The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum

mBio

Chungyu Chang¹  Truc Thanh Luong¹  Asis Das¹  Bethany L. Tiner²  Andreas Tauch³  Hung Ton-That³  Cuong T. Nguyen³  Yi-Wei Chen³  Matthew Scheible⁴  Martha I. Camacho⁴  Chenggang Wu⁴  Manuel Wittchen⁴  Ju Huck Lee⁴ 

[1] Molecular Genetics, University of Texas McGovern Medical School, Houston, Texas, USA;Center for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, Germany;;Department of Microbiology &Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California, USA;

关键词: Fusobacterium nucleatum;    MsrAB;    adherence;    cell invasion;    gene regulation;    oxidative stress;   

DOI  :  10.1128/mbio.03022-21

来源: DOAJ

【 摘 要 】

ABSTRACT Fusobacterium nucleatum, an anaerobic Gram-negative bacterium frequently found in the human oral cavity and some extra-oral sites, is implicated in several important diseases: periodontitis, adverse pregnancy outcomes, and colorectal cancer. To date, how this obligate anaerobe copes with oxidative stress and host immunity within multiple human tissues remains unknown. Here, we uncovered a critical role in this process of a multigene locus encoding a single, fused methionine sulfoxide reductase (MsrAB), a two-component signal transduction system (ModRS), and thioredoxin (Trx)- and cytochrome c (CcdA)-like proteins, which are induced when fusobacterial cells are exposed to hydrogen peroxide. Comparative transcriptome analysis revealed that the response regulator ModR regulates a large regulon that includes trx, ccdA, and many metabolic genes. Significantly, specific mutants of the msrAB locus, including msrAB, are sensitive to reactive oxygen species and defective in adherence/invasion of colorectal epithelial cells. Strikingly, the msrAB mutant is also defective in survival in macrophages, and it is severely attenuated in virulence in a mouse model of preterm birth, consistent with its failure to spread to the amniotic fluid and colonize the placenta. Clearly, the MsrAB system regulated by the two-component system ModRS represents a major oxidative stress defense pathway that protects fusobacteria against oxidative damage in immune cells and confers virulence by enabling attachment and invasion of multiple target tissues. IMPORTANCE F. nucleatum colonizes various human tissues, including oral cavity, placenta, and colon. How this obligate anaerobe withstands oxidative stress in host immune cells has not been described. We report here that F. nucleatum possesses a five-gene locus encoding a fused methionine sulfoxide reductase (MsrAB), a two-component signal transduction system (ModRS), and thioredoxin- and cytochrome c-like proteins. Regulated by ModRS, MsrAB is essential for resistance to reactive oxygen species, adherence/invasion of colorectal epithelial cells, and survival in macrophage. Unable to colonize placenta and spread to amniotic fluid, the msrAB mutant failed to induce preterm birth in a murine model.

【 授权许可】

Unknown