Crosstalk between E-Cadherin/β-Catenin and NF-κB Signaling Pathways: The Regulation of Host-Pathogen Interaction during Leptospirosis

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.

Leptospira borgpetersenii Leucine-Rich Repeat Proteins Provide Strong Protective Efficacy as Novel Leptospiral Vaccine Candidates

“…Proteins containing leucine-rich repeats (LRRs) have been predicted and reported to function in bacterial host-pathogen interactions, membrane anchoring, and invasions, such as proteins Internalin A, B and J, YopM, and LRR20 [ 34 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ]. LRR proteins containing the LPXTG motif, a cell wall anchoring motif [LPXTG cell wall anchor domain (IPR019931), (accessed on 1 Febuary 2019)], have been reported as virulence factor such as internalin J (InlJ) [ 55 ].…”

“…It is interesting to concentrate on the pathogenic Leptospira LRR proteins as immunogens. Pathogenic Leptospira LRRs are can compete with the functions of the host to adhere and invade host cells such as LRR20 [ 34 , 35 ]. The role of rLRR20 in leptospirosis revealed that rLRR20 was observed to colocalize with E-cadherin on the cell surface and activate the downstream transcription factor, beta-catenin, which subsequently promoted the expression of MMP7, a kidney injury biomarker [ 34 , 35 ].…”

“…Pathogenic Leptospira LRRs are can compete with the functions of the host to adhere and invade host cells such as LRR20 [ 34 , 35 ]. The role of rLRR20 in leptospirosis revealed that rLRR20 was observed to colocalize with E-cadherin on the cell surface and activate the downstream transcription factor, beta-catenin, which subsequently promoted the expression of MMP7, a kidney injury biomarker [ 34 , 35 ]. Recently, some bioinformatics studies revealed that the pathogenic Leptospira strains possess more leucine-rich repeat (LRR) genes than the saprophytic strains [ 36 , 37 ].…”

Insight into the Structure, Functions, and Dynamics of the Leptospira Outer Membrane Proteins with the Pathogenicity

“…Leptospirosis-associated acute kidney injury is associated with the secretion of NGAL, a downstream upregulated biomarker of the NF-kB signal transduction pathway. The crosstalk between E-cadherin/β-catenin and NF-kB signal transduction pathways during Leptospira infection was, therefore, proposed in Figure 3 [ 92 ]. 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.…”

Leptospira borgpetersenii Leucine-Rich Repeat Proteins and Derived Peptides in an Indirect ELISA Development for the Diagnosis of Canine Leptospiral Infections

“…The molecular mimicry is a well-known process by which leucine-rich repeat proteins (such as LRR20) of the pathogen compete with the functions of the host to adhere to and invade the host cell [ 29 , 30 , 31 ]. Proteins containing leucine-rich repeats (LRRs) have been predicted and reported to function in bacterial host–pathogen interactions, membrane anchoring and invasion, such as proteins Internalin A, B, YopM, and LRR20 [ 30 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Therefore, Leptospiral LRR proteins may be of interest as candidates for the development of Leptospirosis diagnostic tools.…”