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The fused methionine sulfoxide reductase MsrAB promotes oxidative stress defense and bacterial virulence in Fusobacterium nucleatum

ABSTRACT: Recognizably associated with oral infections, adverse pregnancy outcomes, and colorectal cancer, the Gram-negative oral bacterium Fusobacterium nucleatum is known to colonize many extraoral sites including placenta and colon. How this anaerobe copes with oxidative stress imposed by the host immune response in various tissues is unknown. Here, we revealed that F. nucleatum harbors a gene locus coding for a single, fused methionine sulfoxide reductase (MsrAB), a two-component transduction system (ModRS), thioredoxin (Trx)- and cytochrome c (CcdA)-like proteins. Considering their role in oxidative stress responses, we demonstrated that these genes were increasingly expressed when fusobacterial cells were exposed to hydrogen peroxide. Comparative transcriptome analysis of the parental and modR mutant strains revealed that the response regulator ModR regulates a large regulon including trx, ccdA, and many metabolic genes. Significantly, mutants lacking individual genes within the msrAB locus, including msrAB, were sensitive to reactive oxygen species and defective in adherence/invasion of colorectal epithelial cells, as compared to the parental strain. The msrAB mutant was also defective in survival in macrophage, unlike the rescued and parental strains. Strikingly, in an experimental model of preterm birth this mutant was severely attenuated in virulence, for it failed to colonize the placenta and spread to the amniotic fluid. The results support that the MsrAB system represents a major pathway that protects fusobacteria against oxidative damage and confers virulence and that MsrAB-mediated oxidative stress defense is subjected to regulation by the two-component transduction system ModRS.

ORGANISM(S): Fusobacterium nucleatum subsp. nucleatum

PROVIDER: GSE174320 | GEO | 2022/03/28

REPOSITORIES: GEO

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Project description:Background The Gram-negative bacteria Fusobacterium nucleatum and Porphyromonas gingivalis are associated with periodontitis and members of a complex microbial biofilm. The self-produced extracellular polymeric matrix (EPM) of biofilms generally consists of lipids, exopolysaccharides, nucleic acids and proteins. The proteinaceous components of the biofilm matrix play many roles in biofilm development and function. In this study the protein composition of the matrices in mono- and dual-species biofilms of F. nucleatum and P. gingivalis were analyzed. Methods The bacteria were grown in a static biofilm model. Extraction of EPM was performed by careful mechanical shearing and filtration. Initial tryptic digestion of EPMs was followed by liquid chromatography-tandem mass spectrometry to analyze the resulting peptide mixtures. Quantitative proteomic software MaxQuant was then employed for protein identifications and label-free quantitative (LFQ) analysis. Functional analyses of identified proteins were applied in classification and prediction of their possible roles in EPM. Results We identified 542 proteins in the matrix of F. nucleatum, 93 proteins in the matrix of P. gingivalis and 280 proteins in the dual-species biofilm matrix. Similarly, relative quantification based on LFQ intensity scores identified generally higher protein amounts in F. nucleatum and dual species EMPs, when compared to P. gingivalis EPM. Acetyl-CoA acetyltransferase, alkyl hydroperoxide reductase C22 protein, neutrophil-activating protein A, tryptophanase and glutamate dehydrogenase were the top five proteins in the matrix of F. nucleatum biofilm. The oxidoreductase NAD-specific glutamate dehydrogenase and the proteolytic and adhesive protein Lys-gingipain were most abundant in P. gingivalis EPM. In the dual species EPM, F. nucleatum contributed to four out of the five with glutamate dehydrogenase on top. NAD-specific dehydrogenase from P. gingivalis was among the top five. Functional analyses with respect to virulence for example, revealed the stress-induced protein yicC in F. nucleatum EPM, while hemagglutinin HagA and fimbriae minor component FimD were among the top 5 in P. gingivalis EPM. Conclusions We showed that the biofilm matrix of two important periodontal pathogens is abundant in proteins and nearly 70% of all EPM proteins originate from F. nucleatum when grown together with P. gingivalis. Outer membrane proteins, virulence related and oxidative stress proteins were among the most abundant proteins identified.

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The fused methionine sulfoxide reductase MsrAB promotes oxidative stress defense and bacterial virulence in Fusobacterium nucleatum

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