Mycobacterium tuberculosis glyceraldehyde‐3‐phosphate dehydrogenase plays a dual role—As an adhesin and as a receptor for plasmin(ogen)

Abstract

The spread of infection is directly determined by the ability of a pathogen to invade and infect host tissues. The process involves adherence due to host–pathogen interactions and traversal into deeper tissues. Mycobacterium tuberculosis (Mtb) primarily infects the lung but is unique in its ability to infect almost any other organ of the human host including immune privileged sites such as the central nervous system (CNS). The extreme invasiveness of this bacterium is not fully understood. In the current study, we report that cell surface Mtb glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) functions as a virulence factor by multiple mechanisms. Firstly, it serves as a dual receptor for both plasminogen (Plg) and plasmin (Plm). CRISPRi‐mediated silencing of this essential enzyme confirmed its role in the recruitment of Plg/Plm. Our studies further demonstrate that soluble GAPDH can re‐associate on Mtb bacilli to promote plasmin(ogen) recruitment. The direct association of plasmin(ogen) via cell surface GAPDH or by the re‐association of soluble GAPDH enhanced bacterial adherence to and traversal across lung epithelial cells. Furthermore, the association of GAPDH with host extracellular matrix (ECM) proteins coupled with its ability to recruit plasmin(ogen) may endow cells with the ability of directed proteolytic activity vital for tissue invasion.

A novel chimeric vaccine containing multiple epitopes for simulating robust immune activation against Klebsiella pneumoniae

“…Recombinant pneumococcal glycolytic proteins, including GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) and FBA [ 40 ], are produced inside Escherichia coli and elicit the production of antibodies that exhibit specificity towards various serotypes. Research [ 41 ] shows an observed interaction between pneumococcal serotypes and vaccinations targeting choline-binding enzymes (CBPs).…”

Enolase of Staphylococcus lugdunensis Is a Surface-Exposed Moonlighting Protein That Binds to Extracellular Matrix and the Plasminogen/Plasmin System

“…The ECM degradation definitely increases the bacterial invasion into tissue and facilitates invasion and dissemination within the infected host as already has been shown for other pathogens ( Pancholi and Fischetti, 1998 ; Bergmann et al, 2005 ; Lahteenmaki et al, 2005 ; Hemmadi and Biswas, 2021 ). Whereas we proved the binding of SlEno to different ECM proteins using rather indirect methods, Gani et al (2021) applied two different genetic manipulation strategies (overexpression and a siRNA strategy) to show a binding of the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) of Mycobacterium tuberculosis with ECM matrix and the ability to recruit plasmin(ogen) ( Gani et al, 2021 ). Thus, new molecular methods should be evolved to analyze further moonlighting candidates in S. lugdunensis and are currently under intensive investigation.…”

Mycobacterial Adhesion: From Hydrophobic to Receptor-Ligand Interactions

“…Several additional mycobacterial adhesins have been identified that bind host extracellular matrix proteins [166][167][168][169][170]. To name a few briefly, these include Rv1759c (a PE_PGRS that binds fibronectin) [171], malate synthase (a glyoxalate shunt enzyme that is secreted by an unknown mechanism and that binds laminin as well as fibronectin) [172], and GAPDH (a glycolytic enzyme that binds plasminogen and plasmin with relatively high affinity hence offering a means to degrade extracellular matrix components) [173].…”