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

Abstract

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.

Keywords: Borrelia burgdorferi; Salp15; T cell; immunomodulation; therapeutic effects; tick.

Figure 1

Phylogenetic analysis of Salp15 protein family. A phylogenetic tree of Salp15 homologs was generated using amino acid sequences from I. scapularis, I. pacificus, I. ricinus, I. persulcatus, I. holocyclus, and I. sinensis. Accession numbers for the sequences are shown. Sequences were aligned using ClustalW software online, and the phylogenetic tree was constructed using MEGA 5 software.

Figure 2

Salp15 specifically binds to CD4 molecules on the surface of T lymphocytes, thus inhibiting TCR-mediated signal transduction. Under normal circumstances, CD4 binds to the MHC-II molecule and TCR binds to the peptide created when the TCR complex interacts with the peptide-MHC complex; this activates LCK and initiates a biochemical cascade reaction. Binding between Salp15 and CD4 can impede the activation of LCK during the activation of CD4+ T cells. During the activation of CD4+ T cells, Salp15, and CD4 binding inhibits LCK activation and prevents the activation of a series of downstream substrates, including ZAP70, LAT, and PLC-γ1. Eventually, there is a significant reduction in the intracellular calcium flux when CD4+ T cells are activated, which reduces the binding ability of NF-AT and NF-κB to DNA and impairs the production of IL-2. However, AP-1 transcriptional activity and other non-TCR-mediated signaling events are not affected by Salp15. ER, endoplasmic reticulum; LAT, linker of activation in T cells.