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.

• Klíčová slova
• Cathepsin, Crystal structure, Immune responses, Ixodes ricinus, Saliva,
• MeSH
• cystatiny klasifikace   genetika   farmakologie   MeSH
• cytokiny metabolismus   MeSH
• epoxidové sloučeniny metabolismus   MeSH
• fylogeneze MeSH
• imunosupresiva chemie   metabolismus   farmakologie   MeSH
• klíště chemie   genetika   metabolismus   MeSH
• krystalografie rentgenová MeSH
• makrofágy účinky léků   metabolismus   MeSH
• oxid dusnatý metabolismus   MeSH
• proteiny členovců chemie   genetika   farmakologie   MeSH
• proteolýza účinky léků   MeSH
• sekvence aminokyselin MeSH
• sekvenční homologie aminokyselin MeSH
• slinné cystatiny chemie   genetika   farmakologie   MeSH
• T-lymfocyty účinky léků   metabolismus   MeSH
• tyrosin analogy a deriváty   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cathestatin C MeSH Prohlížeč
• cystatiny MeSH
• cytokiny MeSH
• epoxidové sloučeniny MeSH
• imunosupresiva MeSH
• oxid dusnatý MeSH
• proteiny členovců MeSH
• slinné cystatiny MeSH
• tyrosin MeSH

The publication of the first tick sialome (salivary gland transcriptome) heralded a new era of research of tick protease inhibitors, which represent important constituents of the proteins secreted via tick saliva into the host. Three major groups of protease inhibitors are secreted into saliva: Kunitz inhibitors, serpins, and cystatins. Kunitz inhibitors are anti-hemostatic agents and tens of proteins with one or more Kunitz domains are known to block host coagulation and/or platelet aggregation. Serpins and cystatins are also anti-hemostatic effectors, but intriguingly, from the translational perspective, also act as pluripotent modulators of the host immune system. Here we focus especially on this latter aspect of protease inhibition by ticks and describe the current knowledge and data on secreted salivary serpins and cystatins and their role in tick-host-pathogen interaction triad. We also discuss the potential therapeutic use of tick protease inhibitors.

• Klíčová slova
• cystatins, immunomodulation, protease inhibitors, serpins, tick-host interaction,
• MeSH
• cystatiny fyziologie   terapeutické užití   MeSH
• imunomodulace MeSH
• inhibitory proteas klasifikace   metabolismus   terapeutické užití   MeSH
• inhibitory serinových proteinas fyziologie   terapeutické užití   MeSH
• interakce hostitele a parazita MeSH
• klíšťata metabolismus   MeSH
• lidé MeSH
• serpiny fyziologie   terapeutické užití   MeSH
• sliny enzymologie   metabolismus   MeSH
• transkriptom MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cystatiny MeSH
• inhibitory proteas MeSH
• inhibitory serinových proteinas MeSH
• serpiny MeSH

Coevolution of ticks and the vertebrate immune system has led to the development of immunosuppressive molecules that prevent immediate response of skin-resident immune cells to quickly fend off the parasite. In this article, we demonstrate that the tick-derived immunosuppressor sialostatin L restrains IL-9 production by mast cells, whereas degranulation and IL-6 expression are both unaffected. In addition, the expression of IL-1β and IRF4 is strongly reduced in the presence of sialostatin L. Correspondingly, IRF4- or IL-1R-deficient mast cells exhibit a strong impairment in IL-9 production, demonstrating the importance of IRF4 and IL-1 in the regulation of the Il9 locus in mast cells. Furthermore, IRF4 binds to the promoters of Il1b and Il9, suggesting that sialostatin L suppresses mast cell-derived IL-9 preferentially by inhibiting IRF4. In an experimental asthma model, mast cell-specific deficiency in IRF4 or administration of sialostatin L results in a strong reduction in asthma symptoms, demonstrating the immunosuppressive potency of tick-derived molecules.

• MeSH
• bronchiální astma genetika   imunologie   patologie   MeSH
• cystatiny imunologie   farmakologie   MeSH
• degranulace buněk imunologie   MeSH
• genetická transkripce MeSH
• imunosupresiva farmakologie   MeSH
• interakce hostitele a parazita imunologie   MeSH
• interferonové regulační faktory nedostatek   genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• interleukin-6 genetika   imunologie   MeSH
• interleukin-9 antagonisté a inhibitory   genetika   imunologie   MeSH
• mastocyty účinky léků   imunologie   patologie   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• přirozená imunita účinky léků   MeSH
• promotorové oblasti (genetika) MeSH
• receptory interleukinu-1 genetika   imunologie   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• vazba proteinů MeSH
• vazebná místa 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
• cystatiny MeSH
• imunosupresiva MeSH
• interferon regulatory factor-4 MeSH Prohlížeč
• interferonové regulační faktory MeSH
• interleukin-1beta MeSH
• interleukin-6 MeSH
• interleukin-9 MeSH
• receptory interleukinu-1 MeSH
• sialostatin L, Ixodes scapularis MeSH Prohlížeč

Ticks developed a multitude of different immune evasion strategies to obtain a blood meal. Sialostatin L is an immunosuppressive cysteine protease inhibitor present in the saliva of the hard tick Ixodes scapularis. In this study, we demonstrate that sialostatin L strongly inhibits the production of IL-9 by Th9 cells. Because we could show recently that Th9-derived IL-9 is essentially involved in the induction of asthma symptoms, sialostatin L was used for the treatment of experimental asthma. Application of sialostatin L in a model of experimental asthma almost completely abrogated airway hyperresponsiveness and eosinophilia. Our data suggest that sialostatin L can prevent experimental asthma, most likely by inhibiting the IL-9 production of Th9 cells. Thus, alternative to IL-9 neutralization sialostatin L provides the basis for the development of innovative therapeutic strategies to treat asthma.

• MeSH
• bronchiální astma imunologie   metabolismus   prevence a kontrola   MeSH
• cystatiny imunologie   farmakologie   MeSH
• cytokiny imunologie   metabolismus   MeSH
• ELISA MeSH
• interleukin-9 biosyntéza   imunologie   MeSH
• Ixodidae imunologie   MeSH
• kvantitativní polymerázová řetězová reakce MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši knockoutované MeSH
• myši MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• průtoková cytometrie MeSH
• separace buněk MeSH
• T-lymfocyty - podskupiny imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cystatiny MeSH
• cytokiny MeSH
• interleukin-9 MeSH
• sialostatin L, Ixodes scapularis MeSH Prohlížeč