To successfully feed, ticks inject pharmacoactive molecules into the vertebrate host including cystatin cysteine protease inhibitors. However, the molecular and cellular events modulated by tick saliva remain largely unknown. Here, we describe and characterize a novel immunomodulatory cystatin, Iristatin, which is upregulated in the salivary glands of feeding Ixodes ricinus ticks. We present the crystal structure of Iristatin at 1.76 Å resolution. Purified recombinant Iristatin inhibited the proteolytic activity of cathepsins L and C and diminished IL-2, IL-4, IL-9, and IFN-γ production by different T-cell populations, IL-6 and IL-9 production by mast cells, and nitric oxide production by macrophages. Furthermore, Iristatin inhibited OVA antigen-induced CD4+ T-cell proliferation and leukocyte recruitment in vivo and in vitro. Our results indicate that Iristatin affects wide range of anti-tick immune responses in the vertebrate host and may be exploitable as an immunotherapeutic.
- MeSH
- Cystatins classification genetics pharmacology MeSH
- Cytokines metabolism MeSH
- Epoxy Compounds metabolism MeSH
- Phylogeny MeSH
- Immunosuppressive Agents chemistry metabolism pharmacology MeSH
- Ixodes chemistry genetics metabolism MeSH
- Crystallography, X-Ray MeSH
- Macrophages drug effects metabolism MeSH
- Nitric Oxide metabolism MeSH
- Arthropod Proteins chemistry genetics pharmacology MeSH
- Proteolysis drug effects MeSH
- Amino Acid Sequence MeSH
- Sequence Homology, Amino Acid MeSH
- Salivary Cystatins chemistry genetics pharmacology MeSH
- T-Lymphocytes drug effects metabolism MeSH
- Tyrosine analogs & derivatives metabolism MeSH
- Animals MeSH
- Check Tag
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
