The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum
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 ox...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Microbiology
2022-06-01
|
| Series: | mBio |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03022-21 |
| _version_ | 1818545549266124800 |
|---|---|
| author | Matthew Scheible Cuong T. Nguyen Truc Thanh Luong Ju Huck Lee Yi-Wei Chen Chungyu Chang Manuel Wittchen Martha I. Camacho Bethany L. Tiner Chenggang Wu Andreas Tauch Asis Das Hung Ton-That |
| author_facet | Matthew Scheible Cuong T. Nguyen Truc Thanh Luong Ju Huck Lee Yi-Wei Chen Chungyu Chang Manuel Wittchen Martha I. Camacho Bethany L. Tiner Chenggang Wu Andreas Tauch Asis Das Hung Ton-That |
| author_sort | Matthew Scheible |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T07:41:35Z |
| format | Article |
| id | doaj.art-b73cb6181f5f4f71bab115251d5e506d |
| institution | Directory Open Access Journal |
| issn | 2150-7511 |
| language | English |
| last_indexed | 2024-12-12T07:41:35Z |
| publishDate | 2022-06-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj.art-b73cb6181f5f4f71bab115251d5e506d2022-12-22T00:32:46ZengAmerican Society for MicrobiologymBio2150-75112022-06-0113310.1128/mbio.03022-21The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatumMatthew Scheible0Cuong T. Nguyen1Truc Thanh Luong2Ju Huck Lee3Yi-Wei Chen4Chungyu Chang5Manuel Wittchen6Martha I. Camacho7Bethany L. Tiner8Chenggang Wu9Andreas Tauch10Asis Das11Hung Ton-That12Division of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California, USADepartment of Microbiology & Molecular Genetics, University of Texas McGovern Medical School, Houston, Texas, USADivision of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California, USADepartment of Microbiology & Molecular Genetics, University of Texas McGovern Medical School, Houston, Texas, USADivision of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California, USADivision of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California, USACenter for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, GermanyDivision of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California, USADepartment of Microbiology & Molecular Genetics, University of Texas McGovern Medical School, Houston, Texas, USADepartment of Microbiology & Molecular Genetics, University of Texas McGovern Medical School, Houston, Texas, USACenter for Biotechnology (CeBiTec), Bielefeld University, Bielefeld, GermanyDepartment of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, Connecticut, USADivision of Oral Biology and Medicine, School of Dentistry, University of California, Los Angeles, California, USAABSTRACT 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.https://journals.asm.org/doi/10.1128/mbio.03022-21Fusobacterium nucleatumMsrABadherencecell invasiongene regulationoxidative stress |
| spellingShingle | Matthew Scheible Cuong T. Nguyen Truc Thanh Luong Ju Huck Lee Yi-Wei Chen Chungyu Chang Manuel Wittchen Martha I. Camacho Bethany L. Tiner Chenggang Wu Andreas Tauch Asis Das Hung Ton-That The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum mBio Fusobacterium nucleatum MsrAB adherence cell invasion gene regulation oxidative stress |
| title | The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum |
| title_full | The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum |
| title_fullStr | The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum |
| title_full_unstemmed | The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum |
| title_short | The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum |
| title_sort | fused methionine sulfoxide reductase msrab promotes oxidative stress defense and bacterial virulence in fusobacterium nucleatum |
| topic | Fusobacterium nucleatum MsrAB adherence cell invasion gene regulation oxidative stress |
| url | https://journals.asm.org/doi/10.1128/mbio.03022-21 |
| work_keys_str_mv | AT matthewscheible thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT cuongtnguyen thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT tructhanhluong thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT juhucklee thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT yiweichen thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT chungyuchang thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT manuelwittchen thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT marthaicamacho thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT bethanyltiner thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT chenggangwu thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT andreastauch thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT asisdas thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT hungtonthat thefusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT matthewscheible fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT cuongtnguyen fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT tructhanhluong fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT juhucklee fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT yiweichen fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT chungyuchang fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT manuelwittchen fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT marthaicamacho fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT bethanyltiner fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT chenggangwu fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT andreastauch fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT asisdas fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum AT hungtonthat fusedmethioninesulfoxidereductasemsrabpromotesoxidativestressdefenseandbacterialvirulenceinfusobacteriumnucleatum |