Toxoplasma gondii serine-protease inhibitor-1: A new adjuvant candidate for asthma therapy

Soto, Ariadna Soledad; Fenoy, Ignacio Martín; Sánchez, Vanesa Roxana; March, Florencia; Sibilia, Matías Damián Perrone; Aldirico, María de los ängeles; Picchio, Mariano S.; Arcon, Nadia; Acosta, Patricio L.; Polack, Fernando P.; Martin, Valentina; Goldman, Alejandra

doi:10.1371/journal.pone.0187002

Cited by 9 publications

(11 citation statements)

References 46 publications

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“…In our study, HSP60 was identified just after the cat was infected with T. gondii , which further shows that HSP60 does play an important role in the differentiation of oocysts after cat infection. Serine protease inhibitors display immunomodulatory properties [ 46 ], and T. gondii serine protease inhibitor 1 (TgPI1) not only affects the virulence of T. gondii but also affects the differentiation of bradyzoites [ 47 ]. It has been speculated that this may occur through inhibition of T. gondii and/or host serine protease [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Glycosylation Analysis of Feline Small Intestine Following Toxoplasma gondii Infection

Zhai

Xie

Peng

et al. 2022

Animals

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Toxoplasma gondii (T. gondii) is responsible for severe human and livestock diseases, huge economic losses, and adversely affects the health of the public and the development of animal husbandry. Glycosylation is a common posttranslational modification of proteins in eukaryotes, and N-glycosylation is closely related to the biological functions of proteins. However, glycosylation alterations in the feline small intestine following T. gondii infection have not been reported. In this study, the experimental group was intragastrically challenged with 600 brain cysts of the Prugniuad (Pru) strain that were collected from infected mice. The cats’ intestinal epithelial tissues were harvested at 10 days post-infection and then sent for protein glycosylation analysis. High-performance liquid chromatography coupled to tandem mass spectrometry was used to analyze the glycosylation alterations in the small intestine of cats infected with T. gondii. The results of the present study showed that 56 glycosylated peptides were upregulated and 37 glycosylated peptides were downregulated in the feline small intestine infected by T. gondii. Additionally, we also identified eight N-glycosylated proteins of T. gondii including eight N-glycopeptides and eight N-glycosylation sites. The protein A0A086JND6_TOXGO (eEF2) and its corresponding peptide sequence were identified in T. gondii infection. Some special GO terms (i.e., cellular process and metabolic process, cell and cell part, and catalytic activity) were significantly enriched, and the Clusters of Orthologous Groups of proteins (COG) function prediction results showed that posttranslational modification, protein turnover, and chaperones (11%) had the highest enrichment for T. gondii. Interestingly, eEF2, a protein of T. gondii, is also involved in the significantly enriched T. gondii MAPK pathway. The host proteins ICAM-1 and PPT1 and the endoplasmic reticulum stress pathway may play an important role in the glycosylation of Toxoplasma-infected hosts. This is the first report showing that T. gondii oocysts can undergo N-glycosylation in the definitive host and that eEF2 is involved, which may provide a new target for T. gondii detection to prevent the spread of T. gondii oocysts in the future.

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Section: Discussionmentioning

confidence: 99%

Glycosylation Analysis of Feline Small Intestine Following Toxoplasma gondii Infection

Zhai

Xie

Peng

et al. 2022

Animals

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“…Plates were read in a plate reader (Sunrise RC, Tecan) at 450 nm with λ correction at 570 nm after the addition of stop solution (H 2 SO 4 ). Results are shown as optical density (OD) for a fixed dilution …”

Section: Methodsmentioning

confidence: 99%

Azelastine potentiates antiasthmatic dexamethasone effect on a murine asthma model

Zappia

Soto

Granja-Galeano

et al. 2019

Pharmacology Res & Perspec

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Glucocorticoids are among the most effective drugs to treat asthma. However, the severe adverse effects associated generate the need for its therapeutic optimization. Conversely, though histamine is undoubtedly related to asthma development, there is a lack of efficacy of antihistamines in controlling its symptoms, which prevents their clinical application. We have reported that antihistamines potentiate glucocorticoids’ responses in vitro and recent observations have indicated that the coadministration of an antihistamine and a synthetic glucocorticoid has synergistic effects on a murine model of allergic rhinitis. Here, the aim of this work is to establish if this therapeutic combination could be beneficial in a murine model of asthma. We used an allergen‐induced model of asthma (employing ovalbumin) to evaluate the effects of the synthetic glucocorticoid dexamethasone combined with the antihistamine azelastine. Our results indicate that the cotreatment with azelastine and a suboptimal dose of dexamethasone can improve allergic lung inflammation as shown by a decrease in eosinophils in bronchoalveolar lavage, fewer peribronchial and perivascular infiltrates, and mucin‐producing cells. In addition, serum levels of allergen‐specific IgE and IgG1 were also reduced, as well as the expression of lung inflammatory‐related genes IL‐4, IL‐5, Muc5AC, and Arginase I. The potentiation of dexamethasone effects by azelastine could allow to reduce the effective glucocorticoid dose needed to achieve a therapeutic effect. These findings provide first new insights into the potential benefits of glucocorticoids and antihistamines combination for the treatment of asthma and grants further research to evaluate this approach in other related inflammatory conditions.

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“…The full-length recombinant protein rTgPI-1 and its truncated versions, Nt (containing domains 1 and 2) or Ct (containing domains 3 and 4), were previously generated by Pszenny et al [12]. rTgPI-1 was expressed and purified as described by Soto et al [6]. Expression and purification of truncated proteins were performed using the same protocol as rTgPI-1.…”

Section: Expression and Purification Of The Recombinant Proteinsmentioning

confidence: 99%

“…Asthmatic mice intranasally treated with a mixture of rTgPI-1 and allergen showed higher reduction in asthma hallmarks compared with the administration of rTgPI-1 alone. Moreover, a reduction in allergen-specific T-cell proliferation in thoracic lymph nodes and spleen and an expansion of Tregs was only seen in the co-administered group, suggesting that this inhibitor may function as a tolerogenic adjuvant [6]. Hence, rTgPI-1 emerges as a novel adjuvant candidate to be included in SIT formulations.…”

Section: Introductionmentioning

confidence: 99%

Contribution of Kazal-Like Domains of the Serine Protease Inhibitor-1 from Toxoplasma gondii in Asthma Therapeutic Vaccination Effectiveness

Soto¹,

Sibilia²,

Sánchez³

et al. 2022

Int Arch Allergy Immunol

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Background: We have previously showed rTgPI-1 tolerogenic adjuvant properties in asthma treatment, turning it a promising candidate for allergen-specific immunotherapy. This therapy is an alternative treatment to control asthma that still presents several concerns related to its formulation. rTgPI-1 contains independent inhibitory domains able to inhibit trypsin and neutrophil elastase, both involved in asthma pathology. Objectives: In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. Methods: BALB/c mice were rendered allergic by intraperitoneal OVA-alum sensitization and airway challenged. Once the asthmatic phenotype was achieved, mice were intranasally treated with OVA combined with the full-length recombinant protein rTgPI-1 or its truncated versions, Nt (containing trypsin-inhibitory domains) or Ct (containing neutrophil elastase-inhibitory domains). Afterward, mice were aerosol re-challenged. Results: Asthmatic mice treated with the neutrophil elastase- or the trypsin-inhibitory domains separately failed to improve allergic lung inflammation. Only when all inhibitory domains were simultaneously administered, an improvement was achieved. Still, a better outcome was obtained when mice were treated with the full-length rTgPI-1. Conclusions: Adjuvant ability depends on the presence of all its inhibitory domains in a single entity, so it should be included in potential asthma treatment formulations as a full-length protein.

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Toxoplasma gondii serine-protease inhibitor-1: A new adjuvant candidate for asthma therapy

Cited by 9 publications

References 46 publications

Glycosylation Analysis of Feline Small Intestine Following Toxoplasma gondii Infection

Glycosylation Analysis of Feline Small Intestine Following Toxoplasma gondii Infection

Azelastine potentiates antiasthmatic dexamethasone effect on a murine asthma model

Contribution of Kazal-Like Domains of the Serine Protease Inhibitor-1 from <b><i>Toxoplasma gondii</i></b> in Asthma Therapeutic Vaccination Effectiveness

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