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  • Metabolic crosstalk regulates Porphyromonas gingivalis colonization and virulence during oral polymicrobial infection
    Nat. Microbiol. Pub Date : 2017-09-18
    Masae Kuboniwa, John R. Houser, Erik L. Hendrickson, Qian Wang, Samar A. Alghamdi, Akito Sakanaka, Daniel P. Miller, Justin A. Hutcherson, Tiansong Wang, David A. C. Beck, Marvin Whiteley, Atsuo Amano, Huizhi Wang, Edward M. Marcotte, Murray Hackett, Richard J. Lamont

    Many human infections are polymicrobial in origin, and interactions among community inhabitants shape colonization patterns and pathogenic potential1. Periodontitis, which is the sixth most prevalent infectious disease worldwide2, ensues from the action of dysbiotic polymicrobial communities3. The keystone pathogen Porphyromonas gingivalis and the accessory pathogen Streptococcus gordonii interact to form communities in vitro and exhibit increased fitness in vivo3,4. The mechanistic basis of this polymicrobial synergy, however, has not been fully elucidated. Here we show that streptococcal 4-aminobenzoate/para-amino benzoic acid (pABA) is required for maximal accumulation of P. gingivalis in dual-species communities. Metabolomic and proteomic data showed that exogenous pABA is used for folate biosynthesis, and leads to decreased stress and elevated expression of fimbrial adhesins. Moreover, pABA increased the colonization and survival of P. gingivalis in a murine oral infection model. However, pABA also caused a reduction in virulence in vivo and suppressed extracellular polysaccharide production by P. gingivalis. Collectively, these data reveal a multidimensional aspect to P. gingivalis–S. gordonii interactions and establish pABA as a critical cue produced by a partner species that enhances the fitness of P. gingivalis while diminishing its virulence.

    更新日期:2017-09-19
  • Communication via extracellular vesicles enhances viral infection of a cosmopolitan alga
    Nat. Microbiol. Pub Date : 2017-09-18
    Daniella Schatz, Shilo Rosenwasser, Sergey Malitsky, Sharon G. Wolf, Ester Feldmesser, Assaf Vardi

    Communication between microorganisms in the marine environment has immense ecological impact by mediating trophic-level interactions and thus determining community structure1. Extracellular vesicles (EVs) are produced by bacteria2,3, archaea4, protists5 and metazoans, and can mediate pathogenicity6 or act as vectors for intercellular communication. However, little is known about the involvement of EVs in microbial interactions in the marine environment7. Here we investigated the signalling role of EVs produced during interactions between the cosmopolitan alga Emiliania huxleyi and its specific virus (EhV, Phycodnaviridae)8, which leads to the demise of these large-scale oceanic blooms9,10. We found that EVs are highly produced during viral infection or when bystander cells are exposed to infochemicals derived from infected cells. These vesicles have a unique lipid composition that differs from that of viruses and their infected host cells, and their cargo is composed of specific small RNAs that are predicted to target sphingolipid metabolism and cell-cycle pathways. EVs can be internalized by E. huxleyi cells, which consequently leads to a faster viral infection dynamic. EVs can also prolong EhV half-life in the extracellular milieu. We propose that EVs are exploited by viruses to sustain efficient infectivity and propagation across E. huxleyi blooms. As these algal blooms have an immense impact on the cycling of carbon and other nutrients11,12, this mode of cell–cell communication may influence the fate of the blooms and, consequently, the composition and flow of nutrients in marine microbial food webs.

    更新日期:2017-09-19
  • APOLs with low pH dependence can kill all African trypanosomes
    Nat. Microbiol. Pub Date : 2017-09-18
    Frédéric Fontaine, Laurence Lecordier, Gilles Vanwalleghem, Pierrick Uzureau, Nick Van Reet, Martina Fontaine, Patricia Tebabi, Benoit Vanhollebeke, Philippe Büscher, David Pérez-Morga, Etienne Pays

    The primate-specific serum protein apolipoprotein L1 (APOL1) is the only secreted member of a family of cell death promoting proteins1,2,3,4. APOL1 kills the bloodstream parasite Trypanosoma brucei brucei, but not the human sleeping sickness agents T.b. rhodesiense and T.b. gambiense3. We considered the possibility that intracellular members of the APOL1 family, against which extracellular trypanosomes could not have evolved resistance, could kill pathogenic T. brucei subspecies. Here we show that recombinant APOL3 (rAPOL3) kills all African trypanosomes, including T.b. rhodesiense, T.b. gambiense and the animal pathogens Trypanosoma evansi, Trypanosoma congolense and Trypanosoma vivax. However, rAPOL3 did not kill more distant trypanosomes such as Trypanosoma theileri or Trypanosoma cruzi. This trypanolytic potential was partially shared by rAPOL1 from Papio papio (rPpAPOL1). The differential killing ability of rAPOL3 and rAPOL1 was associated with a distinct dependence on acidic pH for activity. Due both to its instability and toxicity when injected into mice, rAPOL3 cannot be used for the treatment of infection, but an experimental rPpAPOL1 mutant inspired by APOL3 exhibited enhanced trypanolytic activity in vitro and the ability to completely inhibit T.b. gambiense infection in mice. We conclude that pH dependence influences the trypanolytic potential of rAPOLs.

    更新日期:2017-09-19
  • Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life
    Nat. Microbiol. Pub Date : 2017-09-11
    Donovan H. Parks, Christian Rinke, Maria Chuvochina, Pierre-Alain Chaumeil, Ben J. Woodcroft, Paul N. Evans, Philip Hugenholtz, Gene W. Tyson

    Challenges in cultivating microorganisms have limited the phylogenetic diversity of currently available microbial genomes. This is being addressed by advances in sequencing throughput and computational techniques that allow for the cultivation-independent recovery of genomes from metagenomes. Here, we report the reconstruction of 7,903 bacterial and archaeal genomes from >1,500 public metagenomes. All genomes are estimated to be ≥50% complete and nearly half are ≥90% complete with ≤5% contamination. These genomes increase the phylogenetic diversity of bacterial and archaeal genome trees by >30% and provide the first representatives of 17 bacterial and three archaeal candidate phyla. We also recovered 245 genomes from the Patescibacteria superphylum (also known as the Candidate Phyla Radiation) and find that the relative diversity of this group varies substantially with different protein marker sets. The scale and quality of this data set demonstrate that recovering genomes from metagenomes provides an expedient path forward to exploring microbial dark matter.

    更新日期:2017-09-11
  • Structural basis for the shielding function of the dynamic trypanosome variant surface glycoprotein coat
    Nat. Microbiol. Pub Date : 2017-09-11
    Thomas Bartossek, Nicola G. Jones, Christin Schäfer, Mislav Cvitković, Marius Glogger, Helen R. Mott, Jochen Kuper, Martha Brennich, Mark Carrington, Ana-Sunčana Smith, Susanne Fenz, Caroline Kisker, Markus Engstler

    The most prominent defence of the unicellular parasite Trypanosoma brucei against the host immune system is a dense coat that comprises a variant surface glycoprotein (VSG). Despite the importance of the VSG family, no complete structure of a VSG has been reported. Making use of high-resolution structures of individual VSG domains, we employed small-angle X-ray scattering to elucidate the first two complete VSG structures. The resulting models imply that the linker regions confer great flexibility between domains, which suggests that VSGs can adopt two main conformations to respond to obstacles and changes of protein density, while maintaining a protective barrier at all times. Single-molecule diffusion measurements of VSG in supported lipid bilayers substantiate this possibility, as two freely diffusing populations could be detected. This translates into a highly flexible overall topology of the surface VSG coat, which displays both lateral movement in the plane of the membrane and variation in the overall thickness of the coat.

    更新日期:2017-09-11
  • A viral protein antibiotic inhibits lipid II flippase activity
    Nat. Microbiol. Pub Date : 2017-09-11
    Karthik R. Chamakura, Lok-To Sham, Rebecca M. Davis, Lorna Min, Hongbaek Cho, Natividad Ruiz, Thomas G. Bernhardt, Ry Young

    For bacteriophage infections, the cell walls of bacteria, consisting of a single highly polymeric molecule of peptidoglycan (PG), pose a major problem for the release of progeny virions. Phage lysis proteins that overcome this barrier can point the way to new antibacterial strategies1, especially small lytic single-stranded DNA (the microviruses) and RNA phages (the leviviruses) that effect host lysis using a single non-enzymatic protein2. Previously, the A2 protein of levivirus Qβ and the E protein of the microvirus ϕX174 were shown to be ‘protein antibiotics’ that inhibit the MurA and MraY steps of the PG synthesis pathway2,3,4. Here, we investigated the mechanism of action of an unrelated lysis protein, LysM, of the Escherichia coli levivirus M5. We show that LysM inhibits the translocation of the final lipid-linked PG precursor called lipid II across the cytoplasmic membrane by interfering with the activity of MurJ. The finding that LysM inhibits a distinct step in the PG synthesis pathway from the A2 and E proteins indicates that small phages, particularly the single-stranded RNA (ssRNA) leviviruses, have a previously unappreciated capacity for evolving novel inhibitors of PG biogenesis despite their limited coding potential.

    更新日期:2017-09-11
  • CD81 association with SAMHD1 enhances HIV-1 reverse transcription by increasing dNTP levels
    Nat. Microbiol. Pub Date : 2017-09-04
    Vera Rocha-Perugini, Henar Suárez, Susana Álvarez, Soraya López-Martín, Gina M. Lenzi, Felipe Vences-Catalán, Shoshana Levy, Baek Kim, María A. Muñoz-Fernández, Francisco Sánchez-Madrid, Maria Yáñez-Mó

    In this study, we report that the tetraspanin CD81 enhances human immunodeficiency virus (HIV)-1 reverse transcription in HIV-1-infected cells. This is enabled by the direct interaction of CD81 with the deoxynucleoside triphosphate phosphohydrolase SAMHD1. This interaction prevents endosomal accumulation and favours the proteasome-dependent degradation of SAMHD1. Consequently, CD81 depletion results in SAMHD1 increased expression, decreasing the availability of deoxynucleoside triphosphates (dNTP) and thus HIV-1 reverse transcription. Conversely, CD81 overexpression, but not the expression of a CD81 carboxy (C)-terminal deletion mutant, increases cellular dNTP content and HIV-1 reverse transcription. Our results demonstrate that the interaction of CD81 with SAMHD1 controls the metabolic rate of HIV-1 replication by tuning the availability of building blocks for reverse transcription, namely dNTPs. Together with its role in HIV-1 entry and budding into host cells, the data herein indicate that HIV-1 uses CD81 as a rheostat that controls different stages of the infection.

    更新日期:2017-09-04
  • Interspecies quorum sensing in co-infections can manipulate trypanosome transmission potential
    Nat. Microbiol. Pub Date : 2017-09-04
    Eleanor Silvester, Julie Young, Alasdair Ivens, Keith R. Matthews

    Quorum sensing (QS) is commonly used in microbial communities and some unicellular parasites to coordinate group behaviours1,2. An example is Trypanosoma brucei, which causes human African trypanosomiasis, as well as the livestock disease, nagana. Trypanosomes are spread by tsetse flies, their transmission being enabled by cell-cycle arrested ‘stumpy forms’ that are generated in a density-dependent manner in mammalian blood. QS is mediated through a small (<500 Da), non-proteinaceous, stable but unidentified ‘stumpy induction factor’3, whose signal response pathway has been identified. Although QS is characterized in T. brucei, co-infections with other trypanosome species (Trypanosoma congolense and Trypanosoma vivax) are common in animals, generating the potential for interspecies interactions. Here, we show that T. congolense exhibits density-dependent growth control in vivo and conserves QS regulatory genes, of which one can complement a T. brucei QS signal-blind mutant to restore stumpy formation. Thereafter, we demonstrate that T. congolense-conditioned culture medium promotes T. brucei stumpy formation in vitro, which is dependent on the integrity of the QS signalling pathway. Finally, we show that, in vivo, co-infection with T. congolense accelerates differentiation to stumpy forms in T. brucei, which is also QS dependent. These cross-species interactions have important implications for trypanosome virulence, transmission, competition and evolution in the field.

    更新日期:2017-09-04
  • TRIM23 mediates virus-induced autophagy via activation of TBK1
    Nat. Microbiol. Pub Date : 2017-09-04
    Konstantin M. J. Sparrer, Sebastian Gableske, Matthew A. Zurenski, Zachary M. Parker, Florian Full, Gavin J. Baumgart, Jiro Kato, Gustavo Pacheco-Rodriguez, Chengyu Liang, Owen Pornillos, Joel Moss, Martha Vaughan, Michaela U. Gack

    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, much less is known about their involvement in autophagy in response to different viral pathogens. Through a targeted RNAi screen examining the relevance of selected TRIM proteins in autophagy induced by herpes simplex virus 1 (HSV-1), encephalomyocarditis virus (EMCV) and influenza A virus (IAV), we identified several TRIM proteins that regulate autophagy in a virus-species-specific manner, as well as a few TRIM proteins that were essential for autophagy triggered by all three viruses and rapamycin, among them TRIM23. TRIM23 was critical for autophagy-mediated restriction of multiple viruses, and this activity was dependent on both its RING E3 ligase and ADP-ribosylation factor (ARF) GTPase activity. Mechanistic studies revealed that unconventional K27-linked auto-ubiquitination of the ARF domain is essential for the GTP hydrolysis activity of TRIM23 and activation of TANK-binding kinase 1 (TBK1) by facilitating its dimerization and ability to phosphorylate the selective autophagy receptor p62. Our work identifies the TRIM23-TBK1-p62 axis as a key component of selective autophagy and further reveals a role for K27-linked ubiquitination in GTPase-dependent TBK1 activation.

    更新日期:2017-09-04
  • Specific inhibition of NLRP3 in chikungunya disease reveals a role for inflammasomes in alphavirus-induced inflammation
    Nat. Microbiol. Pub Date : 2017-08-28
    Weiqiang Chen, Suan-Sin Foo, Ali Zaid, Terk-Shin Teng, Lara J. Herrero, Stefan Wolf, Kothila Tharmarajah, Luan D. Vu, Caryn van Vreden, Adam Taylor, Joseph R. Freitas, Rachel W. Li, Trent M. Woodruff, Richard Gordon, David M. Ojcius, Helder I. Nakaya, Thirumala-Devi Kanneganti, Luke A. J. O’Neill, Avril A. B. Robertson, Nicholas J. King, Andreas Suhrbier, Matthew A. Cooper, Lisa F. P. Ng, Suresh Mahalingam

    Mosquito-borne viruses can cause severe inflammatory diseases and there are limited therapeutic solutions targeted specifically at virus-induced inflammation. Chikungunya virus (CHIKV), a re-emerging alphavirus responsible for several outbreaks worldwide in the past decade, causes debilitating joint inflammation and severe pain. Here, we show that CHIKV infection activates the NLRP3 inflammasome in humans and mice. Peripheral blood mononuclear cells isolated from CHIKV-infected patients showed elevated NLRP3, caspase-1 and interleukin-18 messenger RNA expression and, using a mouse model of CHIKV infection, we found that high NLRP3 expression was associated with peak inflammatory symptoms. Inhibition of NLRP3 activation using the small-molecule inhibitor MCC950 resulted in reduced CHIKV-induced inflammation and abrogated osteoclastogenic bone loss and myositis, but did not affect in vivo viral replication. Mice treated with MCC950 displayed lower expression levels of the cytokines interleukin-6, chemokine ligand 2 and tumour necrosis factor in joint tissue. Interestingly, MCC950 treatment abrogated disease signs in mice infected with a related arthritogenic alphavirus, Ross River virus, but not in mice infected with West Nile virus—a flavivirus. Here, using mouse models of alphavirus-induced musculoskeletal disease, we demonstrate that NLRP3 inhibition in vivo can reduce inflammatory pathology and that further development of therapeutic solutions targeting inflammasome function could help treat arboviral diseases.

    更新日期:2017-08-28
  • A microfluidics-based in situ chemotaxis assay to study the behaviour of aquatic microbial communities
    Nat. Microbiol. Pub Date : 2017-08-28
    Bennett S. Lambert, Jean-Baptiste Raina, Vicente I. Fernandez, Christian Rinke, Nachshon Siboni, Francesco Rubino, Philip Hugenholtz, Gene W. Tyson, Justin R. Seymour, Roman Stocker

    Microbial interactions influence the productivity and biogeochemistry of the ocean, yet they occur in miniscule volumes that cannot be sampled by traditional oceanographic techniques. To investigate the behaviours of marine microorganisms at spatially relevant scales, we engineered an in situ chemotaxis assay (ISCA) based on microfluidic technology. Here, we describe the fabrication, testing and first field results of the ISCA, demonstrating its value in accessing the microbial behaviours that shape marine ecosystems.

    更新日期:2017-08-28
  • Efficient invasion by Toxoplasma depends on the subversion of host protein networks
    Nat. Microbiol. Pub Date : 2017-08-28
    Amandine Guérin, Rosa Milagros Corrales, Michele L. Parker, Mauld H. Lamarque, Damien Jacot, Hiba El Hajj, Dominique Soldati-Favre, Martin J. Boulanger, Maryse Lebrun

    Apicomplexan parasites are important pathogens of humans and domestic animals, including Plasmodium species (the agents of malaria) and Toxoplasma gondii, which is responsible for toxoplasmosis. They replicate within the cells of their animal hosts, to which they gain access using a unique parasite-driven invasion process. At the core of the invasion machine is a structure at the interface between the invading parasite and host cell called the moving junction (MJ)1. The MJ serves as both a molecular doorway to the host cell and an anchor point enabling the parasite to engage its motility machinery to drive the penetration of the host cell2, ultimately yielding a protective vacuole3. The MJ is established through self-assembly of parasite proteins at the parasite–host interface4. However, it is unknown whether host proteins are subverted for MJ formation. Here, we show that Toxoplasma parasite rhoptry neck proteins (RON2, RON4 and RON5) cooperate to actively recruit the host CIN85, CD2AP and the ESCRT-I components ALIX and TSG101 to the MJ during invasion. We map the interactions in detail and demonstrate that the parasite mimics and subverts conserved binding interfaces with remarkable specificity. Parasite mutants unable to recruit these host proteins show inefficient host cell invasion in culture and attenuated virulence in mice. This study reveals molecular mechanisms by which parasites subvert widely conserved host machinery to force highly efficient host cell access.

    更新日期:2017-08-28
  • Viral pathogenesis: Unlocking Ebola persistence
    Nat. Microbiol. Pub Date : 2017-08-24
    Trina Racine, Gary P. Kobinger

    Viral pathogenesis: Unlocking Ebola persistence Nature Microbiology, Published online: 24 August 2017; doi:10.1038/nmicrobiol.2017.124 The 2013–2016 West African Ebola virus outbreak evidenced that the virus can persist in survivors long-term, leading to sequelae and risks of new transmission chains. Ebola virus has now been shown to behave similarly in rhesus macaques, enabling their use to study persistence and intervention strategies.

    更新日期:2017-08-24
  • Stress and stability: applying the Anna Karenina principle to animal microbiomes
    Nat. Microbiol. Pub Date : 2017-08-24
    Jesse R. Zaneveld, Ryan McMinds, Rebecca Vega Thurber

    All animals studied to date are associated with symbiotic communities of microorganisms. These animal microbiotas often play important roles in normal physiological function and susceptibility to disease; predicting their responses to perturbation represents an essential challenge for microbiology. Most studies of microbiome dynamics test for patterns in which perturbation shifts animal microbiomes from a healthy to a dysbiotic stable state. Here, we consider a complementary alternative: that the microbiological changes induced by many perturbations are stochastic, and therefore lead to transitions from stable to unstable community states. The result is an ‘Anna Karenina principle’ for animal microbiomes, in which dysbiotic individuals vary more in microbial community composition than healthy individuals—paralleling Leo Tolstoy's dictum that “all happy families look alike; each unhappy family is unhappy in its own way”. We argue that Anna Karenina effects are a common and important response of animal microbiomes to stressors that reduce the ability of the host or its microbiome to regulate community composition. Patterns consistent with Anna Karenina effects have been found in systems ranging from the surface of threatened corals exposed to above-average temperatures, to the lungs of patients suffering from HIV/AIDs. However, despite their apparent ubiquity, these patterns are easily missed or discarded by some common workflows, and therefore probably underreported. Now that a substantial body of research has established the existence of these patterns in diverse systems, rigorous testing, intensive time-series datasets and improved stochastic modelling will help to explore their importance for topics ranging from personalized medicine to theories of the evolution of host–microorganism symbioses.

    更新日期:2017-08-24
  • Structural biology: Loading T4SS substrates
    Nat. Microbiol. Pub Date : 2017-08-24
    Peter J. Christie

    Structural biology: Loading T4SS substrates Nature Microbiology, Published online: 24 August 2017; doi:10.1038/nmicrobiol.2017.125 Structural analyses of the type IV coupling protein of the Dot/Icm type IV secretion system from Legionella pneumophila reveal how this platform recruits a plethora of substrates for translocation.

    更新日期:2017-08-24
  • Marine microbiology: Roommates in space and time
    Nat. Microbiol. Pub Date : 2017-08-24
    Meinhard Simon

    Marine microbiology: Roommates in space and time Nature Microbiology, Published online: 24 August 2017; doi:10.1038/nmicrobiol.2017.122 Proteomics analyses reveal how the long-term coexistence of the marine picocyanobacterium Synechococcus and the heterotroph Ruegeria pomeroyi, of the globally abundant marine Roseobacter group, is based on the mutual and beneficial recycling of inorganic and organic nitrogen compounds.

    更新日期:2017-08-24
  • Change advice on antibiotics with caution
    Nat. Microbiol. Pub Date : 2017-08-24

    Change advice on antibiotics with caution Nature Microbiology, Published online: 24 August 2017; doi:10.1038/nmicrobiol.2017.126 The recommendation that antibiotic courses are always completed should be dropped according to a recent analysis. While a welcome addition to discussion on the role of stewardship in tackling resistance, caution should be applied before advice on prescription practices and communication with patients is altered.

    更新日期:2017-08-24
  • Translational fidelity and mistranslation in the cellular response to stress
    Nat. Microbiol. Pub Date : 2017-08-24
    Kyle Mohler, Michael Ibba

    Faithful translation of mRNA into the corresponding polypeptide is a complex multistep process, requiring accurate amino acid selection, transfer RNA (tRNA) charging and mRNA decoding on the ribosome. Key players in this process are aminoacyl-tRNA synthetases (aaRSs), which not only catalyse the attachment of cognate amino acids to their respective tRNAs, but also selectively hydrolyse incorrectly activated non-cognate amino acids and/or misaminoacylated tRNAs. This aaRS proofreading provides quality control checkpoints that exclude non-cognate amino acids during translation, and in so doing helps to prevent the formation of an aberrant proteome. However, despite the intrinsic need for high accuracy during translation, and the widespread evolutionary conservation of aaRS proofreading pathways, requirements for translation quality control vary depending on cellular physiology and changes in growth conditions, and translation errors are not always detrimental. Recent work has demonstrated that mistranslation can also be beneficial to cells, and some organisms have selected for a higher degree of mistranslation than others. The aims of this Review Article are to summarize the known mechanisms of protein translational fidelity and explore the diversity and impact of mistranslation events as a potentially beneficial response to environmental and cellular stress.

    更新日期:2017-08-24
  • Broadly protective murine monoclonal antibodies against influenza B virus target highly conserved neuraminidase epitopes
    Nat. Microbiol. Pub Date : 2017-08-21
    Teddy John Wohlbold, Kira A. Podolsky, Veronika Chromikova, Ericka Kirkpatrick, Veronica Falconieri, Philip Meade, Fatima Amanat, Jessica Tan, Benjamin R. tenOever, Gene S. Tan, Sriram Subramaniam, Peter Palese, Florian Krammer

    A substantial proportion of influenza-related childhood deaths are due to infection with influenza B viruses, which co-circulate in the human population as two antigenically distinct lineages defined by the immunodominant receptor binding protein, haemagglutinin. While broadly cross-reactive, protective monoclonal antibodies against the haemagglutinin of influenza B viruses have been described, none targeting the neuraminidase, the second most abundant viral glycoprotein, have been reported. Here, we analyse a panel of five murine anti-neuraminidase monoclonal antibodies that demonstrate broad binding, neuraminidase inhibition, in vitro antibody-dependent cell-mediated cytotoxicity and in vivo protection against influenza B viruses belonging to both haemagglutinin lineages and spanning over 70 years of antigenic drift. Electron microscopic analysis of two neuraminidase–antibody complexes shows that the conserved neuraminidase epitopes are located on the head of the molecule and that they are distinct from the enzymatic active site. In the mouse model, one therapeutic dose of antibody 1F2 was more protective than the current standard of treatment, oseltamivir, given twice daily for six days.

    更新日期:2017-08-21
  • A plasmid from an Antarctic haloarchaeon uses specialized membrane vesicles to disseminate and infect plasmid-free cells
    Nat. Microbiol. Pub Date : 2017-08-21
    Susanne Erdmann, Bernhard Tschitschko, Ling Zhong, Mark J. Raftery, Ricardo Cavicchioli

    The major difference between viruses and plasmids is the mechanism of transferring their genomic information between host cells. Here, we describe the archaeal plasmid pR1SE from an Antarctic species of haloarchaea that transfers via a mechanism similar to a virus. pR1SE encodes proteins that are found in regularly shaped membrane vesicles, and the vesicles enclose the plasmid DNA. The released vesicles are capable of infecting a plasmid-free strain, which then gains the ability to produce plasmid-containing vesicles. pR1SE can integrate and replicate as part of the host genome, resolve out with fragments of host DNA incorporated or portions of the plasmid left behind, form vesicles and transfer to new hosts. The pR1SE mechanism of transfer of DNA could represent the predecessor of a strategy used by viruses to pass on their genomic DNA and fulfil roles in gene exchange, supporting a strong evolutionary connection between plasmids and viruses.

    更新日期:2017-08-21
  • Asian Zika virus strains target CD14+ blood monocytes and induce M2-skewed immunosuppression during pregnancy
    Nat. Microbiol. Pub Date : 2017-08-21
    Suan-Sin Foo, Weiqiang Chen, Yen Chan, James W. Bowman, Lin-Chun Chang, Younho Choi, Ji Seung Yoo, Jianning Ge, Genhong Cheng, Alexandre Bonnin, Karin Nielsen-Saines, Patrícia Brasil, Jae U. Jung

    Blood CD14+ monocytes are frontline immunomodulators categorized into classical, intermediate or non-classical subsets, and subsequently differentiated into M1 pro- or M2 anti-inflammatory macrophages on stimulation. Although the Zika virus (ZIKV) rapidly establishes viraemia, the target cells and immune responses, particularly during pregnancy, remain elusive. Furthermore, it is unknown whether African- and Asian-lineage ZIKV have different phenotypic impacts on host immune responses. Using human blood infection, we identified CD14+ monocytes as the primary target for African- or Asian-lineage ZIKV infection. When immunoprofiles of human blood infected with ZIKV were compared, a classical/intermediate monocyte-mediated M1-skewed inflammation by the African-lineage ZIKV infection was observed, in contrast to a non-classical monocyte-mediated M2-skewed immunosuppression by the Asian-lineage ZIKV infection. Importantly, infection of the blood of pregnant women revealed an enhanced susceptibility to ZIKV infection. Specifically, Asian-lineage ZIKV infection of pregnant women’s blood led to an exacerbated M2-skewed immunosuppression of non-classical monocytes in conjunction with a global suppression of type I interferon-signalling pathway and an aberrant expression of host genes associated with pregnancy complications. Also, 30 ZIKV+ sera from symptomatic pregnant patients showed elevated levels of M2-skewed immunosuppressive cytokines and pregnancy-complication-associated fibronectin-1. This study demonstrates the differential immunomodulatory responses of blood monocytes, particularly during pregnancy, on infection with different lineages of ZIKV.

    更新日期:2017-08-21
  • Hexahydroquinolines are antimalarial candidates with potent blood-stage and transmission-blocking activity
    Nat. Microbiol. Pub Date : 2017-08-14
    Manu Vanaerschot, Leonardo Lucantoni, Tao Li, Jill M. Combrinck, Andrea Ruecker, T. R. Santha Kumar, Kelly Rubiano, Pedro E. Ferreira, Giulia Siciliano, Sonia Gulati, Philipp P. Henrich, Caroline L. Ng, James M. Murithi, Victoria C. Corey, Sandra Duffy, Ori J. Lieberman, M. Isabel Veiga, Robert E. Sinden, Pietro Alano, Michael J. Delves, Kim Lee Sim, Elizabeth A. Winzeler, Timothy J. Egan, Stephen L. Hoffman, Vicky M. Avery, David A. Fidock

    Antimalarial compounds with dual therapeutic and transmission-blocking activity are desired as high-value partners for combination therapies. Here, we report the identification and characterization of hexahydroquinolines (HHQs) that show low nanomolar potency against both pathogenic and transmissible intra-erythrocytic forms of the malaria parasite Plasmodium falciparum. This activity translates into potent transmission-blocking potential, as shown by in vitro male gamete formation assays and reduced oocyst infection and prevalence in Anopheles mosquitoes. In vivo studies illustrated the ability of lead HHQs to suppress Plasmodium berghei blood-stage parasite proliferation. Resistance selection studies, confirmed by CRISPR–Cas9-based gene editing, identified the digestive vacuole membrane-spanning transporter PfMDR1 (P. falciparum multidrug resistance gene-1) as a determinant of parasite resistance to HHQs. Haemoglobin and haem fractionation assays suggest a mode of action that results in reduced haemozoin levels and might involve inhibition of host haemoglobin uptake into intra-erythrocytic parasites. Furthermore, parasites resistant to HHQs displayed increased susceptibility to several first-line antimalarial drugs, including lumefantrine, confirming that HHQs have a different mode of action to other antimalarials drugs for which PfMDR1 is known to confer resistance. This work evokes therapeutic strategies that combine opposing selective pressures on this parasite transporter as an approach to countering the emergence and transmission of multidrug-resistant P. falciparum malaria.

    更新日期:2017-08-14
  • Environmental drivers of a microbial genomic transition zone in the ocean’s interior
    Nat. Microbiol. Pub Date : 2017-08-14
    Daniel R. Mende, Jessica A. Bryant, Frank O. Aylward, John M. Eppley, Torben Nielsen, David M. Karl, Edward F. DeLong

    The core properties of microbial genomes, including GC content and genome size, are known to vary widely among different bacteria and archaea1,2. Several hypotheses have been proposed to explain this genomic variability, but the fundamental drivers that shape bacterial and archaeal genomic properties remain uncertain3,4,5,6,7. Here, we report the existence of a sharp genomic transition zone below the photic zone, where bacterial and archaeal genomes and proteomes undergo a community-wide punctuated shift. Across a narrow range of increasing depth of just tens of metres, diverse microbial clades trend towards larger genome size, higher genomic GC content, and proteins with higher nitrogen but lower carbon content. These community-wide changes in genome features appear to be driven by gradients in the surrounding environmental energy and nutrient fields. Collectively, our data support hypotheses invoking nutrient limitation as a central driver in the evolution of core bacterial and archaeal genomic and proteomic properties.

    更新日期:2017-08-14
  • Gut-homing Δ42PD1+Vδ2 T cells promote innate mucosal damage via TLR4 during acute HIV type 1 infection
    Nat. Microbiol. Pub Date : 2017-08-14
    Allen Ka Loon Cheung, Hau-yee Kwok, Yiru Huang, Min Chen, Yufei Mo, Xilin Wu, Ka-shing Lam, Hoi-Kuan Kong, Terrence Chi Kong Lau, Jingying Zhou, Jingjing Li, Lin Cheng, Boon Kiat Lee, Qiaoli Peng, Xiaofan Lu, Minghui An, Hui Wang, Hong Shang, Boping Zhou, Hao Wu, Aimin Xu, Kwok-Yung Yuen, Zhiwei Chen

    The innate immune cells underlying mucosal inflammatory responses and damage during acute HIV-1 infection remain incompletely understood. Here, we report a Vδ2 subset of gut-homing γδ T cells with significantly upregulated Δ42PD1 (a PD1 isoform) in acute (~20%) HIV-1 patients compared to chronic HIV-1 patients (~11%) and healthy controls (~2%). The frequency of Δ42PD1+Vδ2 cells correlates positively with plasma levels of pro-inflammatory cytokines and fatty-acid-binding protein before detectable lipopolysaccharide in acute patients. The expression of Δ42PD1 can be induced by in vitro HIV-1 infection and is accompanied by high co-expression of gut-homing receptors CCR9/CD103. To investigate the role of Δ42PD1+Vδ2 cells in vivo, they were adoptively transferred into autologous humanized mice, resulting in small intestinal inflammatory damage, probably due to the interaction of Δ42PD1 with its cognate receptor Toll-like receptor 4 (TLR4). In addition, blockade of Δ42PD1 or TLR4 successfully reduced the cytokine effect induced by Δ42PD1+Vδ2 cells in vitro, as well as the mucosal pathological effect in humanized mice. Our findings have therefore uncovered a Δ42PD1–TLR4 pathway exhibited by virus-induced gut-homing Vδ2 cells that may contribute to innate immune activation and intestinal pathogenesis during acute HIV-1 infection. Δ42PD1+Vδ2 cells may serve as a target for the investigation of diseases with mucosal inflammation.

    更新日期:2017-08-14
  • An anti-CRISPR from a virulent streptococcal phage inhibits Streptococcus pyogenes Cas9
    Nat. Microbiol. Pub Date : 2017-08-07
    Alexander P. Hynes, Geneviève M. Rousseau, Marie-Laurence Lemay, Philippe Horvath, Dennis A. Romero, Christophe Fremaux, Sylvain Moineau

    The CRISPR–Cas system owes its utility as a genome-editing tool to its origin as a prokaryotic immune system. The first demonstration of its activity against bacterial viruses (phages) is also the first record of phages evading that immunity1. This evasion can be due to point mutations1, large-scale deletions2, DNA modifications3, or phage-encoded proteins that interfere with the CRISPR–Cas system, known as anti-CRISPRs (Acrs)4. The latter are of biotechnological interest, as Acrs can serve as off switches for CRISPR-based genome editing5. Every Acr characterized to date originated from temperate phages, genomic islands, or prophages4,5,6,7,8, and shared properties with the first Acr discovered. Here, with a phage-oriented approach, we have identified an unrelated Acr in a virulent phage of Streptococcus thermophilus. In challenging a S. thermophilus strain CRISPR-immunized against a set of virulent phages, we found one that evaded the CRISPR-encoded immunity >40,000× more often than the others. Through systematic cloning of its genes, we identified an Acr solely responsible for the abolished immunity. We extended our findings by demonstrating activity in another S. thermophilus strain, against unrelated phages, and in another bacterial genus immunized using the heterologous SpCas9 system favoured for genome editing. This Acr completely abolishes SpCas9-mediated immunity in our assays.

    更新日期:2017-08-07
  • A myovirus encoding both photosystem I and II proteins enhances cyclic electron flow in infected Prochlorococcus cells
    Nat. Microbiol. Pub Date : 2017-08-07
    Svetlana Fridman, José Flores-Uribe, Shirley Larom, Onit Alalouf, Oded Liran, Iftach Yacoby, Faris Salama, Benjamin Bailleul, Fabrice Rappaport, Tamar Ziv, Itai Sharon, Francisco M. Cornejo-Castillo, Alon Philosof, Christopher L. Dupont, Pablo Sánchez, Silvia G. Acinas, Forest L. Rohwer, Debbie Lindell, Oded Béjà

    Cyanobacteria are important contributors to primary production in the open oceans. Over the past decade, various photosynthesis-related genes have been found in viruses that infect cyanobacteria (cyanophages). Although photosystem II (PSII) genes are common in both cultured cyanophages and environmental samples1,2,3,4, viral photosystem I (vPSI) genes have so far only been detected in environmental samples5,6. Here, we have used a targeted strategy to isolate a cyanophage from the tropical Pacific Ocean that carries a PSI gene cassette with seven distinct PSI genes (psaJF, C, A, B, K, E, D) as well as two PSII genes (psbA, D). This cyanophage, P-TIM68, belongs to the T4-like myoviruses, has a prolate capsid, a long contractile tail and infects Prochlorococcus sp. strain MIT9515. Phage photosynthesis genes from both photosystems are expressed during infection, and the resultant proteins are incorporated into membranes of the infected host. Moreover, photosynthetic capacity in the cell is maintained throughout the infection cycle with enhancement of cyclic electron flow around PSI. Analysis of metagenomic data from the Tara Oceans expedition7 shows that phages carrying PSI gene cassettes are abundant in the tropical Pacific Ocean, composing up to 28% of T4-like cyanomyophages. They are also present in the tropical Indian and Atlantic Oceans. P-TIM68 populations, specifically, compose on average 22% of the PSI-gene-cassette carrying phages. Our results suggest that cyanophages carrying PSI and PSII genes are likely to maintain and even manipulate photosynthesis during infection of their Prochlorococcus hosts in the tropical oceans.

    更新日期:2017-08-07
  • Clonal differences in Staphylococcus aureus bacteraemia-associated mortality
    Nat. Microbiol. Pub Date : 2017-08-07
    Mario Recker, Maisem Laabei, Michelle S. Toleman, Sandra Reuter, Rebecca B. Saunderson, Beth Blane, M. Estee Török, Khadija Ouadi, Emily Stevens, Maho Yokoyama, Joseph Steventon, Luke Thompson, Gregory Milne, Sion Bayliss, Leann Bacon, Sharon J. Peacock, Ruth C. Massey

    The bacterium Staphylococcus aureus is a major human pathogen for which the emergence of antibiotic resistance is a global public health concern. Infection severity, and in particular bacteraemia-associated mortality, has been attributed to several host-related factors, such as age and the presence of comorbidities. The role of the bacterium in infection severity is less well understood, as it is complicated by the multifaceted nature of bacterial virulence, which has so far prevented a robust mapping between genotype, phenotype and infection outcome. To investigate the role of bacterial factors in contributing to bacteraemia-associated mortality, we phenotyped a collection of sequenced clinical S. aureus isolates from patients with bloodstream infections, representing two globally important clonal types, CC22 and CC30. By adopting a genome-wide association study approach we identified and functionally verified several genetic loci that affect the expression of cytolytic toxicity and biofilm formation. By analysing the pooled data comprising bacterial genotype and phenotype together with clinical metadata within a machine-learning framework, we found significant clonal differences in the determinants most predictive of poor infection outcome. Whereas elevated cytolytic toxicity in combination with low levels of biofilm formation was predictive of an increased risk of mortality in infections by strains of a CC22 background, these virulence-specific factors had little influence on mortality rates associated with CC30 infections. Our results therefore suggest that different clones may have adopted different strategies to overcome host responses and cause severe pathology. Our study further demonstrates the use of a combined genomics and data analytic approach to enhance our understanding of bacterial pathogenesis at the individual level, which will be an important step towards personalized medicine and infectious disease management.

    更新日期:2017-08-07
  • Group A streptococcal M protein activates the NLRP3 inflammasome
    Nat. Microbiol. Pub Date : 2017-08-07
    J. Andrés Valderrama, Angelica M. Riestra, Nina J. Gao, Christopher N. LaRock, Naveen Gupta, Syed Raza Ali, Hal M. Hoffman, Partho Ghosh, Victor Nizet

    Group A Streptococcus (GAS) is among the top ten causes of infection-related mortality in humans. M protein is the most abundant GAS surface protein, and M1 serotype GAS strains are associated with invasive infections, including necrotizing fasciitis and toxic shock syndrome. Here, we report that released, soluble M1 protein triggers programmed cell death in macrophages (Mϕ). M1 served as a second signal for caspase-1-dependent NLRP3 inflammasome activation, inducing maturation and release of proinflammatory cytokine interleukin-1β (IL-1β) and macrophage pyroptosis. The structurally dynamic B-repeat domain of M1 was critical for inflammasome activation, which involved K+ efflux and M1 protein internalization by clathrin-mediated endocytosis. Mouse intraperitoneal challenge showed that soluble M1 was sufficient and specific for IL-1β activation, which may represent an early warning to activate host immunity against the pathogen. Conversely, in systemic infection, hyperinflammation associated with M1-mediated pyroptosis and IL-1β release could aggravate tissue injury.

    更新日期:2017-08-07
  • Coordinated regulation of growth, activity and transcription in natural populations of the unicellular nitrogen-fixing cyanobacterium Crocosphaera
    Nat. Microbiol. Pub Date : 2017-07-31
    Samuel T. Wilson, Frank O. Aylward, Francois Ribalet, Benedetto Barone, John R. Casey, Paige E. Connell, John M. Eppley, Sara Ferrón, Jessica N. Fitzsimmons, Christopher T. Hayes, Anna E. Romano, Kendra A. Turk-Kubo, Alice Vislova, E. Virginia Armbrust, David A. Caron, Matthew J. Church, Jonathan P. Zehr, David M. Karl, Edward F. DeLong

    The temporal dynamics of phytoplankton growth and activity have large impacts on fluxes of matter and energy, yet obtaining in situ metabolic measurements of sufficient resolution for even dominant microorganisms remains a considerable challenge. We performed Lagrangian diel sampling with synoptic measurements of population abundances, dinitrogen (N2) fixation, mortality, productivity, export and transcription in a bloom of Crocosphaera over eight days in the North Pacific Subtropical Gyre (NPSG). Quantitative transcriptomic analyses revealed clear diel oscillations in transcript abundances for 34% of Crocosphaera genes identified, reflecting a systematic progression of gene expression in diverse metabolic pathways. Significant time-lagged correspondence was evident between nifH transcript abundance and maximal N2 fixation, as well as sepF transcript abundance and cell division, demonstrating the utility of transcriptomics to predict the occurrence and timing of physiological and biogeochemical processes in natural populations. Indirect estimates of carbon fixation by Crocosphaera were equivalent to 11% of net community production, suggesting that under bloom conditions this diazotroph has a considerable impact on the wider carbon cycle. Our cross-scale synthesis of molecular, population and community-wide data underscores the tightly coordinated in situ metabolism of the keystone N2-fixing cyanobacterium Crocosphaera, as well as the broader ecosystem-wide implications of its activities.

    更新日期:2017-08-02
  • Correction: Stop neglecting fungi
    Nat. Microbiol. Pub Date : 2017-07-31

    Correction: Stop neglecting fungi Nature Microbiology, Published online: 31 July 2017; doi:10.1038/nmicrobiol.2017.123

    更新日期:2017-08-02
  • Making magic bullets
    Nat. Microbiol. Pub Date : 2017-07-25
    Jessica Blair

    Making magic bullets Nature Microbiology, Published online: 25 July 2017; doi:10.1038/nmicrobiol.2017.110

    更新日期:2017-07-28
  • Stop neglecting fungi
    Nat. Microbiol. Pub Date : 2017-07-25

    Stop neglecting fungi Nature Microbiology, Published online: 25 July 2017; doi:10.1038/nmicrobiol.2017.120 Fungal pathogens are virtually ignored by the press, the public and funding bodies, despite posing a significant threat to public health, food biosecurity and biodiversity.

    更新日期:2017-07-28
  • The importance of anabolism in microbial control over soil carbon storage
    Nat. Microbiol. Pub Date : 2017-07-25
    Chao Liang, Joshua P. Schimel, Julie D. Jastrow

    The importance of anabolism in microbial control over soil carbon storage Nature Microbiology, Published online: 25 July 2017; doi:10.1038/nmicrobiol.2017.105 This Perspective looks at how microbial anabolism and the soil microbial carbon pump control microbial necromass accumulation and stabilization; the ‘entombing effect’.

    更新日期:2017-07-28
  • Archaeal evolution: The methanogenic roots of Archaea
    Nat. Microbiol. Pub Date : 2017-07-25
    Anja Spang, Thijs J. G. Ettema

    Archaeal evolution: The methanogenic roots of Archaea Nature Microbiology, Published online: 25 July 2017; doi:10.1038/nmicrobiol.2017.109 The discovery and genomic characterization of a new group of extreme halophilic methanogens sheds light on the origin of methanogenesis and the evolution of the Haloarchaea.

    更新日期:2017-07-28
  • Synthetic biology: Engineered stable ecosystems
    Nat. Microbiol. Pub Date : 2017-07-25
    Alfonso Jaramillo

    Synthetic biology: Engineered stable ecosystems Nature Microbiology, Published online: 25 July 2017; doi:10.1038/nmicrobiol.2017.119 Co-culture of bacterial cells engineered with quorum-sensing and self-lysis circuits allows coupled oscillatory dynamics and stable states, opening the way to engineered microbial ecosystems with targeted dynamics and extending gene circuits to the ecosystem level.

    更新日期:2017-07-28
  • Mechanical strain sensing implicated in cell shape recovery in Escherichia coli
    Nat. Microbiol. Pub Date : 2017-07-24
    Felix Wong, Lars D. Renner, Gizem Özbaykal, Jayson Paulose, Douglas B. Weibel, Sven van Teeffelen, Ariel Amir

    The shapes of most bacteria are imparted by the structures of their peptidoglycan cell walls, which are determined by many dynamic processes that can be described on various length scales ranging from short-range glycan insertions to cellular-scale elasticity1,​ 2,​ 3,​ 4,​ 5,​ 6,​ 7,​ 8,​ 9,​ 10,​ 11 . Understanding the mechanisms that maintain stable, rod-like morphologies in certain bacteria has proved to be challenging due to an incomplete understanding of the feedback between growth and the elastic and geometric properties of the cell wall3,4,12,​ 13,​ 14 . Here, we probe the effects of mechanical strain on cell shape by modelling the mechanical strains caused by bending and differential growth of the cell wall. We show that the spatial coupling of growth to regions of high mechanical strain can explain the plastic response of cells to bending4 and quantitatively predict the rate at which bent cells straighten. By growing filamentous Escherichia coli cells in doughnut-shaped microchambers, we find that the cells recovered their straight, native rod-shaped morphologies when released from captivity at a rate consistent with the theoretical prediction. We then measure the localization of MreB, an actin homologue crucial to cell wall synthesis, inside confinement and during the straightening process, and find that it cannot explain the plastic response to bending or the observed straightening rate. Our results implicate mechanical strain sensing, implemented by components of the elongasome yet to be fully characterized, as an important component of robust shape regulation in E. coli.

    更新日期:2017-07-25
  • Biphasic growth dynamics control cell division in Caulobacter crescentus
    Nat. Microbiol. Pub Date : 2017-07-24
    Shiladitya Banerjee, Klevin Lo, Matthew K. Daddysman, Alan Selewa, Thomas Kuntz, Aaron R. Dinner, Norbert F. Scherer

    Cell size is specific to each species and impacts cell function. Various phenomenological models for cell size regulation have been proposed, but recent work in bacteria has suggested an ‘adder’ model, in which a cell increments its size by a constant amount between each division. However, the coupling between cell size, shape and constriction remains poorly understood. Here, we investigate size control and the cell cycle dependence of bacterial growth using multigenerational cell growth and shape data for single Caulobacter crescentus cells. Our analysis reveals a biphasic mode of growth: a relative timer phase before constriction where cell growth is correlated to its initial size, followed by a pure adder phase during constriction. Cell wall labelling measurements reinforce this biphasic model, in which a crossover from uniform lateral growth to localized septal growth is observed. We present a mathematical model that quantitatively explains this biphasic ‘mixer’ model for cell size control.

    更新日期:2017-07-25
  • Architecture of the type IV coupling protein complex of Legionella pneumophila
    Nat. Microbiol. Pub Date : 2017-07-17
    Mi-Jeong Kwak, J. Dongun Kim, Hyunmin Kim, Cheolhee Kim, James W. Bowman, Seonghoon Kim, Keehyoung Joo, Jooyoung Lee, Kyeong Sik Jin, Yeon-Gil Kim, Nam Ki Lee, Jae U. Jung, Byung-Ha Oh

    Many bacteria, including Legionella pneumophila, rely on the type IV secretion system to translocate a repertoire of effector proteins into the hosts for their survival and growth. Type IV coupling protein (T4CP) is a hexameric ATPase that links translocating substrates to the transenvelope secretion conduit. Yet, how a large number of effector proteins are selectively recruited and processed by T4CPs remains enigmatic. DotL, the T4CP of L. pneumophila, contains an ATPase domain and a C-terminal extension whose function is unknown. Unlike T4CPs involved in plasmid DNA translocation, DotL appeared to function by forming a multiprotein complex with four other proteins. Here, we show that the C-terminal extension of DotL interacts with DotN, IcmS, IcmW and an additionally identified subunit LvgA, and that this pentameric assembly binds Legionella effector proteins. We determined the crystal structure of this assembly and built an architecture of the T4CP holocomplex by combining a homology model of the ATPase domain of DotL. The holocomplex is a hexamer of a bipartite structure composed of a membrane-proximal ATPase domain and a membrane-distal substrate-recognition assembly. The presented information demonstrates the architecture and functional dissection of the multiprotein T4CP complexes and provides important insights into their substrate recruitment and processing.

    更新日期:2017-07-19
  • Identification and pathological characterization of persistent asymptomatic Ebola virus infection in rhesus monkeys
    Nat. Microbiol. Pub Date : 2017-07-17
    Xiankun Zeng, Candace D. Blancett, Keith A. Koistinen, Christopher W. Schellhase, Jeremy J. Bearss, Sheli R. Radoshitzky, Shelley P. Honnold, Taylor B. Chance, Travis K. Warren, Jeffrey W. Froude, Kathleen A. Cashman, John M. Dye, Sina Bavari, Gustavo Palacios, Jens H. Kuhn, Mei G. Sun

    Ebola virus (EBOV) persistence in asymptomatic humans and Ebola virus disease (EVD) sequelae have emerged as significant public health concerns since the 2013–2016 EVD outbreak in Western Africa. Until now, studying how EBOV disseminates into and persists in immune-privileged sites was impossible due to the absence of a suitable animal model. Here, we detect persistent EBOV replication coinciding with systematic inflammatory responses in otherwise asymptomatic rhesus monkeys that had survived infection in the absence of or after treatment with candidate medical countermeasures. We document progressive EBOV dissemination into the eyes, brain and testes through vascular structures, similar to observations in humans. We identify CD68+ cells (macrophages/monocytes) as the cryptic EBOV reservoir cells in the vitreous humour and its immediately adjacent tissue, in the tubular lumina of the epididymides, and in foci of histiocytic inflammation in the brain, but not in organs typically affected during acute infection. In conclusion, our data suggest that persistent EBOV infection in rhesus monkeys could serve as a model for persistent EBOV infection in humans, and we demonstrate that promising candidate medical countermeasures may not completely clear EBOV infection. A rhesus monkey model may lay the foundation to study EVD sequelae and to develop therapies to abolish EBOV persistence.

    更新日期:2017-07-19
  • Bacteriophage evolution differs by host, lifestyle and genome
    Nat. Microbiol. Pub Date : 2017-07-10
    Travis N. Mavrich, Graham F. Hatfull

    Bacteriophages play key roles in microbial evolution1,2, marine nutrient cycling3 and human disease4. Phages are genetically diverse, and their genome architectures are characteristically mosaic, driven by horizontal gene transfer with other phages and host genomes5. As a consequence, phage evolution is complex and their genomes are composed of genes with distinct and varied evolutionary histories6,7. However, there are conflicting perspectives on the roles of mosaicism and the extent to which it generates a spectrum of genome diversity8 or genetically discrete populations9,10. Here, we show that bacteriophages evolve within two general evolutionary modes that differ in the extent of horizontal gene transfer by an order of magnitude. Temperate phages distribute into high and low gene flux modes, whereas lytic phages share only the lower gene flux mode. The evolutionary modes are also a function of the bacterial host and different proportions of temperate and lytic phages are distributed in either mode depending on the host phylum. Groups of genetically related phages fall into either the high or low gene flux modes, suggesting there are genetic as well as ecological drivers of horizontal gene transfer rates. Consequently, genome mosaicism varies depending on the host, lifestyle and genetic constitution of phages.

    更新日期:2017-07-11
  • Structural basis for human respiratory syncytial virus NS1-mediated modulation of host responses
    Nat. Microbiol. Pub Date : 2017-06-30
    Srirupa Chatterjee, Priya Luthra, Ekaterina Esaulova, Eugene Agapov, Benjamin C. Yen, Dominika M. Borek, Megan R. Edwards, Anuradha Mittal, David S. Jordan, Parameshwar Ramanan, Martin L. Moore, Rohit V. Pappu, Michael J. Holtzman, Maxim N. Artyomov, Christopher F. Basler, Gaya K. Amarasinghe, Daisy W. Leung

    Human respiratory syncytial virus (hRSV) is a major cause of morbidity and mortality in the paediatric, elderly and immune-compromised populations1,2. A gap in our understanding of hRSV disease pathology is the interplay between virally encoded immune antagonists and host components that limit hRSV replication. hRSV encodes for non-structural (NS) proteins that are important immune antagonists3,​ 4,​ 5,​ 6 ; however, the role of these proteins in viral pathogenesis is incompletely understood. Here, we report the crystal structure of hRSV NS1 protein, which suggests that NS1 is a structural paralogue of hRSV matrix (M) protein. Comparative analysis of the shared structural fold with M revealed regions unique to NS1. Studies on NS1 wild type or mutant alone or in recombinant RSVs demonstrate that structural regions unique to NS1 contribute to modulation of host responses, including inhibition of type I interferon responses, suppression of dendritic cell maturation and promotion of inflammatory responses. Transcriptional profiles of A549 cells infected with recombinant RSVs show significant differences in multiple host pathways, suggesting that NS1 may have a greater role in regulating host responses than previously appreciated. These results provide a framework to target NS1 for therapeutic development to limit hRSV-associated morbidity and mortality.

    更新日期:2017-07-01
  • ETX2514 is a broad-spectrum β-lactamase inhibitor for the treatment of drug-resistant Gram-negative bacteria including Acinetobacter baumannii
    Nat. Microbiol. Pub Date : 2017-06-30
    Thomas F. Durand-Réville, Satenig Guler, Janelle Comita-Prevoir, Brendan Chen, Neil Bifulco, Hoan Huynh, Sushmita Lahiri, Adam B. Shapiro, Sarah M. McLeod, Nicole M. Carter, Samir H. Moussa, Camilo Velez-Vega, Nelson B. Olivier, Robert McLaughlin, Ning Gao, Jason Thresher, Tiffany Palmer, Beth Andrews, Robert A. Giacobbe, Joseph V. Newman, David E. Ehmann, Boudewijn de Jonge, John O'Donnell, John P. Mueller, Rubén A. Tommasi, Alita A. Miller

    Multidrug-resistant (MDR) bacterial infections are a serious threat to public health. Among the most alarming resistance trends is the rapid rise in the number and diversity of β-lactamases, enzymes that inactivate β-lactams, a class of antibiotics that has been a therapeutic mainstay for decades. Although several new β-lactamase inhibitors have been approved or are in clinical trials, their spectra of activity do not address MDR pathogens such as Acinetobacter baumannii. This report describes the rational design and characterization of expanded-spectrum serine β-lactamase inhibitors that potently inhibit clinically relevant class A, C and D β-lactamases and penicillin-binding proteins, resulting in intrinsic antibacterial activity against Enterobacteriaceae and restoration of β-lactam activity in a broad range of MDR Gram-negative pathogens. One of the most promising combinations is sulbactam–ETX2514, whose potent antibacterial activity, in vivo efficacy against MDR A. baumannii infections and promising preclinical safety demonstrate its potential to address this significant unmet medical need.

    更新日期:2017-07-01
  • Metabolism: Built on stable catalysts
    Nat. Microbiol. Pub Date : 2017-06-27
    Jens Nielsen

    Metabolism: Built on stable catalysts Nature Microbiology, Published online: 27 June 2017; doi:10.1038/nmicrobiol.2017.85 Coenzymes serve as the catalytic core in many metabolic reactions, but despite their extensive use and intrinsic chemical reactivity, they are remarkably stable.

    更新日期:2017-06-28
  • Fungal pathogenesis: Combatting the oxidative burst
    Nat. Microbiol. Pub Date : 2017-06-27
    Antonio Di Pietro, Nicholas J. Talbot

    Fungal pathogenesis: Combatting the oxidative burst Nature Microbiology, Published online: 27 June 2017; doi:10.1038/nmicrobiol.2017.95 Plants respond to microbial attack with a lethal burst of reactive oxygen species. How then, do pathogens successfully invade plants? Unexpectedly, a link between primary metabolism and suppression of plant immunity allows the rice blast fungus Magnaporthe oryzae to grow in such a hostile environment.

    更新日期:2017-06-28
  • Advocating for vaccination in a climate of science denial
    Nat. Microbiol. Pub Date : 2017-06-27
    Cornelia Betsch

    Advocating for vaccination in a climate of science denial Nature Microbiology, Published online: 27 June 2017; doi:10.1038/nmicrobiol.2017.106 In many countries, the success of misinformation, alternative facts or fake news is promoting a climate of science denial, where false claims such as vaccination causing autism can spread. Learning lessons from behavioural studies can help advocate for vaccination in the face of vaccine refusers and deniers.

    更新日期:2017-06-28
  • Host response: Inflammation promotes TB growth
    Nat. Microbiol. Pub Date : 2017-06-27
    Christina L. Stallings

    Host response: Inflammation promotes TB growth Nature Microbiology, Published online: 27 June 2017; doi:10.1038/nmicrobiol.2017.102 Nitric oxide synthase has long been associated with control of Mycobacterium tuberculosis infection. However, new work reveals that instead of directing an antibacterial killing response, nitric oxide is critical for restraining granulocytic inflammation, which can provide a nutrient-rich niche for increased bacterial growth.

    更新日期:2017-06-28
  • Vector control gets new impetus and direction
    Nat. Microbiol. Pub Date : 2017-06-27

    Vector control gets new impetus and direction Nature Microbiology, Published online: 27 June 2017; doi:10.1038/nmicrobiol.2017.111 The WHO's plans to bolster global vector control measures blend audacious goals with a sensible approach that could save lives and stimulate economic growth and development in many of the world's poorest nations.

    更新日期:2017-06-28
  • Nutrient recycling facilitates long-term stability of marine microbial phototroph–heterotroph interactions
    Nat. Microbiol. Pub Date : 2017-06-26
    Joseph A. Christie-Oleza, Despoina Sousoni, Matthew Lloyd, Jean Armengaud, David J. Scanlan

    Biological interactions underpin the functioning of marine ecosystems, be it via competition, predation, mutualism or symbiosis processes. Microbial phototroph–heterotroph interactions propel the engine that results in the biogeochemical cycling of individual elements, and they are critical for understanding and modelling global ocean processes. Unfortunately, studies thus far have focused on exponentially growing cultures in nutrient-rich media, meaning knowledge of such interactions under in situ conditions is rudimentary at best. Here, we have performed long-term phototroph–heterotroph co-culture experiments under nutrient-amended and natural seawater conditions, and show that it is not the concentration of nutrients but rather their circulation that maintains a stable interaction and a dynamic system. Using the Synechococcus–Roseobacter interaction as a model phototroph–heterotroph case study, we show that although Synechococcus is highly specialized for carrying out photosynthesis and carbon fixation, it relies on the heterotroph to remineralize the inevitably leaked organic matter, making nutrients circulate in a mutualistic system. In this sense we challenge the general belief that marine phototrophs and heterotrophs compete for the same scarce nutrients and niche space, and instead suggest that these organisms more probably benefit from each other because of their different levels of specialization and complementarity within long-term stable-state systems.

    更新日期:2017-06-27
  • Type VI secretion TssK baseplate protein exhibits structural similarity with phage receptor-binding proteins and evolved to bind the membrane complex
    Nat. Microbiol. Pub Date : 2017-06-26
    Van Son Nguyen, Laureen Logger, Silvia Spinelli, Pierre Legrand, Thi Thanh Huyen Pham, Thi Trang Nhung Trinh, Yassine Cherrak, Abdelrahim Zoued, Aline Desmyter, Eric Durand, Alain Roussel, Christine Kellenberger, Eric Cascales, Christian Cambillau

    The type VI secretion system (T6SS) is a multiprotein machine widespread in Gram-negative bacteria that delivers toxins into both eukaryotic and prokaryotic cells. The mechanism of action of the T6SS is comparable to that of contractile myophages. The T6SS builds a tail-like structure made of an inner tube wrapped by a sheath, assembled under an extended conformation. Contraction of the sheath propels the inner tube towards the target cell. The T6SS tail is assembled on a platform—the baseplate—which is functionally similar to bacteriophage baseplates. In addition, the baseplate docks the tail to a trans-envelope membrane complex that orients the tail towards the target. Here, we report the crystal structure of TssK, a central component of the T6SS baseplate. We show that TssK is composed of three domains, and establish the contribution of each domain to the interaction with TssK partners. Importantly, this study reveals that the N-terminal domain of TssK is structurally homologous to the shoulder domain of phage receptor-binding proteins, and the C-terminal domain binds the membrane complex. We propose that TssK has conserved the domain of attachment to the virion particle but has evolved the reception domain to use the T6SS membrane complex as receptor.

    更新日期:2017-06-27
  • Illuminating vital surface molecules of symbionts in health and disease
    Nat. Microbiol. Pub Date : 2017-06-26
    Jason E. Hudak, David Alvarez, Ashwin Skelly, Ulrich H. von Andrian, Dennis L. Kasper

    The immunomodulatory surface molecules of commensal and pathogenic bacteria are critical to microorganisms' survival and the host's response1,2. Recent studies have highlighted the unique and important responses elicited by commensal-derived surface macromolecules3,​ 4,​ 5 . However, the technology available to track these molecules in host cells and tissues remains primitive. We report, here, an interdisciplinary approach that uses metabolic labelling combined with bioorthogonal click chemistry (that is, reactions performed in living organisms)6 to specifically tag up to three prominent surface immunomodulatory macromolecules—peptidoglycan, lipopolysaccharide and capsular polysaccharide—either simultaneously or individually in live anaerobic commensal bacteria. Importantly, the peptidoglycan labelling enables, for the first time, the specific labelling of live endogenous, anaerobic bacteria within the mammalian host. This approach has allowed us to image and track the path of labelled surface molecules from live, luminal bacteria into specific intestinal immune cells in the living murine host during health and disease. The chemical labelling of three specific macromolecules within a live organism offers the potential for in-depth visualization of host–pathogen interactions.

    更新日期:2017-06-27
  • Division site selection linked to inherited cell surface wave troughs in mycobacteria
    Nat. Microbiol. Pub Date : 2017-06-26
    Haig A. Eskandarian, Pascal D. Odermatt, Joëlle X. Y. Ven, Mélanie T. M. Hannebelle, Adrian P. Nievergelt, Neeraj Dhar, John D. McKinney, Georg E. Fantner

    Cell division is tightly controlled in space and time to maintain cell size and ploidy within narrow bounds. In bacteria, the canonical Minicell (Min) and nucleoid occlusion (Noc) systems together ensure that division is restricted to midcell after completion of chromosome segregation1. It is unknown how division site selection is controlled in bacteria that lack homologues of the Min and Noc proteins, including mycobacteria responsible for tuberculosis and other chronic infections2. Here, we use correlated optical and atomic-force microscopy3,4 to demonstrate that morphological landmarks (waveform troughs) on the undulating surface of mycobacterial cells correspond to future sites of cell division. Newborn cells inherit wave troughs from the (grand)mother cell and ultimately divide at the centre-most wave trough, making these morphological features the earliest known landmark of future division sites. In cells lacking the chromosome partitioning (Par) system, missegregation of chromosomes is accompanied by asymmetric cell division at off-centre wave troughs, resulting in the formation of anucleate cells. These results demonstrate that inherited morphological landmarks and chromosome positioning together restrict mycobacterial division to the midcell position.

    更新日期:2017-06-27
  • HBV RNA pre-genome encodes specific motifs that mediate interactions with the viral core protein that promote nucleocapsid assembly
    Nat. Microbiol. Pub Date : 2017-06-19
    Nikesh Patel, Simon J. White, Rebecca F. Thompson, Richard Bingham, Eva U. Weiß, Daniel P. Maskell, Adam Zlotnick, Eric C. Dykeman, Roman Tuma, Reidun Twarock, Neil A. Ranson, Peter G. Stockley

    Formation of the hepatitis B virus nucleocapsid is an essential step in the viral lifecycle, but its assembly is not fully understood. We report the discovery of sequence-specific interactions between the viral pre-genome and the hepatitis B core protein that play roles in defining the nucleocapsid assembly pathway. Using RNA SELEX and bioinformatics, we identified multiple regions in the pre-genomic RNA with high affinity for core protein dimers. These RNAs form stem-loops with a conserved loop motif that trigger sequence-specific assembly of virus-like particles (VLPs) at much higher fidelity and yield than in the absence of RNA. The RNA oligos do not interact with preformed RNA-free VLPs, so their effects must occur during particle assembly. Asymmetric cryo-electron microscopy reconstruction of the T = 4 VLPs assembled in the presence of one of the RNAs reveals a unique internal feature connected to the main core protein shell via lobes of density. Biophysical assays suggest that this is a complex involving several RNA oligos interacting with the C-terminal arginine-rich domains of core protein. These core protein–RNA contacts may play one or more roles in regulating the organization of the pre-genome during nucleocapsid assembly, facilitating subsequent reverse transcription and acting as a nucleation complex for nucleocapsid assembly.

    更新日期:2017-06-20
  • Short-chain alkanes fuel mussel and sponge Cycloclasticus symbionts from deep-sea gas and oil seeps
    Nat. Microbiol. Pub Date : 2017-06-19
    Maxim Rubin-Blum, Chakkiath Paul Antony, Christian Borowski, Lizbeth Sayavedra, Thomas Pape, Heiko Sahling, Gerhard Bohrmann, Manuel Kleiner, Molly C. Redmond, David L. Valentine, Nicole Dubilier

    Cycloclasticus bacteria are ubiquitous in oil-rich regions of the ocean and are known for their ability to degrade polycyclic aromatic hydrocarbons (PAHs). In this study, we describe Cycloclasticus that have established a symbiosis with Bathymodiolus heckerae mussels and poecilosclerid sponges from asphalt-rich, deep-sea oil seeps at Campeche Knolls in the southern Gulf of Mexico. Genomic and transcriptomic analyses revealed that, in contrast to all previously known Cycloclasticus, the symbiotic Cycloclasticus appears to lack the genes needed for PAH degradation. Instead, these symbionts use propane and other short-chain alkanes such as ethane and butane as carbon and energy sources, thus expanding the limited range of substrates known to power chemosynthetic symbioses. Analyses of short-chain alkanes in the environment of the Campeche Knolls symbioses revealed that these are present at high concentrations (in the μM to mM range). Comparative genomic analyses revealed high similarities between the genes used by the symbiotic Cycloclasticus to degrade short-chain alkanes and those of free-living Cycloclasticus that bloomed during the Deepwater Horizon oil spill. Our results indicate that the metabolic versatility of bacteria within the Cycloclasticus clade is higher than previously assumed, and highlight the expanded role of these keystone species in the degradation of marine hydrocarbons.

    更新日期:2017-06-20
  • Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection
    Nat. Microbiol. Pub Date : 2017-06-19
    Manlio Di Cristina, Zhicheng Dou, Matteo Lunghi, Geetha Kannan, My-Hang Huynh, Olivia L. McGovern, Tracey L. Schultz, Aric J. Schultz, Alyssa J. Miller, Beth M. Hayes, Wouter van der Linden, Carla Emiliani, Matthew Bogyo, Sébastien Besteiro, Isabelle Coppens, Vern B. Carruthers

    Globally, nearly 2 billion people are infected with the intracellular protozoan Toxoplasma gondii1. This persistent infection can cause severe disease in immunocompromised people and is epidemiologically linked to major mental illnesses2 and cognitive impairment3. There are currently no options for curing this infection. The lack of effective therapeutics is due partly to a poor understanding of the essential pathways that maintain long-term infection. Although it is known that Toxoplasma replicates slowly within intracellular cysts demarcated with a cyst wall, precisely how it sustains itself and remodels organelles in this niche is unknown. Here, we identify a key role for proteolysis within the parasite lysosomal organelle (the vacuolar compartment or VAC) in turnover of autophagosomes and persistence during neural infection. We found that disrupting a VAC-localized cysteine protease compromised VAC digestive function and markedly reduced chronic infection. Death of parasites lacking the VAC protease was preceded by accumulation of undigested autophagosomes in the parasite cytoplasm. These findings suggest an unanticipated function for parasite lysosomal degradation in chronic infection, and identify an intrinsic role for autophagy in the T. gondii parasite and its close relatives. This work also identifies a key element of Toxoplasma persistence and suggests that VAC proteolysis is a prospective target for pharmacological development.

    更新日期:2017-06-20
  • A parts list for fungal cellulosomes revealed by comparative genomics
    Nat. Microbiol. Pub Date : 2017-05-30
    Charles H. Haitjema, Sean P. Gilmore, John K. Henske, Kevin V. Solomon, Randall de Groot, Alan Kuo, Stephen J. Mondo, Asaf A. Salamov, Kurt LaButti, Zhiying Zhao, Jennifer Chiniquy, Kerrie Barry, Heather M. Brewer, Samuel O. Purvine, Aaron T. Wright, Matthieu Hainaut, Brigitte Boxma, Theo van Alen, Johannes H. P. Hackstein, Bernard Henrissat, Scott E. Baker, Igor V. Grigoriev, Michelle A. O'Malley

    Cellulosomes are large, multiprotein complexes that tether plant biomass-degrading enzymes together for improved hydrolysis1. These complexes were first described in anaerobic bacteria, where species-specific dockerin domains mediate the assembly of enzymes onto cohesin motifs interspersed within protein scaffolds1. The versatile protein assembly mechanism conferred by the bacterial cohesin–dockerin interaction is now a standard design principle for synthetic biology2,3. For decades, analogous structures have been reported in anaerobic fungi, which are known to assemble by sequence-divergent non-catalytic dockerin domains (NCDDs)4. However, the components, modular assembly mechanism and functional role of fungal cellulosomes remain unknown5,6. Here, we describe a comprehensive set of proteins critical to fungal cellulosome assembly, including conserved scaffolding proteins unique to the Neocallimastigomycota. High-quality genomes of the anaerobic fungi Anaeromyces robustus, Neocallimastix californiae and Piromyces finnis were assembled with long-read, single-molecule technology. Genomic analysis coupled with proteomic validation revealed an average of 312 NCDD-containing proteins per fungal strain, which were overwhelmingly carbohydrate active enzymes (CAZymes), with 95 large fungal scaffoldins identified across four genera that bind to NCDDs. Fungal dockerin and scaffoldin domains have no similarity to their bacterial counterparts, yet several catalytic domains originated via horizontal gene transfer with gut bacteria. However, the biocatalytic activity of anaerobic fungal cellulosomes is expanded by the inclusion of GH3, GH6 and GH45 enzymes. These findings suggest that the fungal cellulosome is an evolutionarily chimaeric structure—an independently evolved fungal complex that co-opted useful activities from bacterial neighbours within the gut microbiome.

    更新日期:2017-06-17
  • Zooming in on the phycosphere: the ecological interface for phytoplankton–bacteria relationships
    Nat. Microbiol. Pub Date : 2017-05-30
    Justin R. Seymour, Shady A. Amin, Jean-Baptiste Raina, Roman Stocker

    By controlling nutrient cycling and biomass production at the base of the food web, interactions between phytoplankton and bacteria represent a fundamental ecological relationship in aquatic environments. Although typically studied over large spatiotemporal scales, emerging evidence indicates that this relationship is often governed by microscale interactions played out within the region immediately surrounding individual phytoplankton cells. This microenvironment, known as the phycosphere, is the planktonic analogue of the rhizosphere in plants. The exchange of metabolites and infochemicals at this interface governs phytoplankton–bacteria relationships, which span mutualism, commensalism, antagonism, parasitism and competition. The importance of the phycosphere has been postulated for four decades, yet only recently have new technological and conceptual frameworks made it possible to start teasing apart the complex nature of this unique microbial habitat. It has subsequently become apparent that the chemical exchanges and ecological interactions between phytoplankton and bacteria are far more sophisticated than previously thought and often require close proximity of the two partners, which is facilitated by bacterial colonization of the phycosphere. It is also becoming increasingly clear that while interactions taking place within the phycosphere occur at the scale of individual microorganisms, they exert an ecosystem-scale influence on fundamental processes including nutrient provision and regeneration, primary production, toxin biosynthesis and biogeochemical cycling. Here we review the fundamental physical, chemical and ecological features of the phycosphere, with the goal of delivering a fresh perspective on the nature and importance of phytoplankton–bacteria interactions in aquatic ecosystems.

    更新日期:2017-06-17
  • A decade of discovery: CRISPR functions and applications
    Nat. Microbiol. Pub Date : 2017-06-05
    Rodolphe Barrangou, Philippe Horvath

    This year marks the tenth anniversary of the identification of the biological function of CRISPR–Cas as adaptive immune systems in bacteria. In just a decade, the characterization of CRISPR–Cas systems has established a novel means of adaptive immunity in bacteria and archaea and deepened our understanding of the interplay between prokaryotes and their environment, and CRISPR-based molecular machines have been repurposed to enable a genome editing revolution. Here, we look back on the historical milestones that have paved the way for the discovery of CRISPR and its function, and discuss the related technological applications that have emerged, with a focus on microbiology. Lastly, we provide a perspective on the impacts the field has had on science and beyond.

    更新日期:2017-06-17
  • Epigenetic silencing of IRF1 dysregulates type III interferon responses to respiratory virus infection in epithelial to mesenchymal transition
    Nat. Microbiol. Pub Date : 2017-06-05
    Jun Yang, Bing Tian, Hong Sun, Roberto P. Garofalo, Allan R. Brasier

    Chronic oxidative injury produced by airway disease triggers a transforming growth factor-β (TGF-β)-mediated epigenetic reprogramming known as the epithelial–mesenchymal transition (EMT). We observe that EMT silences protective mucosal interferon (IFN)-I and III production associated with enhanced rhinovirus (RV) and respiratory syncytial virus (RSV) replication. Mesenchymal transitioned cells are defective in inducible interferon regulatory factor 1 (IRF1) expression by occluding RelA and IRF3 access to the promoter. IRF1 is necessary for the expression of type III IFNs (IFNLs 1 and 2/3). Induced by the EMT, zinc finger E-box binding homeobox 1 (ZEB1) binds and silences IRF1. Ectopic ZEB1 is sufficient for IRF1 silencing, whereas ZEB1 knockdown partially restores IRF1-IFNL upregulation. ZEB1 silences IRF1 through the catalytic activity of the enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), forming repressive H3K27(me3) marks. We observe that IRF1 expression is mediated by ZEB1 de-repression, and our study demonstrates how airway remodelling/fibrosis is associated with a defective mucosal antiviral response through ZEB1-initiated epigenetic silencing.

    更新日期:2017-06-17
  • Attenuation of RNA viruses by redirecting their evolution in sequence space
    Nat. Microbiol. Pub Date : 2017-06-05
    Gonzalo Moratorio, Rasmus Henningsson, Cyril Barbezange, Lucia Carrau, Antonio V. Bordería, Hervé Blanc, Stephanie Beaucourt, Enzo Z. Poirier, Thomas Vallet, Jeremy Boussier, Bryan C. Mounce, Magnus Fontes, Marco Vignuzzi

    RNA viruses pose serious threats to human health. Their success relies on their capacity to generate genetic variability and, consequently, on their adaptive potential. We describe a strategy to attenuate RNA viruses by altering their evolutionary potential. We rationally altered the genomes of Coxsackie B3 and influenza A viruses to redirect their evolutionary trajectories towards detrimental regions in sequence space. Specifically, viral genomes were engineered to harbour more serine and leucine codons with nonsense mutation targets: codons that could generate Stop mutations after a single nucleotide substitution. Indeed, these viruses generated more Stop mutations both in vitro and in vivo, accompanied by significant losses in viral fitness. In vivo, the viruses were attenuated, generated high levels of neutralizing antibodies and protected against lethal challenge. Our study demonstrates that cornering viruses in ‘risky’ areas of sequence space may be implemented as a broad-spectrum vaccine strategy against RNA viruses.

    更新日期:2017-06-17
  • A stabilized microbial ecosystem of self-limiting bacteria using synthetic quorum-regulated lysis
    Nat. Microbiol. Pub Date : 2017-06-12
    Spencer R. Scott, M. Omar Din, Philip Bittihn, Liyang Xiong, Lev S. Tsimring, Jeff Hasty

    Microbial ecologists are increasingly turning to small, synthesized ecosystems1,​ 2,​ 3,​ 4,​ 5 as a reductionist tool to probe the complexity of native microbiomes6,7. Concurrently, synthetic biologists have gone from single-cell gene circuits8,​ 9,​ 10,​ 11 to controlling whole populations using intercellular signalling12,​ 13,​ 14,​ 15,​ 16 . The intersection of these fields is giving rise to new approaches in waste recycling17, industrial fermentation18, bioremediation19 and human health16,20. These applications share a common challenge7 well-known in classical ecology21,22—stability of an ecosystem cannot arise without mechanisms that prohibit the faster-growing species from eliminating the slower. Here, we combine orthogonal quorum-sensing systems and a population control circuit with diverse self-limiting growth dynamics to engineer two ‘ortholysis’ circuits capable of maintaining a stable co-culture of metabolically competitive Salmonella typhimurium strains in microfluidic devices. Although no successful co-cultures are observed in a two-strain ecology without synthetic population control, the ‘ortholysis’ design dramatically increases the co-culture rate from 0% to approximately 80%. Agent-based and deterministic modelling reveal that our system can be adjusted to yield different dynamics, including phase-shifted, antiphase or synchronized oscillations, as well as stable steady-state population densities. The ‘ortholysis’ approach establishes a paradigm for constructing synthetic ecologies by developing stable communities of competitive microorganisms without the need for engineered co-dependency.

    更新日期:2017-06-17
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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