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

Abstract

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; 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. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; In view of the need to design rational therapies, herein we investigated the contribution of the different inhibitory domains in rTgPI-1 therapeutic effectiveness. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; 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. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; 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. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; 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.

Diversity analysis of sea anemone peptide toxins in different tissues of Heteractis crispa based on transcriptomics

“…Kazal-like belongs to serine protease inhibitor family and plays crucial roles in host physiological blood coagulation 91 , 92 , development regulation, and immunological functions 93 , in which protease activity is modulated by protease inhibitors 94 . PI-actitoxin-Avd5a is an elastase inhibitor from Anemonia sulcata , a 'non-classical' Kazal-type protein, and PI-actitoxin-Avd5a reveals strong inhibition against Streptomyces griseus protease B (SGPB) 95 , 96 .…”