Open AccessSchistosoma mansoni SmKI-1 serine protease inhibitor binds to elastase and impairs neutrophil function and inflammation
Author(s) -
Suellen B. Morais,
Bárbara C. Figueiredo,
Natan R. G. Assis,
Débora Moreira Alvarenga,
Mariana Torquato Quezado de Magalhães,
Rafaela Salgado Ferreira,
Angélica T. Vieira,
Gustavo B. Menezes,
Sérgio C. Oliveira
Publication year - 2018
Publication title -
plos pathogens
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.719
H-Index - 206
eISSN - 1553-7374
pISSN - 1553-7366
DOI - 10.1371/journal.ppat.1006870
Subject(s) - neutrophil elastase , inflammation , elastase , schistosoma mansoni , proteases , serine protease , biology , in vivo , arthritis , cysteine protease , immunology , protease , biochemistry , enzyme , schistosomiasis , microbiology and biotechnology , helminths
Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni Sm KI-1 serine protease inhibitor in parasite development and as a molecule capable of regulating different models of inflammatory diseases. First, we determine that recombinant (r) Sm KI-1 and its Kunitz domain but not the C-terminal region possess inhibitory activity against trypsin and neutrophil elastase (NE). To better understand the molecular basis of NE inhibition by S m KI-1, molecular docking studies were also conducted. Docking results suggest a complete blockage of NE active site by Sm KI-1 Kunitz domain. Additionally, r Sm KI-1 markedly inhibited the capacity of NE to kill schistosomes. In order to further investigate the role of Sm KI-1 in the parasite, we designed specific siRNA to knockdown Sm KI-1 in S . mansoni . SmKI-1 gene suppression in larval stage of S . mansoni robustly impact in parasite development in vitro and in vivo . To determine the ability of Sm KI-1 to interfere with neutrophil migration and function, we tested Sm KI-1 anti-inflammatory potential in different murine models of inflammatory diseases. Treatment with Sm KI-1 rescued acetaminophen (APAP)-mediated liver damage, with a significant reduction in both neutrophil recruitment and elastase activity. In the model of gout arthritis, this protein reduced neutrophil accumulation, IL-1β secretion, hypernociception, and overall pathological score. Finally, we demonstrated the ability of Sm KI-1 to inhibit early events that trigger neutrophil recruitment in pleural cavities of mice in response to carrageenan. In conclusion, Sm KI-1 is a key protein in S . mansoni survival and it has the ability to inhibit neutrophil function as a promising therapeutic molecule against inflammatory diseases.