Nejvíce citovaný článek - PubMed ID 34502392
Ixodes ricinus Salivary Serpin Iripin-8 Inhibits the Intrinsic Pathway of Coagulation and Complement
BACKGROUND: Ticks, hematophagous Acari, pose a significant threat by transmitting various pathogens to their vertebrate hosts during feeding. Despite advances in tick genomics, high-quality genomes were lacking until recently, particularly in the genus Ixodes, which includes the main vectors of Lyme disease. RESULTS: Here, we present the genome sequences of four tick species, derived from a single female individual, with a particular focus on the European species Ixodes ricinus, achieving a chromosome-level assembly. Additionally, draft assemblies were generated for the three other Ixodes species, I. persulcatus, I. pacificus, and I. hexagonus. The quality of the four genomes and extensive annotation of several important gene families have allowed us to study the evolution of gene repertoires at the level of the genus Ixodes and of the tick group. We have determined gene families that have undergone major amplifications during the evolution of ticks, while an expression atlas obtained for I. ricinus reveals striking patterns of specialization both between and within gene families. Notably, several gene family amplifications are associated with a proliferation of single-exon genes-most strikingly for fatty acid elongases and sulfotransferases. CONCLUSIONS: The integration of our data with existing genomes establishes a solid framework for the study of gene evolution, improving our understanding of tick biology. In addition, our work lays the foundations for applied research and innovative control targeting these organisms.
- Klíčová slova
- Comparative genomics, Duplication, Hematophagy, Parasite, Retroposition,
- MeSH
- biologická evoluce * MeSH
- fylogeneze MeSH
- genom * MeSH
- klíště * genetika klasifikace MeSH
- molekulární evoluce * MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Iripin-4, one of the many salivary serpins from Ixodes ricinus ticks with an as-yet unexplained function, crystallized in two different structural conformations, namely the native partially relaxed state and the cleaved serpin. The native structure was solved at a resolution of 2.3 Å and the structure of the cleaved conformation was solved at 2.0 Å resolution. Furthermore, structural changes were observed when the reactive-centre loop transitioned from the native conformation to the cleaved conformation. In addition to this finding, it was confirmed that Glu341 represents a primary substrate-recognition site for the inhibitory mechanism. The presence of glutamate instead of the typical arginine in the P1 recognition site of all structurally characterized I. ricinus serpins (PDB entries 7b2t, 7pmu and 7ahp), except for the tyrosine in the P1 site of Iripin-2 (formerly IRS-2; PDB entry 3nda), would explain the absence of inhibition of the tested proteases that cleave their substrate after arginine. Further research on Iripin-4 should focus on functional analysis of this interesting serpin.
- Klíčová slova
- Iripin-4, Ixodes ricinus, X-ray structure, cleaved conformation, native conformation, serpins,
- MeSH
- arginin MeSH
- klíště * MeSH
- konformace proteinů MeSH
- molekulární modely MeSH
- serpiny * chemie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- arginin MeSH
- serpiny * MeSH
Arthropod disease vectors not only transmit malaria but many other serious diseases, many of which are, to a greater or lesser degree, neglected [...].
Serpins are widely distributed and functionally diverse inhibitors of serine proteases. Ticks secrete serpins with anti-coagulation, anti-inflammatory, and immunomodulatory activities via their saliva into the feeding cavity to modulate host's hemostatic and immune reaction initiated by the insertion of tick's mouthparts into skin. The suppression of the host's immune response not only allows ticks to feed on a host for several days but also creates favorable conditions for the transmission of tick-borne pathogens. Herein we present the functional and structural characterization of Iripin-1 (Ixodes ricinus serpin-1), whose expression was detected in the salivary glands of the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Of 16 selected serine proteases, Iripin-1 inhibited primarily trypsin and further exhibited weaker inhibitory activity against kallikrein, matriptase, and plasmin. In the mouse model of acute peritonitis, Iripin-1 enhanced the production of the anti-inflammatory cytokine IL-10 and chemokines involved in neutrophil and monocyte recruitment, including MCP-1/CCL2, a potent histamine-releasing factor. Despite increased chemokine levels, the migration of neutrophils and monocytes to inflamed peritoneal cavities was significantly attenuated following Iripin-1 administration. Based on the results of in vitro experiments, immune cell recruitment might be inhibited due to Iripin-1-mediated reduction of the expression of chemokine receptors in neutrophils and adhesion molecules in endothelial cells. Decreased activity of serine proteases in the presence of Iripin-1 could further impede cell migration to the site of inflammation. Finally, we determined the tertiary structure of native Iripin-1 at 2.10 Å resolution by employing the X-ray crystallography technique. In conclusion, our data indicate that Iripin-1 facilitates I. ricinus feeding by attenuating the host's inflammatory response at the tick attachment site.
- Klíčová slova
- anti-inflammatory protein, cell migration, iripin, ixodes ricinus, serpin, tick saliva, tick-host interaction, ticks,
- MeSH
- antiflogistika farmakologie MeSH
- chemokiny MeSH
- endoteliální buňky metabolismus MeSH
- klíště * metabolismus MeSH
- monocyty metabolismus MeSH
- myši MeSH
- serpiny * metabolismus MeSH
- trypsin MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
- Názvy látek
- antiflogistika MeSH
- chemokiny MeSH
- serpiny * MeSH
- trypsin MeSH
Tick saliva has been extensively studied in the context of tick-host interactions because it is involved in host homeostasis modulation and microbial pathogen transmission to the host. Accumulated knowledge about the tick saliva composition at the molecular level has revealed that serine protease inhibitors play a key role in the tick-host interaction. Serpins are one highly expressed group of protease inhibitors in tick salivary glands, their expression can be induced during tick blood-feeding, and they have many biological functions at the tick-host interface. Indeed, tick serpins have an important role in inhibiting host hemostatic processes and in the modulation of the innate and adaptive immune responses of their vertebrate hosts. Tick serpins have also been studied as potential candidates for therapeutic use and vaccine development. In this review, we critically summarize the current state of knowledge about the biological role of tick serpins in shaping tick-host interactions with emphasis on the mechanisms by which they modulate host immunity. Their potential use in drug and vaccine development is also discussed.
- Klíčová slova
- anti-tick vaccine, immunomodulation, serpins, therapeutic effects, tick host interaction, tick saliva,
- MeSH
- inhibitory serinových proteinas fyziologie MeSH
- klíšťata * metabolismus MeSH
- serpiny * metabolismus MeSH
- slinné žlázy metabolismus MeSH
- sliny metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- inhibitory serinových proteinas MeSH
- serpiny * MeSH
