Protease Inhibitors in Tick Saliva: The Role of Serpins and Cystatins in Tick-host-Pathogen Interaction

Chmelař, Jindrǐch; Kotál, Jan; Langhansová, Helena; Kotsyfakis, Michail

doi:10.3389/fcimb.2017.00216

Cited by 83 publications

(105 citation statements)

References 174 publications

(245 reference statements)

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“…Serpins are evolutionarily conserved and also widely distributed in arthropods . Large numbers of protease inhibitors were found to be expressed in the tick salivary glands, including Cystatin, Serpin and Kunitz‐like family . cDNAs encoding serpin‐like proteins have now been cloned from several tick species, including Ixodes scapularis , Ixodes ricinus , Boophilus microplus , Haemaphysalis longicornis and Rhipicephalus appendiculatus .…”

Section: Introductionmentioning

confidence: 99%

“…cDNAs encoding serpin‐like proteins have now been cloned from several tick species, including Ixodes scapularis , Ixodes ricinus , Boophilus microplus , Haemaphysalis longicornis and Rhipicephalus appendiculatus . Some tick serpins have been shown to be associated with counter defense against anti‐tick responses in the host, such as inflammation, complement activation, platelet aggregation, and blood clotting . In other studies, tick serpins are suggested as being important in tick feeding physiology, as significant reductions in feeding efficiency had been observed in ticks that fed on animals immunized with recombinant tick serpins .…”

Section: Introductionmentioning

confidence: 99%

“…Some tick serpins have been shown to be associated with counter defense against anti‐tick responses in the host, such as inflammation, complement activation, platelet aggregation, and blood clotting . In other studies, tick serpins are suggested as being important in tick feeding physiology, as significant reductions in feeding efficiency had been observed in ticks that fed on animals immunized with recombinant tick serpins . However, very little information has been provided for the mechanisms of how these arthropod serpins act as immunosuppressants and how to utilize these large proteins in disease models in a proper way.…”

Section: Introductionmentioning

confidence: 99%

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The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

et al. 2019

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Summary Serpins are evolutionarily conserved serine protease inhibitors that are widely distributed in animals, plants and microbes. In this study, we reported the cloning and functional characterizations of two novel serpin genes, HlSerpin‐a and HlSerpin‐b, from the hard tick Haemaphysalis longicornis of China. Recombinant HlSerpin‐a and HlSerpin‐b displayed protease inhibitory activities against multiple mammalian proteases. Similar to other tick serpins, HlSerpin‐a and HlSerpin‐b suppressed the expression of inflammatory cytokines such as TNF‐α, interleukin (IL)‐6 and IL‐1β from lipopolysaccharide‐stimulated mouse bone‐marrow‐derived macrophages (BMDMs) or mouse bone‐marrow‐derived dendritic cells (BMDCs). The minimum active region (reaction centre loop) of HlSerpin‐a, named SA‐RCL, showed similar biological activities as HlSerpin‐a in the protease inhibition and immune suppression assays. The immunosuppressive activities of full‐length HlSerpin‐a and SA‐RCL are impaired in Cathepsin G or Cathepsin B knockout mouse macrophages, suggesting that the immunomodulation functions of SA and SA‐RCL are dependent on their protease inhibitory activity. Finally, we showed that both full‐length HlSerpins and SA‐RCL can relieve the joint swelling and inflammatory response in collagen‐induced mouse arthritis models. These results suggested that HlSerpin‐a and HlSerpin‐b are two functional arthropod serpins, and the minimal reactive peptide SA‐RCL is a potential candidate for drug development against inflammatory diseases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

et al. 2019

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“…To date, approximately 20 tick cystatins, all belonging to family types 1 and 2, have been reported [48]. Their functions include immunomodulatory (host or itself), Borrelia and Anaplasma phagocytophilum infections, and tick feeding, attachment, and hatching.…”

Section: Discussionmentioning

confidence: 99%

A Tick Cysteine Protease Inhibitor RHcyst-1 Exhibits Antitumor Potential

Wei

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: We previously identified a potent and tight-binding inhibitor of cysteine proteases from Rhipicephalus haemaphysaloides, RHcyst-1, which belongs to the cystatin type 1 family. Cathepsins, which are members of the cysteine protease family, participate in various pathological processes, including the initiation and development of cancers. The present study aimed to investigate the antitumor effects of RHcyst-1 and to explore the underlying mechanism of these effects. Methods: Different tumor cells were treated with RHcyst-1 in vitro. Proliferation activity was evaluated using Cell Counting Kit-8, and migration and invasion were determined by wound healing and Transwell® invasion assays. In addition, a mouse tumor therapy model was established by inoculating the left forelimb of mice with B16-F10 cells, and tumor progression was evaluated by assessing tumor volume and survival. Flow cytometry was conducted to evaluate myeloid-derived suppressor cells (MDSCs), CD4⁺, and CD8⁺ T cell levels in PBMCs and spleens. Immunohistochemistry was performed to analyze immune cell infiltration and angiogenesis in the tumors. Results: RHcyst-1 significantly inhibited the proliferation, migration, and invasion of all four different tumor cells in vitro. Additionally, it inhibited tumor growth and improved survival in vivo. A decrease and an increase in MDSCs levels were observed in PBMCs and in the spleen, respectively, after RHcyst-1 application. Conclusions: Tick RHcyst-1 has potential antitumor efficacy, and the observed antitumor activities may be partly attributable to changes in cathepsin expression and MDSCs levels in the PBMCs and spleens. The findings of the present study suggest that RHcyst-1 may have the potential to be utilized in cancer treatment.

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“…These complex processes allow the ticks to remain attached for a prolonged period and compensate for different host defense mechanisms and requirements of the tick feeding cycle. Tick salivary molecules can be grouped into major categories based on their function, such as lipocalins (acting as kratagonists of biogenic amines and prostanoids), metalloproteases (having fibrinolytic activity), Kunitz-domain containing peptides (having putative sodium channel blocking or anticlotting activities), basic tail polypeptides (a unique protein family having anti-thrombin or plasminogen-activating activities), the salp-15 family (having immunosuppressive activity), the Isac family (having anticomplement activity), glycine-rich peptides (immunogenic components of the tick cement) (Francischetti et al, 2009;Blisnick et al, 2017;Chmelar et al, 2017;Šimo et al, 2017). Interestingly, not all molecules are secreted simultaneously .…”

Section: Introductionmentioning

confidence: 99%

Tick-Borne Encephalitis Virus Infection Alters the Sialome of Ixodes ricinus Ticks During the Earliest Stages of Feeding

Hart

Ribeiro

Kazimírová

et al. 2020

Front. Cell. Infect. Microbiol.

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Ticks are hematophagous arthropods that transmit a number of pathogens while feeding. Among these is tick-borne encephalitis virus (TBEV), a flavivirus transmitted by Ixodes ricinus ticks in the temperate zone of Europe. The infection results in febrile illness progressing to encephalitis and meningitis with a possibility of fatality or long-term neurological sequelae. The composition of tick saliva plays an essential role in the initial virus transmission during tick feeding. Ticks secrete a diverse range of salivary proteins to modulate the host response, such as lipocalins to control the itch and inflammatory response, and both proteases and protease inhibitors to prevent blood coagulation. Here, the effect of viral infection of adult females of Ixodes ricinus was studied with the goal of determining how the virus alters the tick sialome to modulate host tissue response at the site of infection. Uninfected ticks or those infected with TBEV were fed on mice and removed and dissected one-and 3-h post-attachment. RNA from the salivary glands of these ticks, as well as from unfed ticks, was extracted and subjected to next-generation sequencing to determine the expression of key secreted proteins at each timepoint. Genes showing statistically significant up-or down-regulation between infected and control ticks were selected and compared to published literature to ascertain their function. From this, the effect of tick viral infection on the modulation of the tick-host interface was determined. Infected ticks were found to differentially express a number of uncategorized genes, proteases, Kunitz-type serine protease inhibitors, cytotoxins, and lipocalins at different timepoints. These virus-induced changes to the tick sialome may play a significant role in facilitating virus transmission during the early stages of tick feeding.

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Protease Inhibitors in Tick Saliva: The Role of Serpins and Cystatins in Tick-host-Pathogen Interaction

Cited by 83 publications

References 174 publications

The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

The immunosuppressive functions of two novel tick serpins, HlSerpin‐a and HlSerpin‐b, from Haemaphysalis longicornis

A Tick Cysteine Protease Inhibitor RHcyst-1 Exhibits Antitumor Potential

Tick-Borne Encephalitis Virus Infection Alters the Sialome of Ixodes ricinus Ticks During the Earliest Stages of Feeding

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