Schistosoma mansoni SmKI-1 serine protease inhibitor binds to elastase and impairs neutrophil function and inflammation

Abstract

Protease inhibitors have important function during homeostasis, inflammation and tissue injury. In this study, we described the role of Schistosoma mansoni SmKI-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) SmKI-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 SmKI-1, molecular docking studies were also conducted. Docking results suggest a complete blockage of NE active site by SmKI-1 Kunitz domain. Additionally, rSmKI-1 markedly inhibited the capacity of NE to kill schistosomes. In order to further investigate the role of SmKI-1 in the parasite, we designed specific siRNA to knockdown SmKI-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 SmKI-1 to interfere with neutrophil migration and function, we tested SmKI-1 anti-inflammatory potential in different murine models of inflammatory diseases. Treatment with SmKI-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 SmKI-1 to inhibit early events that trigger neutrophil recruitment in pleural cavities of mice in response to carrageenan. In conclusion, SmKI-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.

Echinococcosis: Advances in the 21st Century

“…The worms secrete serine protease inhibitors (serpins) which counteract the potentially lethal effects of these host intestinal proteases and thereby likely play a key protective role in preventing proteolytic enzyme attack, ensuring survival of E. granulosus within its canine hosts. These, along with molecular chaperones, neurotransmitter receptors and transporters, and other protease inhibitors, specifically expressed in adult worms, likely represent additional vaccine candidates that warrant future study (261,285,(321)(322)(323).…”

Identification and Characterization of ShSPI, a Kazal-Type Elastase Inhibitor from the Venom of Scolopendra Hainanum

“…SPIs are widely distributed in a variety of species [29,30]. They are able to inhibit the catalytic activity of proteolytic enzymes and guarantee the inhibiting proteolysis of proteinase, which are important in poisonous animals' biological processes for survival [31,32].…”

“…Lyophilized human plasma (400100, Cayman, Ann Arbor, MI, USA) was resuspended in sterile water according to the instruction, then ShSPI was added to each equivalent volume with a final concentration of 500 nM, and samples were co-incubated at 37 • C for two days. Triplicate samples were collected at selected time points (0, 6,12,18,24,30,36,42, and 48 h) and protease activity was tested as described above.…”

Comparative Transcriptome Analyses of Schistosoma japonicum Derived From SCID Mice and BALB/c Mice: Clues to the Abnormality in Parasite Growth and Development

“…In chronic diseases, eggs trapped in various tissues induce the formation of granulomatous inflammation, which subsequently results in fibrosis that causes many of the pathological conditions. It is believed that parasites definitely cause damage to their host, and the host resists against the invading parasites by its immune response (Han et al, 2009;The Schistosoma japonicum Genome Sequencing and Functional Analysis Consortium, 2009;deWalick et al, 2012;Duan et al, 2014;Morais et al, 2018;Roderfeld et al, 2018). However, several studies have already observed that host factors such as the immune factors can modulate parasite development and maturation (Amiri et al, 1992;Hernandez et al, 2004;LoVerde et al, 2009;Beckmann et al, 2010;deWalick et al, 2012).…”