Abstract
Approximately 1 million cases of leptospirosis, an emerging infectious zoonotic disease, are reported each year. Pathogenic Leptospira species express leucine-rich repeat (LRR) proteins that are rarely expressed in non-pathogenic Leptospira species. The LRR domain-containing protein family is vital for the virulence of pathogenic Leptospira species. In this study, the biological mechanisms of an essential LRR domain protein from pathogenic Leptospira were examined. The effects of Leptospira and recombinant LRR20 (rLRR20) on the expression levels of factors involved in signal transduction were examined using microarray, quantitative real-time polymerase chain reaction, and western blotting. The secreted biomarkers were measured using an enzyme-linked immunosorbent assay. rLRR20 colocalized with E-cadherin on the cell surface and activated the downstream transcription factor β-catenin, which subsequently promoted the expression of MMP7, a kidney injury biomarker. Additionally, MMP7 inhibitors were used to demonstrate that the secreted MMP7 degrades surface E-cadherin. This feedback inhibition mechanism downregulated surface E-cadherin expression and inhibited the colonization of Leptospira. The degradation of surface E-cadherin activated the NF-κB signal transduction pathway. Leptospirosis-associated acute kidney injury is associated with the secretion of NGAL, a downstream upregulated biomarker of the NF-κB signal transduction pathway. A working model was proposed to illustrate the crosstalk between E-cadherin/β-catenin and NF-κB signal transduction pathways during Leptospira infection. Thus, rLRR20 of Leptospira induces kidney injury in host cells and inhibits the adhesion and invasion of Leptospira through the upregulation of MMP7 and NGAL.
Highlights
In the last few decades, several biomarkers have been reported for acute and chronic kidney diseases [1,2]
We further demonstrated that recombinant LRR20 (rLRR20) colocalized with E-cadherin on the cell surface and upregulated the levels of activated β-catenin, which is the downstream signal component of
E-cadherin, active matrix metalloproteinase 7 (MMP7), and β-catenin, and the results are similar to rLRR20/ICG-001treated human kidney 2 cells (HK2s) and human renal proximal tubular epithelial cells (hRPTECs) (Figure 5E–H). These results indicated that ICG-001 and JW-67 inhibited the expression of active MMP7 in the rLRR20-treated HK2s and hRPTECs and that β-catenin was located upstream of MMP7 (Figure 5)
Summary
In the last few decades, several biomarkers have been reported for acute and chronic kidney diseases [1,2]. Previous studies have reported that MMP7 and NGAL are associated with the pathogenesis of leptospirosis [9,10]. The authors reported the role of NGAL in leptospirosis and demonstrated the correlation between Leptospira outer membrane components and cell surface receptors. Leptospira is reported to interact with various cell surface receptors, including Ecadherin (CDH1), P-cadherin (CDH3), and VE-cadherin (CDH5) [16]. We further demonstrated that rLRR20 colocalized with E-cadherin on the cell surface and upregulated the levels of activated β-catenin, which is the downstream signal component of. RLRR20 from pathogenic Leptospira is a novel human E-cadherin-binding protein that promotes the expression of MMP7 and NGAL. RLRR20 promoted the MMP7-mediated degradation of surface E-cadherin, which led to the activation of the NF-κB pathway and the stimulation of NGAL expression
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