinus, the major vectors found in North America and Western Europe. Salp15 inhibits the activation of cluster of differentiation (CD)4(+)T-cells through the repression of T-cell receptor (TCR)-triggered calcium fluxes and interleukin (IL)-2 production. Furthermore, Salp15 adheres to the spirochaeta and specifically interacts with its outer surface protein C. The binding of Salp15 to Borrelia burgdorferi protects it from antibody-mediated killing in vitro. The aim of this study is to identify the Salp15 genes in Ixodes persulcatus Schulze, the specific vector for human Lyme borreliosis in Japan. Two cDNA clones encoding the Salp15-like sequence were obtained from salivary glands of fed female ticks. These genes encode 135- and 132-amino acid proteins, designated Salp15 Iper-1 and Salp15 Iper-2, respectively, both having signal peptide sequences and predicted to be secretory proteins. Salp15 Iper-1 and -2 showed 51.8 and 68.2% similarity to I. scapularis Salp15, respectively. Reverse transcriptase PCR analysis showed that Salp15 Iper genes were expressed specifically in the salivary glands throughout life cycle stages of the ticks and were up-regulated by blood feeding. In the I. persulcatus-derived sequences, the C-terminal part, which is the binding domain to the CD4 molecule of T-cells in I. scapularis Salp15, was well conserved. In the future, it will be necessary to analyse immunosuppressive functions of I. persulcatus Salp15 and their interaction with Borrelia spp. in Japan.

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“…Because the regions of CD4 that interact with Salp15 and HIV-1 gp120 overlap, the question arises as to whether Salp15 could act as a competitive gp120 blocking agent. Another study (109) gave a positive answer to this hypothesis. In vitro microtiter and quantitative fusion assays showed that Salp15 blocks the interaction of gp120 and CD4 in a concentration-dependent manner, and the formation of syncytia by cells expressing gp120 and CD4 is significantly reduced in the presence of Salp15.…”

Section: Salp15 Blocks the Binding Of Hiv-1 Gp120 To Cd4mentioning

confidence: 95%

“…As mentioned above, the C-terminal portion (P11) of Salp15 is responsible for the binding of CD4. A previous study suggested that Salp15 competes with gp120 for an association with CD4, owing to spatial effects related to the interaction of the entire Salp15 protein with T cells, and not P11 (109). Nevertheless, P11 is able to bind to gp120, which is at least partly responsible for the competitive effect elicited by Salp15 (109).…”

Section: Salp15 Blocks the Binding Of Hiv-1 Gp120 To Cd4mentioning

confidence: 96%

“…A previous study suggested that Salp15 competes with gp120 for an association with CD4, owing to spatial effects related to the interaction of the entire Salp15 protein with T cells, and not P11 (109). Nevertheless, P11 is able to bind to gp120, which is at least partly responsible for the competitive effect elicited by Salp15 (109). The neutralizing activity of the interaction between Salp15 and HIV-gp120 predicts that this salivary protein may become a new template for the recognition of epitopes in HIV envelope proteins that produce neutralizing antibodies (109).…”

Section: Salp15 Blocks the Binding Of Hiv-1 Gp120 To Cd4mentioning

confidence: 99%

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Salp15, a Multifunctional Protein From Tick Saliva With Potential Pharmaceutical Effects

Wen

Wang

et al. 2020

Front. Immunol.

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Ixodes ticks are the main vectors for a number of zoonotic diseases, including Lyme disease. Ticks secrete saliva directly into a mammalian host while feeding on the host's blood. This action serves to modulate host immunity and coagulation, thus allowing ticks to attach and feed upon their host. One of the most extensively studied components of tick saliva is Salp15. Research has shown that this protein binds specifically to CD4 molecules on the surface of T lymphocytes, interferes with TCR-mediated signaling transduction, inhibits CD4+ T cell activation and proliferation, and impedes the secretion of interleukin 2 (IL-2). Salp15 also binds specifically to dendritic cell dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) to up-regulate the expression of CD73 in regulatory T cells. Collectively, these findings render this salivary protein a potential candidate for a range of therapeutic applications. Here, we discuss our current understanding of Salp15 and the mechanisms that might be used to treat disease.

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The Ixodes scapularis salivary protein, salp15, prevents the association of HIV-1 gp120 and CD4

Cited by 10 publications

References 27 publications

Novel Immunomodulators from Hard Ticks Selectively Reprogramme Human Dendritic Cell Responses

Novel Immunomodulators from Hard Ticks Selectively Reprogramme Human Dendritic Cell Responses

Two novel Salp15‐like immunosuppressant genes from salivary glands of Ixodes persulcatus Schulze tick

Salp15, a Multifunctional Protein From Tick Saliva With Potential Pharmaceutical Effects

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