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  • 1
    Online Resource
    Online Resource
    Genetic Determinants of Hydrogen Sulfide Biosynthesis in Fusobacterium nucleatum Are Required for Bacterial Fitness, Antibiotic Sensitivity, and Virulence
    American Society for Microbiology ; 2022
    In:  mBio Vol. 13, No. 5 ( 2022-10-26)
    Details
    In: mBio, American Society for Microbiology, Vol. 13, No. 5 ( 2022-10-26)
    Abstract: The Gram-negative anaerobe Fusobacterium nucleatum is a major producer of hydrogen sulfide (H 2 S), a volatile sulfur compound that causes halitosis. Here, we dissected the genetic determinants of H 2 S production and its role in bacterial fitness and virulence in this important member of the oral microbiome. F. nucleatum possesses four enzymes, CysK1, CysK2, Hly, and MegL, that presumably metabolize l -cysteine to H 2 S, and CysK1 was previously shown to account for most H 2 S production in vitro , based on correlations of enzymatic activities with gene expression at mid-log phase. Our molecular studies showed that cysK1 and megL were highly expressed at the late exponential growth phase, concomitant with high-level H 2 S production, while the expression levels of the other genes remained substantially lower during all growth phases. Although the genetic deletion of cysK1 without supplementation with a CysK1-catalyzed product, lanthionine, caused cell death, the conditional Δ cysK1 mutant and a mutant lacking hly were highly proficient in H 2 S production. In contrast, a mutant devoid of megL showed drastically reduced H 2 S production, and a cysK2 mutant showed only minor deficiencies. Intriguingly, the exposure of these mutants to various antibiotics revealed that only the megL mutant displayed altered susceptibility compared to the parental strain: partial sensitivity to nalidixic acid and resistance to kanamycin. Most significantly, the megL mutant was attenuated in virulence in a mouse model of preterm birth, with considerable defects in the spread to amniotic fluid and the colonization of the placenta and fetus. Evidently, the l -methionine γ-lyase MegL is a major H 2 S-producing enzyme in fusobacterial cells that significantly contributes to fusobacterial virulence and antibiotic susceptibility. IMPORTANCE Fusobacterium nucleatum is a key commensal anaerobe of the human oral cavity that plays a significant role in oral biofilm development and contributes to additional pathologies at extraoral sites, such as promoting preterm birth and colorectal cancer. Although F. nucleatum is known as a major producer of hydrogen sulfide (H 2 S), its genetic determinants and physiological functions are not well understood. By a combination of bacterial genetics, biochemical methods, and in vivo models of infection, here, we demonstrate that the l -methionine γ-lyase MegL not only is a major H 2 S-producing enzyme of F. nucleatum but also significantly contributes to the antibiotic susceptibility and virulence of this organism.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.01936-22
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 2557172-2
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  • 2
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    Online Resource
    The Fused Methionine Sulfoxide Reductase MsrAB Promotes Oxidative Stress Defense and Bacterial Virulence in Fusobacterium nucleatum
    American Society for Microbiology ; 2022
    In:  mBio Vol. 13, No. 3 ( 2022-06-28)
    Details
    In: mBio, American Society for Microbiology, Vol. 13, No. 3 ( 2022-06-28)
    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.
    Type of Medium: Online Resource
    ISSN: 2150-7511
    URL: Article
    DOI: 10.1128/mbio.03022-21
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2022
    detail.hit.zdb_id: 2557172-2
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  • 3
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    Online Resource
    Ribonuclease J-Mediated mRNA Turnover Modulates Cell Shape, Metabolism and Virulence in Corynebacterium diphtheriae
    MDPI AG ; 2021
    In:  Microorganisms Vol. 9, No. 2 ( 2021-02-14), p. 389-
    Details
    In: Microorganisms, MDPI AG, Vol. 9, No. 2 ( 2021-02-14), p. 389-
    Abstract: Controlled RNA degradation is a crucial process in bacterial cell biology for maintaining proper transcriptome homeostasis and adaptation to changing environments. mRNA turnover in many Gram-positive bacteria involves a specialized ribonuclease called RNase J (RnJ). To date, however, nothing is known about this process in the diphtheria-causative pathogen Corynebacterium diphtheriae, nor is known the identity of this ribonuclease in this organism. Here, we report that C. diphtheriae DIP1463 encodes a predicted RnJ homolog, comprised of a conserved N-terminal β-lactamase domain, followed by β-CASP and C-terminal domains. A recombinant protein encompassing the β-lactamase domain alone displays 5′-exoribonuclease activity, which is abolished by alanine-substitution of the conserved catalytic residues His186 and His188. Intriguingly, deletion of DIP1463/rnj in C. diphtheriae reduces bacterial growth and generates cell shape abnormality with markedly augmented cell width. Comparative RNA-seq analysis revealed that RnJ controls a large regulon encoding many factors predicted to be involved in biosynthesis, regulation, transport, and iron acquisition. One upregulated gene in the ∆rnj mutant is ftsH, coding for a membrane protease (FtsH) involved in cell division, whose overexpression in the wild-type strain also caused cell-width augmentation. Critically, the ∆rnj mutant is severely attenuated in virulence in a Caenorhabditis elegans model of infection, while the FtsH-overexpressing and toxin-less strains exhibit full virulence as the wild-type strain. Evidently, RNase J is a key ribonuclease in C. diphtheriae that post-transcriptionally influences the expression of numerous factors vital to corynebacterial cell physiology and virulence. Our findings have significant implications for basic biological processes and mechanisms of corynebacterial pathogenesis.
    Type of Medium: Online Resource
    ISSN: 2076-2607
    URL: Article
    DOI: 10.3390/microorganisms9020389
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2720891-6
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  • 4
    Online Resource
    Online Resource
    A cryptic oxidoreductase safeguards oxidative protein folding in Corynebacterium diphtheriae
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 8 ( 2023-02-21)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 8 ( 2023-02-21)
    Abstract: In many gram-positive Actinobacteria, including Actinomyces oris and Corynebacterium matruchotii , the conserved thiol-disulfide oxidoreductase MdbA that catalyzes oxidative folding of exported proteins is essential for bacterial viability by an unidentified mechanism. Intriguingly, in Corynebacterium diphtheriae , the deletion of mdbA blocks cell growth only at 37 °C but not at 30 °C, suggesting the presence of alternative oxidoreductase enzyme(s). By isolating spontaneous thermotolerant revertants of the mdbA mutant at 37 °C, we obtained genetic suppressors, all mapped to a single T-to-G mutation within the promoter region of tsdA , causing its elevated expression. Strikingly, increased expression of tsdA —via suppressor mutations or a constitutive promoter—rescues the pilus assembly and toxin production defects of this mutant, hence compensating for the loss of mdbA . Structural, genetic, and biochemical analyses demonstrated TsdA is a membrane-tethered thiol-disulfide oxidoreductase with a conserved CxxC motif that can substitute for MdbA in mediating oxidative folding of pilin and toxin substrates. Together with our observation that tsdA expression is upregulated at nonpermissive temperature (40 °C) in wild-type cells, we posit that TsdA has evolved as a compensatory thiol-disulfide oxidoreductase that safeguards oxidative protein folding in C. diphtheriae against thermal stress.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2208675120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Genetic and molecular determinants of polymicrobial interactions in Fusobacterium nucleatum
    Proceedings of the National Academy of Sciences ; 2021
    In:  Proceedings of the National Academy of Sciences Vol. 118, No. 23 ( 2021-06-08)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 23 ( 2021-06-08)
    Abstract: A gram-negative colonizer of the oral cavity, Fusobacterium nucleatum not only interacts with many pathogens in the oral microbiome but also has the ability to spread to extraoral sites including placenta and amniotic fluid, promoting preterm birth. To date, however, the molecular mechanism of interspecies interactions—termed coaggregation—by F. nucleatum and how coaggregation affects bacterial virulence remain poorly defined. Here, we employed genome-wide transposon mutagenesis to uncover fusobacterial coaggregation factors, revealing the intertwined function of a two-component signal transduction system (TCS), named CarRS, and a lysine metabolic pathway in regulating the critical coaggregation factor RadD. Transcriptome analysis shows that CarR modulates a large regulon including radD and lysine metabolic genes, such as kamA and kamD , the expression of which are highly up-regulated in the Δ carR mutant. Significantly, the native culture medium of Δ kamA or Δ kamD mutants builds up abundant amounts of free lysine, which blocks fusobacterial coaggregation with streptococci. Our demonstration that lysine-conjugated beads trap RadD from the membrane lysates suggests that lysine utilizes RadD as its receptor to act as a metabolic inhibitor of coaggregation. Lastly, using a mouse model of preterm birth, we show that fusobacterial virulence is significantly attenuated with the Δ kamA and Δ carR mutants, in contrast to the enhanced virulence phenotype observed upon diminishing RadD (Δ radD or Δ carS mutant). Evidently, F. nucleatum employs the TCS CarRS and environmental lysine to modulate RadD-mediated interspecies interaction, virulence, and nutrient acquisition to thrive in the adverse environment of oral biofilms and extraoral sites.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2006482118
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2021
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Portable Molecular Diagnostics Device for Identification of Asini Corii Colla by Loop-Mediated Isothermal Amplification
    MDPI AG ; 2021
    In:  Inventions Vol. 6, No. 3 ( 2021-07-14), p. 51-
    Details
    In: Inventions, MDPI AG, Vol. 6, No. 3 ( 2021-07-14), p. 51-
    Abstract: Asini Corii Colla (ACC; donkey-hide glue) is one of the most valuable tonic traditional Chinese medicines. Because of the large demand for gelatinous Chinese medicines, bovine or swine skin was sometimes used to make adulterated gelatine in recent decades. Food chemicals can greatly harm people’s health, and detecting chemicals in foods is extremely important. A loop-mediated isothermal amplification (LAMP) device with smartphone detection is demonstrated in this study for detecting the DNA of Asini Corii Colla. The complete system is composed of a hand-held box equipped with a smartphone, a cartridge heater, an ultraviolet LED, a disposable reaction tube, and a homemade thermal module. All the processes are powered by a set of rechargeable batteries. Comprehensive experiments of measuring temperature profiles are presented, which showed the accuracy of temperature under thermal control is less than 0.5 °C. By implementing one heating module with an ATmega328p-au microcontroller in the device, the DNA mixture is heated directly up to the reaction temperature within 5 min. Next, a DNA segment of Asini Corii Colla is utilized to evaluate the sensitivity of the DNA amplification in the portable device. A limit of detection to a concentration of 10−4 ng/μL is achieved. Real-time detection of Asini Corii Colla by a smartphone camera can be achieved using this portable device. The unique architecture utilized in this device is ideal for a low-cost DNA analysis system.
    Type of Medium: Online Resource
    ISSN: 2411-5134
    URL: Article
    DOI: 10.3390/inventions6030051
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2856369-4
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  • 7
    Online Resource
    Online Resource
    Ancient DNA indicates human population shifts and admixture in northern and southern China
    American Association for the Advancement of Science (AAAS) ; 2020
    In:  Science Vol. 369, No. 6501 ( 2020-07-17), p. 282-288
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 369, No. 6501 ( 2020-07-17), p. 282-288
    Abstract: Human genetic history in East Asia is poorly understood. To clarify population relationships, we obtained genome-wide data from 26 ancient individuals from northern and southern East Asia spanning 9500 to 300 years ago. Genetic differentiation in this region was higher in the past than the present, which reflects a major episode of admixture involving northern East Asian ancestry spreading across southern East Asia after the Neolithic, thereby transforming the genetic ancestry of southern China. Mainland southern East Asian and Taiwan Strait island samples from the Neolithic show clear connections with modern and ancient individuals with Austronesian-related ancestry, which supports an origin in southern China for proto-Austronesians. Connections among Neolithic coastal groups from Siberia and Japan to Vietnam indicate that migration and gene flow played an important role in the prehistory of coastal Asia.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aba0909
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2020
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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