Mammalian cell entry (Mce) protein of Leptospira interrogans binds extracellular matrix components, plasminogen and β2 integrin

Abstract

A severe re-emergingzoonosis, leptospirosis, is caused by pathogenic spirochetes of the genus Leptospira. Several studies have identified leptospiral surface proteins with the ability to bind ECM and plasma components, which could mediate adhesion and invasion through the hosts. It has been shown that Mce of pathogenic Leptospira spp. is an RGD (Arg-Gly-Asp)-motif-dependent virulence factor, responsible for infection of cells and animals. In the present article, we decided to further study the repertoire of the Mce activities in leptospiral biological properties. We report that the recombinant Mce is a broad-spectrum ECM-binding protein, capable of interacting with laminin, cellular and plasma fibronectin and collagen IV. Dose--r-esponse interaction was observed for all the components, fulfilling ligand--receptor requirements. Mce is a PLG binding protein capable to recruit this component from NHS, generating PLA in the presence of PLG activator. Binding of Mce was also observed with the leukocyte cell receptors αLβ2 [(CD11a/CD18)-LFA-1] and αMβ2 [(CD11b/CD18)-Mac-1], suggesting the involvement of this protein in the host immune response. Indeed, virulent Leptospira L1-130 was capable of binding both integrins, whereas culture-attenuated M-20 strain only bind to αMβ2 [(CD11b/CD18)-Mac-1]. To the best of our knowledge, this is the first work to describe that Mce surface protein could mediate the attachment of Leptospira interrogans to human cell receptors αLβ2(CD11a/CD18) and αMβ2(CD11b/CD18).

Mycobacterium tuberculosisMce3C promotes mycobacteria entry into macrophages through activation of β2 integrin-mediated signalling pathway

“…We next performed yeast two‐hybrid assay to identify mammalian interacting proteins that could potentially serve as receptors for Mce3C. Among the affinity‐enriched proteins, β2 integrin aroused our interest the most because it has been shown that Mce protein from pathogenic Leptospira species is capable of binding β2 integrins (Cosate, Siqueira, de Souza, Vasconcellos, & Nascimento, ). We thus hypothesised that β2 integrin may function as a mammalian ligand for Mtb Mce3C.…”

“…Among all the integrins characterized, α5β1, α8β1, αVβ3, αVβ5, αVβ6, and αVβ8 integrins have been confirmed as receptors for RGD motif‐containing adhesins from bacteria and viruses (Barczyk, Carracedo, & Gullberg, ). Moreover, it has been reported that the Mce protein of pathogenic Leptospira species is an RGD motif‐dependent virulence factor that shows a high binding affinity to β2 integrins (Cosate et al, ). Here, we found that the RGD motif of Mtb Mce3C might be responsible for binding to β2 integrin on the surface of macrophages, because the replacement of RGD motif of Mtb Mce3C with RAA completely abolished the interaction between Mce3C and β2 integrin as well as blocked Mce3C‐mediated mycobacterial association to macrophages.…”

Mycobacterium tuberculosis Uses Mce Proteins to Interfere With Host Cell Signaling

“…Several microbial proteins have been shown to bind integrins via an RGD-motif (Ruoslahti, 1996) but perhaps the most interesting to note here is the Mce protein from Leptospira interrogans strain Lai. It binds to α5ß1, α v ß3, and ß2 integrins to promote pathogen adhesion and invasiveness (Zhang et al, 2012;Cosate et al, 2016).…”

The Actinobacterial mce Operon: Structure and Functions

“…At the same time, it was established that mce operons and their analogs, which are found in the genomes of certain pathogenic bacteria, participate in virulence. In Leptospira interrogans, the Mce protein participates in adhesion, allowing interaction with the receptors of the host cells (Cosate et al, 2016). Expression of gltT gene, an analog of the mce operon of Neisseria meningitidis, results in strains with high invasiveness and hypervirulence (Pagliarulo et al, 2004).…”