Abstract：
:Clostridium difficile infection is the leading cause of hospital-acquired diarrhoea and pseudomembranous colitis. Disease is mediated by the actions of two toxins, TcdA and TcdB, which cause the diarrhoea, as well as inflammation and necrosis within the colon. The toxins are large (308 and 270 kDa, respectively), homologous (47% amino acid identity) glucosyltransferases that target small GTPases within the host. The multidomain toxins enter cells by receptor-mediated endocytosis and, upon exposure to the low pH of the endosome, insert into and deliver two enzymatic domains across the membrane. Eukaryotic inositol-hexakisphosphate (InsP6) binds an autoprocessing domain to activate a proteolysis event that releases the N-terminal glucosyltransferase domain into the cytosol. Here, we report the crystal structure of a 1,832-amino-acid fragment of TcdA (TcdA1832), which reveals a requirement for zinc in the mechanism of toxin autoprocessing and an extended delivery domain that serves as a scaffold for the hydrophobic α-helices involved in pH-dependent pore formation. A surface loop of the delivery domain whose sequence is strictly conserved among all large clostridial toxins is shown to be functionally important, and is highlighted for future efforts in the development of vaccines and novel therapeutics.
journal_name
Nat Microbioljournal_title
Nature microbiologyauthors
Chumbler NM,Rutherford SA,Zhang Z,Farrow MA,Lisher JP,Farquhar E,Giedroc DP,Spiller BW,Melnyk RA,Lacy DBdoi
10.1038/nmicrobiol.2015.2subject
Has Abstractpub_date
2016-01-11 00:00:00pages
15002issn
2058-5276pii
nmicrobiol20152journal_volume
1pub_type
杂志文章abstract：:Host factors that silence provirus transcription in CD4+ memory T cells help HIV-1 escape eradication by the host immune system and by antiviral drugs1. These same factors, however, must be overcome for HIV-1 to propagate. Here we show that Vpx and Vpr encoded by diverse primate immunodeficiency viruses activate provi...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-018-0256-x
更新日期：2018-12-01 00:00:00
abstract：:Retroviral infection involves the reverse transcription of the viral RNA genome into DNA, which is subsequently integrated into the host cell genome. Human immunodeficiency virus type 1 (HIV-1) and other lentiviruses mediate the infection of non-dividing cells through the ability of the capsid protein1 to engage the c...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-020-0735-8
更新日期：2020-09-01 00:00:00
abstract：:The evolution of virulence traits is central for the emergence or re-emergence of microbial pathogens and for their adaptation to a specific host 1-5 . Typhoid toxin is an essential virulence factor of the human-adapted bacterial pathogen Salmonella Typhi 6,7 , the cause of typhoid fever in humans 8-12 . Typhoid toxin...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-017-0033-2
更新日期：2017-12-01 00:00:00
abstract：:Human onchocerciasis is a serious neglected tropical disease caused by the filarial nematode Onchocerca volvulus that can lead to blindness and chronic disability. Control of the disease relies largely on mass administration of a single drug, and the development of new drugs and vaccines depends on a better knowledge ...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/nmicrobiol.2016.216
更新日期：2016-11-21 00:00:00
abstract：:Staphylococcus epidermidis is a conspicuous member of the human microbiome, widely present on healthy skin. Here we show that S. epidermidis has also evolved to become a formidable nosocomial pathogen. Using genomics, we reveal that three multidrug-resistant, hospital-adapted lineages of S. epidermidis (two ST2 and on...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-018-0230-7
更新日期：2018-10-01 00:00:00
abstract：:An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title：Nature microbiology
pub_type： 杂志文章,已发布勘误
doi：10.1038/s41564-020-0698-9
更新日期：2020-04-01 00:00:00
abstract：:Zika virus is a mosquito-borne pathogen that is rapidly spreading across the Americas. Due to associations between Zika virus infection and a range of fetal maladies(1,2), the epidemic trajectory of this viral infection poses a significant concern for the nearly 15 million children born in the Americas each year. Asce...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/nmicrobiol.2016.126
更新日期：2016-07-25 00:00:00
abstract：:Virus taxonomy emerged as a discipline in the middle of the twentieth century. Traditionally, classification by virus taxonomists has been focussed on the grouping of relatively closely related viruses. However, during the past few years, the International Committee on Taxonomy of Viruses (ICTV) has recognized that th...
journal_title：Nature microbiology
pub_type： 杂志文章,评审
doi：10.1038/s41564-020-0709-x
更新日期：2020-05-01 00:00:00
abstract：:Cancer arises from the acquisition of multiple genetic and epigenetic changes in host cells over the span of many years, promoting oncogenic traits and carcinogenesis. Most cancers develop following random somatic alterations of key oncogenic genes, which are favoured by a number of risk factors, including lifestyle, ...
journal_title：Nature microbiology
pub_type： 杂志文章,评审
doi：10.1038/nmicrobiol.2017.8
更新日期：2017-02-22 00:00:00
abstract：:The development of new drug regimens that allow rapid, sterilizing treatment of tuberculosis has been limited by the complexity and time required for genetic manipulations in Mycobacterium tuberculosis. CRISPR interference (CRISPRi) promises to be a robust, easily engineered and scalable platform for regulated gene si...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/nmicrobiol.2016.274
更新日期：2017-02-06 00:00:00
abstract：:Autophagy and interferon (IFN)-mediated innate immunity are critical antiviral defence mechanisms, and recent evidence indicated that tripartite motif (TRIM) proteins are important regulators of both processes. Although the role of TRIM proteins in modulating antiviral cytokine responses has been well established, muc...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-017-0017-2
更新日期：2017-11-01 00:00:00
abstract：:Monkeypox is a viral zoonotic disease on the rise across endemic habitats. Despite the growing importance of monkeypox virus, our knowledge on its host spectrum and sylvatic maintenance is limited. Here, we describe the recent repeated emergence of monkeypox virus in a wild, human-habituated western chimpanzee (Pan tr...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-020-0706-0
更新日期：2020-07-01 00:00:00
abstract：:Coenzymes are vital for cellular metabolism and act on the full spectrum of enzymatic reactions. Intrinsic chemical reactivity, enzyme promiscuity and high flux through their catalytic cycles make coenzymes prone to damage. To counteract such compromising factors and ensure stable levels of functional coenzymes, cells...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/nmicrobiol.2017.73
更新日期：2017-05-15 00:00:00
abstract：:Marine microeukaryotes play a fundamental role in biogeochemical cycling through the transfer of energy to higher trophic levels and vertical carbon transport. Despite their global importance, microeukaryote physiology, nutrient metabolism and contributions to carbon cycling across offshore ecosystems are poorly chara...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-020-00814-7
更新日期：2021-02-01 00:00:00
abstract：:Pathogenic bacteria are armed with potent effector proteins that subvert host signalling processes during infection1. The activities of bacterial effectors and their associated roles within the host cell are often poorly understood, particularly for Chlamydia trachomatis2, a World Health Organization designated neglec...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-018-0271-y
更新日期：2018-12-01 00:00:00
abstract：:Evidence has accumulated to demonstrate that the intestinal microbiota enhances mammalian enteric virus infections1. For example, we and others previously reported that commensal bacteria stimulate acute and persistent murine norovirus infections2-4. However, in apparent contradiction of these results, the virulence o...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-019-0602-7
更新日期：2020-01-01 00:00:00
abstract：:Host adaptation is a key factor contributing to the emergence of new bacterial, viral and parasitic pathogens. Many pathogens are considered promiscuous because they cause disease across a range of host species, while others are host-adapted, infecting particular hosts(1). Host adaptation can potentially progress to h...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/nmicrobiol.2015.23
更新日期：2016-01-25 00:00:00
abstract：:An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title：Nature microbiology
pub_type： 已发布勘误
doi：10.1038/s41564-019-0584-5
更新日期：2019-11-01 00:00:00
abstract：:Despite the sporadic detection of fluoroquinolone-resistant Shigella in Asia in the early 2000s and the subsequent global spread of ciprofloxacin-resistant (cipR) Shigella sonnei from 2010, fluoroquinolones remain the recommended therapy for shigellosis1-7. The potential for cipR S. sonnei to develop resistance to alt...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-019-0645-9
更新日期：2020-02-01 00:00:00
abstract：:Mesalamine serves as the gold standard in treating ulcerative colitis. However, its precise mechanism(s) of action remains unclear. Here, we show that mesalamine treatment rapidly decreases polyphosphate levels in diverse bacteria, including members of the human gut microbiome. This decrease sensitizes bacteria toward...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/nmicrobiol.2016.267
更新日期：2017-01-23 00:00:00
abstract：:Legionella pneumophila, the causative bacterium for Legionnaires' disease, hijacks host membrane trafficking for the maturation of the Legionella-containing vacuole (LCV). The LCV membrane mainly contains PtdIns4P, which is important for anchoring many secreted Legionella effectors onto the LCV. Here, we identify a cr...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/nmicrobiol.2016.236
更新日期：2016-12-12 00:00:00
abstract：:This corrects the article DOI: 10.1038/nmicrobiol.2016.155. ...
journal_title：Nature microbiology
pub_type： 已发布勘误
doi：10.1038/nmicrobiol.2017.107
更新日期：2017-06-12 00:00:00
abstract：:Rod-shaped bacteria grow by adding material into their cell wall via the action of two spatially distinct enzymatic systems: the Rod complex moves around the cell circumference, whereas class A penicillin-binding proteins (aPBPs) do not. To understand how the combined action of these two systems defines bacterial dime...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-019-0439-0
更新日期：2019-08-01 00:00:00
abstract：:Immune responses in insects are differentially triggered depending on the infection route used by the pathogen. In most studies involving Drosophila melanogaster and viruses, infection is done by injection, while oral infection, which is probably the most common route of viral entry in nature, remains unexplored. Here...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-018-0265-9
更新日期：2018-12-01 00:00:00
abstract：:The dysregulation of intestinal microbial communities is associated with inflammatory bowel diseases (IBD). Studies aimed at understanding the contribution of the microbiota to inflammatory diseases have primarily focused on bacteria, yet the intestine harbours a viral component dominated by prokaryotic viruses known ...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-018-0210-y
更新日期：2018-09-01 00:00:00
abstract：:In structured environments, antibiotic-producing microorganisms can gain a selective advantage by inhibiting nearby competing species1. However, despite their genetic potential2,3, natural isolates often make only small amounts of antibiotics, and laboratory evolution can lead to loss rather than enhancement of antibi...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/nmicrobiol.2016.175
更新日期：2016-09-26 00:00:00
abstract：:Cellular adhesion mediates many important plant-microbe interactions. In the devastating blast fungus Magnaporthe oryzae1, powerful glycoprotein-rich mucilage adhesives2 cement melanized and pressurized dome-shaped infection cells-appressoria-to host rice leaf surfaces. Enormous internal turgor pressure is directed on...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-020-0786-x
更新日期：2020-12-01 00:00:00
abstract：:Most microorganisms live in environments where nutrients are limited and fluctuate over time. Cells respond to nutrient fluctuations by sensing and adapting their physiological state. Recent studies suggest phenotypic heterogeneity(1) in isogenic populations as an alternative strategy in fluctuating environments, wher...
journal_title：Nature microbiology
pub_type： 信件
doi：10.1038/nmicrobiol.2016.55
更新日期：2016-05-09 00:00:00
abstract：:An amendment to this paper has been published and can be accessed via a link at the top of the paper. ...
journal_title：Nature microbiology
pub_type： 已发布勘误
doi：10.1038/s41564-020-00825-4
更新日期：2020-12-01 00:00:00
abstract：:Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknow...
journal_title：Nature microbiology
pub_type： 杂志文章
doi：10.1038/s41564-018-0333-1
更新日期：2019-03-01 00:00:00
