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Shigella dysenteriae modulates BMP pathway to induce mucin gene expression in vivo and in vitro.

ABSTRACT: Mucosal epithelial cells in the intestine act as the first line of host defense against pathogens by increasing mucin production for clearance. Despite this fact, the underlying molecular mechanisms by which Shigella dysenteriae transduce mucin gene expression remain poorly defined. The goal of this study was to determine the role of Bone morphogenetic protein (BMP) pathway in mucin gene expression during S. dysenteriae infection. In this study we demonstrate that S. dysenteriae activates BMP signaling to induce MUC2 and MUC5AC gene expression in rat ileal loop model and in vitro. We also observed that BMP pathway regulates CDX2 expression which plays a critical role in induction of MUC2 gene during S. dysenteriae infection. In SMAD4 silenced cells S. dysenteriae infection did not abrogate MUC2 and MUC5AC gene expression whereas in CDX2 silenced cells it induces differential expression of MUC5AC gene. These results suggest that SMAD4-CDX2 induces MUC2 gene expression whereas SMAD4 directly influences differential expression of MUC5AC gene. Altogether, our results show that during S. dysenteriae infection the BMP pathway modulates inflammatory transcription factors CDX2 and SMAD4 to induce MUC2 and MUC5AC gene expression which plays a key role in the regulation of host mucosal defense thereby paving a cue for therapeutic application.

SUBMITTER: Gopal A

PROVIDER: S-EPMC4218725 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Shigella dysenteriae modulates BMP pathway to induce mucin gene expression in vivo and in vitro.

Gopal Ashidha A Iyer Soumya Chidambaram SC Gopal Udhayakumar U Devaraj Niranjali N Halagowder Devaraj D

PloS one 20141103 11

Mucosal epithelial cells in the intestine act as the first line of host defense against pathogens by increasing mucin production for clearance. Despite this fact, the underlying molecular mechanisms by which Shigella dysenteriae transduce mucin gene expression remain poorly defined. The goal of this study was to determine the role of Bone morphogenetic protein (BMP) pathway in mucin gene expression during S. dysenteriae infection. In this study we demonstrate that S. dysenteriae activates BMP si ...[more]

PMID: 25365201

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Project description:Shigella dysenteriae serotype 1 (SD1) causes the most severe form of epidemic bacillary dysentery. Quantitative proteome profiling of Shigella dysenteriae serotype 1 (SD1) in vitro (derived from LB cell cultures) and in vivo (derived from gnotobiotic piglets) was performed by 2D-LC-MS/MS and APEX, a label-free computationally modified spectral counting methodology.Overall, 1761 proteins were quantitated at a 5% FDR (false discovery rate), including 1480 and 1505 from in vitro and in vivo samples, respectively. Identification of 350 cytoplasmic membrane and outer membrane (OM) proteins (38% of in silico predicted SD1 membrane proteome) contributed to the most extensive survey of the Shigella membrane proteome reported so far. Differential protein abundance analysis using statistical tests revealed that SD1 cells switched to an anaerobic energy metabolism under in vivo conditions, resulting in an increase in fermentative, propanoate, butanoate and nitrate metabolism. Abundance increases of transcription activators FNR and Nar supported the notion of a switch from aerobic to anaerobic respiration in the host gut environment. High in vivo abundances of proteins involved in acid resistance (GadB, AdiA) and mixed acid fermentation (PflA/PflB) indicated bacterial survival responses to acid stress, while increased abundance of oxidative stress proteins (YfiD/YfiF/SodB) implied that defense mechanisms against oxygen radicals were mobilized. Proteins involved in peptidoglycan turnover (MurB) were increased, while ?-barrel OM proteins (OmpA), OM lipoproteins (NlpD), chaperones involved in OM protein folding pathways (YraP, NlpB) and lipopolysaccharide biosynthesis (Imp) were decreased, suggesting unexpected modulations of the outer membrane/peptidoglycan layers in vivo. Several virulence proteins of the Mxi-Spa type III secretion system and invasion plasmid antigens (Ipa proteins) required for invasion of colonic epithelial cells, and release of bacteria into the host cell cytosol were increased in vivo.Global proteomic profiling of SD1 comparing in vivo vs. in vitro proteomes revealed differential expression of proteins geared towards survival of the pathogen in the host gut environment, including increased abundance of proteins involved in anaerobic energy respiration, acid resistance and virulence. The immunogenic OspC2, OspC3 and IpgA virulence proteins were detected solely under in vivo conditions, lending credence to their candidacy as potential vaccine targets.

Dataset Information

Shigella dysenteriae modulates BMP pathway to induce mucin gene expression in vivo and in vitro.

Publications

Shigella dysenteriae modulates BMP pathway to induce mucin gene expression in vivo and in vitro.

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