YfiB: An Outer Membrane Protein Involved in the Virulence of Shigella flexneri

Abstract

The intracellular pathogen Shigella flexneri, which is the causative agent of bacillary dysentery, significantly influences the worldwide implication of diarrheal infections, consequentially causing about 1.1 million deaths each year. Due to a nonavailability of an authorized vaccine and the upsurge of multidrug resistance amongst Shigella strains, there has been a huge demand for further genetic analyses which could help in the advancement of new/improved drugs, and finding vaccine candidates against the pathogen. The present study aims to illustrate the role of the yfiB gene in Shigella virulence, part of the periplasmic YfiBNR tripartite signalling system. This system is involved in the regulation of cyclic-di-GMP levels inside the bacterial cells, a vital messenger molecule impacting varied cellular processes such as biofilm formation, cytotoxicity, motility, synthesis of exopolysaccharide, and other virulence mechanisms such as adhesion and invasion of the bacteria. Through a combination of genetic, biochemical, and virulence assays, we show how knocking out the yfiB gene can disrupt the entire YfiBNR system and affect the native c-di-GMP levels. We found that this subsequently causes a negative effect on the biofilm formation, bacterial invasion, host–surface attachment, and the overall virulence of Shigella. This study also carried out a structural and functional assessment of the YfiB protein and determined critical amino acid residues, essential for proper functioning of this signalling system. The present work improves our understanding of the in vivo persistence and survival of Shigella, brings light to the c-di-GMP led regulation of Shigella virulence, and provides a prospective new target to design anti-infection drugs and vaccines against S. flexneri and other bacterial pathogens.

Intact and Degenerate Diguanylate Cyclases regulateShigellaCyclic di-GMP

“…The degenerate DGCs in S. flexneri are among those that synthesize c-di-GMP in other Escherichia / Shigella spp. (21, 57). Expression of these S. flexneri degenerate DGC genes results in multiple protein isoforms, some of which could potentially contain the GGDEF domain (Fig.…”

“…For example, lower pH in the stomach alters the expression of acid-related genes and induces biofilm formation (14,15), bile acids in the small intestine promote initial adhesion and invasion (16)(17)(18), and formate within a host cell promotes cell-to-cell spread (19). Bacteria like S. flexneri encode many different systems to sense and respond to these signals, one of which is the second messenger cyclic-di-guanosine monophosphate (c-di-GMP) signaling system (20,21).…”