Towards predicting the environmental metabolome from metagenomics with a mechanistic model Nat. Microbiol. Pub Date : 2018-03-12 Daniel R. Garza, Marcel C. Verk, Martijn A. Huynen, Bas E. Dutilh
The environmental metabolome and metabolic potential of microorganisms are dominant and essential factors shaping microbial community composition. Recent advances in genome annotation and systems biology now allow us to semiautomatically reconstruct genome-scale metabolic models (GSMMs) of microorganisms based on their genome sequence1. Next, growth of these models in a defined metabolic environment can be predicted in silico, mechanistically linking the metabolic fluxes of individual microbial populations to the community dynamics. A major advantage of GSMMs is that no training data is needed, besides information about the metabolic capacity of individual genes (genome annotation) and knowledge of the available environmental metabolites that allow the microorganism to grow. However, the composition of the environment is often not fully determined and remains difficult to measure2. We hypothesized that the relative abundance of different bacterial species, as measured by metagenomics, can be combined with GSMMs of individual bacteria to reveal the metabolic status of a given biome. Using a newly developed algorithm involving over 1,500 GSMMs of human-associated bacteria, we inferred distinct metabolomes for four human body sites that are consistent with experimental data. Together, we link the metagenome to the metabolome in a mechanistic framework towards predictive microbiome modelling.
Coccolithovirus facilitation of carbon export in the North Atlantic Nat. Microbiol. Pub Date : 2018-03-12 Christien P. Laber, Jonathan E. Hunter, Filipa Carvalho, James R. Collins, Elias J. Hunter, Brittany M. Schieler, Emmanuel Boss, Kuldeep More, Miguel Frada, Kimberlee Thamatrakoln, Christopher M. Brown, Liti Haramaty, Justin Ossolinski, Helen Fredricks, Jozef I. Nissimov, Rebecca Vandzura, Uri Sheyn, Yoav Lehahn, Robert J. Chant, Ana M. Martins, Marco J. L. Coolen, Assaf Vardi, Giacomo R. DiTullio, Benjamin A. S. Van Mooy, Kay D. Bidle
Marine phytoplankton account for approximately half of global primary productivity1, making their fate an important driver of the marine carbon cycle. Viruses are thought to recycle more than one-quarter of oceanic photosynthetically fixed organic carbon2, which can stimulate nutrient regeneration, primary production and upper ocean respiration2 via lytic infection and the ‘virus shunt’. Ultimately, this limits the trophic transfer of carbon and energy to both higher food webs and the deep ocean2. Using imagery taken by the Moderate Resolution Imaging Spectroradiometer (MODIS) onboard the Aqua satellite, along with a suite of diagnostic lipid- and gene-based molecular biomarkers, in situ optical sensors and sediment traps, we show that Coccolithovirus infections of mesoscale (~100 km) Emiliania huxleyi blooms in the North Atlantic are coupled with particle aggregation, high zooplankton grazing and greater downward vertical fluxes of both particulate organic and particulate inorganic carbon from the upper mixed layer. Our analyses captured blooms in different phases of infection (early, late and post) and revealed the highest export flux in ‘early-infected blooms’ with sinking particles being disproportionately enriched with infected cells and subsequently remineralized at depth in the mesopelagic. Our findings reveal viral infection as a previously unrecognized ecosystem process enhancing biological pump efficiency.
The TRiC chaperonin controls reovirus replication through outer-capsid folding Nat. Microbiol. Pub Date : 2018-03-12 Jonathan J. Knowlton, Isabel Fernández de Castro, Alison W. Ashbrook, Daniel R. Gestaut, Paula F. Zamora, Joshua A. Bauer, J. Craig Forrest, Judith Frydman, Cristina Risco, Terence S. Dermody
Viruses are molecular machines sustained through a life cycle that requires replication within host cells. Throughout the infectious cycle, viral and cellular components interact to advance the multistep process required to produce progeny virions. Despite progress made in understanding the virus–host protein interactome, much remains to be discovered about the cellular factors that function during infection, especially those operating at terminal steps in replication. In an RNA interference screen, we identified the eukaryotic chaperonin T-complex protein-1 (TCP-1) ring complex (TRiC; also called CCT for chaperonin containing TCP-1) as a cellular factor required for late events in the replication of mammalian reovirus. We discovered that TRiC functions in reovirus replication through a mechanism that involves folding the viral σ3 major outer-capsid protein into a form capable of assembling onto virus particles. TRiC also complexes with homologous capsid proteins of closely related viruses. Our data define a critical function for TRiC in the viral assembly process and raise the possibility that this mechanism is conserved in related non-enveloped viruses. These results also provide insight into TRiC protein substrates and establish a rationale for the development of small-molecule inhibitors of TRiC as potential antiviral therapeutics.
Publisher Correction: A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells Nat. Microbiol. Pub Date : 2018-03-06 James A. Thomas, Michele S. Y. Tan, Claudine Bisson, Aaron Borg, Trishant R. Umrekar, Fiona Hackett, Victoria L. Hale, Gema Vizcay-Barrena, Roland A. Fleck, Ambrosius P. Snijders, Helen R. Saibil, Michael J. Blackman
Publisher Correction: A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cellsPublisher Correction: A protease cascade regulates release of the human malaria parasite <i>Plasmodium falciparum</i> from host red blood cells, Published online: 06 March 2018; doi:10.1038/s41564-018-0134-6Publisher Correction: A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells
Anti-CRISPR proteins encoded by archaeal lytic viruses inhibit subtype I-D immunity Nat. Microbiol. Pub Date : 2018-03-05 Fei He, Yuvaraj Bhoobalan-Chitty, Lan B. Van, Anders L. Kjeldsen, Matteo Dedola, Kira S. Makarova, Eugene V. Koonin, Ditlev E. Brodersen, Xu Peng
Viruses employ a range of strategies to counteract the prokaryotic adaptive immune system, clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR–Cas), including mutational escape and physical blocking of enzymatic function using anti-CRISPR proteins (Acrs). Acrs have been found in many bacteriophages but so far not in archaeal viruses, despite the near ubiquity of CRISPR–Cas systems in archaea. Here, we report the functional and structural characterization of two archaeal Acrs from the lytic rudiviruses, SIRV2 and SIRV3. We show that a 4 kb deletion in the SIRV2 genome dramatically reduces infectivity in Sulfolobus islandicus LAL14/1 that carries functional CRISPR–Cas subtypes I-A, I-D and III-B. Subsequent insertion of a single gene from SIRV3, gp02 (AcrID1), which is conserved in the deleted fragment, successfully restored infectivity. We demonstrate that AcrID1 protein inhibits the CRISPR–Cas subtype I-D system by interacting directly with Cas10d protein, which is required for the interference stage. Sequence and structural analysis of AcrID1 show that it belongs to a conserved family of compact, dimeric αβ-sandwich proteins characterized by extreme pH and temperature stability and a tendency to form protein fibres. We identify about 50 homologues of AcrID1 in four archaeal viral families demonstrating the broad distribution of this group of anti-CRISPR proteins.
DSYB catalyses the key step of dimethylsulfoniopropionate biosynthesis in many phytoplankton Nat. Microbiol. Pub Date : 2018-02-26 Andrew R. J. Curson, Beth T. Williams, Benjamin J. Pinchbeck, Leanne P. Sims, Ana Bermejo Martínez, Peter Paolo L. Rivera, Deepak Kumaresan, Elena Mercadé, Lewis G. Spurgin, Ornella Carrión, Simon Moxon, Rose Ann Cattolico, Unnikrishnan Kuzhiumparambil, Paul Guagliardo, Peta L. Clode, Jean-Baptiste Raina, Jonathan D. Todd
Dimethylsulfoniopropionate (DMSP) is a globally important organosulfur molecule and the major precursor for dimethyl sulfide. These compounds are important info-chemicals, key nutrients for marine microorganisms, and are involved in global sulfur cycling, atmospheric chemistry and cloud formation1,2,3. DMSP production was thought to be confined to eukaryotes, but heterotrophic bacteria can also produce DMSP through the pathway used by most phytoplankton4, and the DsyB enzyme catalysing the key step of this pathway in bacteria was recently identified5. However, eukaryotic phytoplankton probably produce most of Earth’s DMSP, yet no DMSP biosynthesis genes have been identified in any such organisms. Here we identify functional dsyB homologues, termed DSYB, in many phytoplankton and corals. DSYB is a methylthiohydroxybutryate methyltransferase enzyme localized in the chloroplasts and mitochondria of the haptophyte Prymnesium parvum, and stable isotope tracking experiments support these organelles as sites of DMSP synthesis. DSYB transcription levels increased with DMSP concentrations in different phytoplankton and were indicative of intracellular DMSP. Identification of the eukaryotic DSYB sequences, along with bacterial dsyB, provides the first molecular tools to predict the relative contributions of eukaryotes and prokaryotes to global DMSP production. Furthermore, evolutionary analysis suggests that eukaryotic DSYB originated in bacteria and was passed to eukaryotes early in their evolution.
Disulfide bond formation in prokaryotes Nat. Microbiol. Pub Date : 2018-02-20 Cristina Landeta, Dana Boyd, Jon Beckwith
Interest in protein disulfide bond formation has recently increased because of the prominent role of disulfide bonds in bacterial virulence and survival. The first discovered pathway that introduces disulfide bonds into cell envelope proteins consists of Escherichia coli enzymes DsbA and DsbB. Since its discovery, variations on the DsbAB pathway have been found in bacteria and archaea, probably reflecting specific requirements for survival in their ecological niches. One variation found amongst Actinobacteria and Cyanobacteria is the replacement of DsbB by a homologue of human vitamin K epoxide reductase. Many Gram-positive bacteria express enzymes involved in disulfide bond formation that are similar, but non-homologous, to DsbAB. While bacterial pathways promote disulfide bond formation in the bacterial cell envelope, some archaeal extremophiles express proteins with disulfide bonds both in the cytoplasm and in the extra-cytoplasmic space, possibly to stabilize proteins in the face of extreme conditions, such as growth at high temperatures. Here, we summarize the diversity of disulfide-bond-catalysing systems across prokaryotic lineages, discuss examples for understanding the biological basis of such systems, and present perspectives on how such systems are enabling advances in biomedical engineering and drug development.
Pandemic preparedness and forecast Nat. Microbiol. Pub Date : 2018-02-20 Jeffrey Shaman
Pandemic preparedness and forecast Pandemic preparedness and forecast, Published online: 20 February 2018; doi:10.1038/s41564-018-0117-7 Geographic mapping of pathogen emergence risk, as recently done for viral haemorrhagic fever in Africa, provides an important tool for targeting interventions. More comprehensive preparedness and prediction systems that increase surveillance and forecast infectious disease outbreak growth and spread in real time are also needed.
CRISPRs from scratch Nat. Microbiol. Pub Date : 2018-02-20 Alireza Edraki, Erik J. Sontheimer
CRISPRs from scratch CRISPRs from scratch, Published online: 20 February 2018; doi:10.1038/s41564-018-0115-9 CRISPR immunity begins with the acquisition of sequences from invading nucleic acids through spacer integration into a CRISPR locus. Off-target integration of spacers into other parts of the genome is now implicated as a spontaneous source of new CRISPR loci.
Clinical challenges in antimicrobial resistance Nat. Microbiol. Pub Date : 2018-02-20 Gavin Barlow
Clinical challenges in antimicrobial resistance Clinical challenges in antimicrobial resistance, Published online: 20 February 2018; doi:10.1038/s41564-018-0121-y Antimicrobial resistance is one of the great challenges for twenty-first century healthcare. While new therapeutics are undoubtedly required, there are major challenges in rapidly identifying resistant infections and tailoring therapy accordingly; and in how we deploy antimicrobials with suppression of resistance in mind.
TB diagnosis from the Dark Ages to fluorescence Nat. Microbiol. Pub Date : 2018-02-20 Eric J. Rubin
TB diagnosis from the Dark Ages to fluorescence TB diagnosis from the Dark Ages to fluorescence, Published online: 20 February 2018; doi:10.1038/s41564-018-0118-6 Effective treatment and eradication of tuberculosis requires highly sensitive and specific, easy-to-use detection methods. New advances in molecular tools and technology are driving improved tuberculosis diagnostics, including ways to rapidly identify highly drug-resistant infections.
Another twist on nitrogenases Nat. Microbiol. Pub Date : 2018-02-20 Oliver Einsle
Another twist on nitrogenases Another twist on nitrogenases, Published online: 20 February 2018; doi:10.1038/s41564-018-0116-8 An alternative nitrogenase enzyme that only utilizes iron as its cofactor is shown to reduce carbon dioxide while actively fixing dinitrogen, so that it simultaneously produces ammonium, hydrogen and methane.
Accelerating efforts to end TB Nat. Microbiol. Pub Date : 2018-02-20
Accelerating efforts to end TB Accelerating efforts to end TB, Published online: 20 February 2018; doi:10.1038/s41564-018-0126-6 Fittingly for a bacterium whose slow growth rate has frustrated researchers for decades, progress towards ending the TB epidemic has built only at a snail’s pace. 2018 should see a much needed stimulus, with increased political awareness of the scale of the problems faced, and the adoption of a coordinated global response.
Conditional toxicity and synergy drive diversity among antibacterial effectors Nat. Microbiol. Pub Date : 2018-02-19 Kaitlyn D. LaCourse, S. Brook Peterson, Hemantha D. Kulasekara, Matthew C. Radey, Jungyun Kim, Joseph D. Mougous
Bacteria in polymicrobial habitats contend with a persistent barrage of competitors, often under rapidly changing environmental conditions1. The direct antagonism of competitor cells is thus an important bacterial survival strategy2. Towards this end, many bacterial species employ an arsenal of antimicrobial effectors with multiple activities; however, the benefits conferred by the simultaneous deployment of diverse toxins are unknown. Here we show that the multiple effectors delivered to competitor bacteria by the type VI secretion system (T6SS) of Pseudomonas aeruginosa display conditional efficacy and act synergistically. One of these effectors, Tse4, is most active in high-salinity environments and synergizes with effectors that degrade the cell wall or inactivate intracellular electron carriers. We find Tse4 synergizes with these disparate mechanisms by forming pores that disrupt the ΔΨ component of the proton motive force. Our results provide evidence that the concomitant delivery of a cocktail of effectors serves as a bet-hedging strategy to promote bacterial competitiveness in the face of unpredictable and variable environmental conditions.
Publisher Correction: Enterotypes in the landscape of gut microbial community composition Nat. Microbiol. Pub Date : 2018-02-13 Paul I. Costea, Falk Hildebrand, Manimozhiyan Arumugam, Fredrik Bäckhed, Martin J. Blaser, Frederic D. Bushman, Willem M. de Vos, S. Dusko Ehrlich, Claire M. Fraser, Masahira Hattori, Curtis Huttenhower, Ian B. Jeffery, Dan Knights, James D. Lewis, Ruth E. Ley, Howard Ochman, Paul W. O’Toole, Christopher Quince, David A. Relman, Fergus Shanahan, Shinichi Sunagawa, Jun Wang, George M. Weinstock, Gary D. Wu, Georg Zeller, Liping Zhao, Jeroen Raes, Rob Knight, Peer Bork
Publisher Correction: Enterotypes in the landscape of gut microbial community composition Publisher Correction: Enterotypes in the landscape of gut microbial community composition, Published online: 13 February 2018; doi:10.1038/s41564-018-0114-x Publisher Correction: Enterotypes in the landscape of gut microbial community composition
Publisher Correction: EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans Nat. Microbiol. Pub Date : 2018-02-13 Marc Swidergall, Norma V. Solis, Michail S. Lionakis, Scott G. Filler
Publisher Correction: EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans Publisher Correction: EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans, Published online: 13 February 2018; doi:10.1038/s41564-017-0100-8 Publisher Correction: EphA2 is an epithelial cell pattern recognition receptor for fungal β-glucans
Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens Nat. Microbiol. Pub Date : 2018-02-12 Bradley M. Hover, Seong-Hwan Kim, Micah Katz, Zachary Charlop-Powers, Jeremy G. Owen, Melinda A. Ternei, Jeffrey Maniko, Andreia B. Estrela, Henrik Molina, Steven Park, David S. Perlin, Sean F. Brady
Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide1. In the absence of new therapies, mortality rates due to untreatable infections are predicted to rise more than tenfold by 2050. Natural products (NPs) made by cultured bacteria have been a major source of clinically useful antibiotics. In spite of decades of productivity, the use of bacteria in the search for new antibiotics was largely abandoned due to high rediscovery rates2,3. As only a fraction of bacterial diversity is regularly cultivated in the laboratory and just a fraction of the chemistries encoded by cultured bacteria are detected in fermentation experiments, most bacterial NPs remain hidden in the global microbiome. In an effort to access these hidden NPs, we have developed a culture-independent NP discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples. Here, we describe the application of this platform to the discovery of the malacidins, a distinctive class of antibiotics that are commonly encoded in soil microbiomes but have never been reported in culture-based NP discovery efforts. The malacidins are active against multidrug-resistant pathogens, sterilize methicillin-resistant Staphylococcus aureus skin infections in an animal wound model and did not select for resistance under our laboratory conditions.
Deaminase-mediated multiplex genome editing in Escherichia coli Nat. Microbiol. Pub Date : 2018-02-05 Satomi Banno, Keiji Nishida, Takayuki Arazoe, Hitoshi Mitsunobu, Akihiko Kondo
In eukaryotes, the CRISPR–Cas9 system has now been widely used as a revolutionary genome engineering tool1, 2. However, in prokaryotes, the use of nuclease-mediated genome editing tools has been limited to negative selection for the already modified cells because of its lethality3, 4. Here, we report on deaminase-mediated targeted nucleotide editing (Target-AID)5 adopted in Escherichia coli. Cytidine deaminase PmCDA1 fused to the nuclease-deficient CRISPR–Cas9 system achieved specific point mutagenesis at the target sites in E. coli by introducing cytosine mutations without compromising cell growth. The cytosine-to-thymine substitutions were induced mainly within an approximately five-base window of target sequences on the protospacer adjacent motif-distal side, which can be shifted depending on the length of the single guide RNA sequence. Use of a uracil DNA glycosylase inhibitor6 in combination with a degradation tag (LVA tag)7 resulted in a robustly high mutation efficiency, which allowed simultaneous multiplex editing of six different genes. The major multi-copy transposase genes that consist of at least 41 loci were also simultaneously edited by using four target sequences. As this system does not rely on any additional or host-dependent factors, it may be readily applicable to a wide range of bacteria.
Pore-forming activity of the Pseudomonas aeruginosa type III secretion system translocon alters the host epigenome Nat. Microbiol. Pub Date : 2018-02-05 Laurent Dortet, Charlotte Lombardi, François Cretin, Andréa Dessen, Alain Filloux
Recent studies highlight that bacterial pathogens can reprogram target cells by influencing epigenetic factors. The type III secretion system (T3SS) is a bacterial nanomachine that resembles a syringe on the bacterial surface. The T3SS ‘needle’ delivers translocon proteins into eukaryotic cell membranes, subsequently allowing injection of bacterial effectors into the cytosol. Here we show that Pseudomonas aeruginosa induces early T3SS-dependent dephosphorylation and deacetylation of histone H3 in eukaryotic cells. This is not triggered by any of the P. aeruginosa T3SS effectors, but results from the insertion of the PopB–PopD translocon into the membrane. This suggests that the P. aeruginosa translocon is a genuine T3SS effector acting as a pore-forming toxin. We visualized the translocon plugged into the host cell membrane after the bacterium has left the site of contact, and demonstrate that subsequent ion exchange through this pore is responsible for histone H3 modifications and host cell subversion.
The host-encoded RNase E endonuclease as the crRNA maturation enzyme in a CRISPR–Cas subtype III-Bv system Nat. Microbiol. Pub Date : 2018-02-05 Juliane Behler, Kundan Sharma, Viktoria Reimann, Annegret Wilde, Henning Urlaub, Wolfgang R. Hess
Specialized RNA endonucleases for the maturation of clustered regularly interspaced short palindromic repeat (CRISPR)-derived RNAs (crRNAs) are critical in CRISPR–CRISPR-associated protein (Cas) defence mechanisms. The Cas6 and Cas5d enzymes are the RNA endonucleases in many class 1 CRISPR–Cas systems. In some class 2 systems, maturation and effector functions are combined within a single enzyme or maturation proceeds through the combined actions of RNase III and trans-activating CRISPR RNAs (tracrRNAs). Three separate CRISPR–Cas systems exist in the cyanobacterium Synechocystis sp. PCC 6803. Whereas Cas6-type enzymes act in two of these systems, the third, which is classified as subtype III-B variant (III-Bv), lacks cas6 homologues. Instead, the maturation of crRNAs proceeds through the activity of endoribonuclease E, leaving unusual 13- and 14-nucleotide-long 5′-handles. Overexpression of RNase E leads to overaccumulation and knock-down to the reduced accumulation of crRNAs in vivo, suggesting that RNase E is the limiting factor for CRISPR complex formation. Recognition by RNase E depends on a stem-loop in the CRISPR repeat, whereas base substitutions at the cleavage site trigger the appearance of secondary products, consistent with a two-step recognition and cleavage mechanism. These results suggest the adaptation of an otherwise very conserved housekeeping enzyme to accommodate new substrates and illuminate the impressive plasticity of CRISPR–Cas systems that enables them to function in particular genomic environments.
Differential depth distribution of microbial function and putative symbionts through sediment-hosted aquifers in the deep terrestrial subsurface Nat. Microbiol. Pub Date : 2018-01-29 Alexander J. Probst, Bethany Ladd, Jessica K. Jarett, David E. Geller-McGrath, Christian M. K. Sieber, Joanne B. Emerson, Karthik Anantharaman, Brian C. Thomas, Rex R. Malmstrom, Michaela Stieglmeier, Andreas Klingl, Tanja Woyke, M. Cathryn Ryan, Jillian F. Banfield
An enormous diversity of previously unknown bacteria and archaea has been discovered recently, yet their functional capacities and distributions in the terrestrial subsurface remain uncertain. Here, we continually sampled a CO2-driven geyser (Colorado Plateau, Utah, USA) over its 5-day eruption cycle to test the hypothesis that stratified, sandstone-hosted aquifers sampled over three phases of the eruption cycle have microbial communities that differ both in membership and function. Genome-resolved metagenomics, single-cell genomics and geochemical analyses confirmed this hypothesis and linked microorganisms to groundwater compositions from different depths. Autotrophic Candidatus “Altiarchaeum sp.” and phylogenetically deep-branching nanoarchaea dominate the deepest groundwater. A nanoarchaeon with limited metabolic capacity is inferred to be a potential symbiont of the Ca. “Altiarchaeum”. Candidate Phyla Radiation bacteria are also present in the deepest groundwater and they are relatively abundant in water from intermediate depths. During the recovery phase of the geyser, microaerophilic Fe- and S-oxidizers have high in situ genome replication rates. Autotrophic Sulfurimonas sustained by aerobic sulfide oxidation and with the capacity for N2 fixation dominate the shallow aquifer. Overall, 104 different phylum-level lineages are present in water from these subsurface environments, with uncultivated archaea and bacteria partitioned to the deeper subsurface.
Structural basis for neutralization of Japanese encephalitis virus by two potent therapeutic antibodies Nat. Microbiol. Pub Date : 2018-01-29 Xiaodi Qiu, Yingfeng Lei, Pan Yang, Qiang Gao, Nan Wang, Lei Cao, Shuai Yuan, Xiaofang Huang, Yongqiang Deng, Wenyu Ma, Tianbing Ding, Fanglin Zhang, Xingan Wu, Junjie Hu, Shan-Lu Liu, Chengfeng Qin, Xiangxi Wang, Zhikai Xu, Zihe Rao
Japanese encephalitis virus (JEV), closely related to dengue, Zika, yellow fever and West Nile viruses, remains neglected and not well characterized1. JEV is the leading causative agent of encephalitis, and is responsible for thousands of deaths each year in Asia. Humoral immunity is essential for protecting against flavivirus infections and passive immunization has been demonstrated to be effective in curing disease2,3. Here, we demonstrate that JEV-specific monoclonal antibodies, 2F2 and 2H4, block attachment of the virus to its receptor and also prevent fusion of the virus. Neutralization of JEV by these antibodies is exceptionally potent and confers clear therapeutic benefit in mouse models. A single 20 μg dose of these antibodies resulted in 100% survival and complete clearance of JEV from the brains of mice. The 4.7 Å and 4.6 Å resolution cryo-electron microscopy structures of JEV–2F2-Fab and JEV–2H4-Fab complexes, together with the crystal structure of 2H4 Fab and our recent near-atomic structure of JEV4, unveil the nature and location of epitopes targeted by the antibodies. Both 2F2 and 2H4 Fabs bind quaternary epitopes that span across three adjacent envelope proteins. Our results provide a structural and molecular basis for the application of 2F2 and 2H4 to treat JEV infection.
AXL promotes Zika virus infection in astrocytes by antagonizing type I interferon signalling Nat. Microbiol. Pub Date : 2018-01-29 Jian Chen, Yi-feng Yang, Yu Yang, Peng Zou, Jun Chen, Yongquan He, Sai-lan Shui, Yan-ru Cui, Ru Bai, Ya-jun Liang, Yunwen Hu, Biao Jiang, Lu Lu, Xiaoyan Zhang, Jia Liu, Jianqing Xu
Zika virus (ZIKV) is associated with neonatal microcephaly and Guillain–Barré syndrome1,2. While progress has been made in understanding the causal link between ZIKV infection and microcephaly3,4,5,6,7,8,9, the life cycle and pathogenesis of ZIKV are less well understood. In particular, there are conflicting reports on the role of AXL, a TAM family kinase receptor that was initially described as the entry receptor for ZIKV10,11,12,13,14,15,16,17,18,19,20,21,22. Here, we show that while genetic ablation of AXL protected primary human astrocytes and astrocytoma cell lines from ZIKV infection, AXL knockout did not block the entry of ZIKV. We found, instead, that the presence of AXL attenuated the ZIKV-induced activation of type I interferon (IFN) signalling genes, including several type I IFNs and IFN-stimulating genes. Knocking out type I IFN receptor α chain (IFNAR1) restored the vulnerability of AXL knockout astrocytes to ZIKV infection. Further experiments suggested that AXL regulates the expression of SOCS1, a known type I IFN signalling suppressor, in a STAT1/STAT2-dependent manner. Collectively, our results demonstrate that AXL is unlikely to function as an entry receptor for ZIKV and may instead promote ZIKV infection in human astrocytes by antagonizing type I IFN signalling.
Spontaneous CRISPR loci generation in vivo by non-canonical spacer integration Nat. Microbiol. Pub Date : 2018-01-29 Jeff Nivala, Seth L. Shipman, George M. Church
The adaptation phase of CRISPR–Cas immunity depends on the precise integration of short segments of foreign DNA (spacers) into a specific genomic location within the CRISPR locus by the Cas1–Cas2 integration complex. Although off-target spacer integration outside of canonical CRISPR arrays has been described in vitro, no evidence of non-specific integration activity has been found in vivo. Here, we show that non-canonical off-target integrations can occur within bacterial chromosomes at locations that resemble the native CRISPR locus by characterizing hundreds of off-target integration locations within Escherichia coli. Considering whether such promiscuous Cas1–Cas2 activity could have an evolutionary role through the genesis of neo-CRISPR loci, we combed existing CRISPR databases and available genomes for evidence of off-target integration activity. This search uncovered several putative instances of naturally occurring off-target spacer integration events within the genomes of Yersinia pestis and Sulfolobus islandicus. These results are important in understanding alternative routes to CRISPR array genesis and evolution, as well as in the use of spacer acquisition in technological applications.
Let them eat fruit Nat. Microbiol. Pub Date : 2018-01-22 Roderick I. Mackie, Isaac Cann
Let them eat fruit Let them eat fruit, Published online: 22 January 2018; doi:10.1038/s41564-018-0108-8 Detailed biochemical, structural and growth studies reveal how Bacteroides thetaiotaomicron coordinates a complex enzymatic response to deconstruct pectins — complex dietary components that comprise a tremendous diversity of monosaccharide units and glycosidic linkage combinations.
A multimodal antiretroviral protein Nat. Microbiol. Pub Date : 2018-01-22 Paul D. Bieniasz
A multimodal antiretroviral protein A multimodal antiretroviral protein, Published online: 22 January 2018; doi:10.1038/s41564-017-0104-4 APOBEC3G is an antiviral protein that has long been known to inhibit retrovirus replication by hypermutating viral DNA. An additional mechanism is now identified, in which APOBEC3G binds to the HIV-1 reverse transcriptase, inhibiting viral DNA synthesis.
Increased diversity of peptidic natural products revealed by modification-tolerant database search of mass spectra Nat. Microbiol. Pub Date : 2018-01-22 Alexey Gurevich, Alla Mikheenko, Alexander Shlemov, Anton Korobeynikov, Hosein Mohimani, Pavel A. Pevzner
Peptidic natural products (PNPs) include many antibiotics and other bioactive compounds. While the recent launch of the Global Natural Products Social (GNPS) molecular networking infrastructure is transforming PNP discovery into a high-throughput technology, PNP identification algorithms are needed to realize the potential of the GNPS project. GNPS relies on the assumption that each connected component of a molecular network (representing related metabolites) illuminates the ‘dark matter of metabolomics’ as long as it contains a known metabolite present in a database. We reveal a surprising diversity of PNPs produced by related bacteria and show that, contrary to the ‘comparative metabolomics’ assumption, two related bacteria are unlikely to produce identical PNPs (even though they are likely to produce similar PNPs). Since this observation undermines the utility of GNPS, we developed a PNP identification tool, VarQuest, that illuminates the connected components in a molecular network even if they do not contain known PNPs and only contain their variants. VarQuest reveals an order of magnitude more PNP variants than all previous PNP discovery efforts and demonstrates that GNPS already contains spectra from 41% of the currently known PNP families. The enormous diversity of PNPs suggests that biosynthetic gene clusters in various microorganisms constantly evolve to generate a unique spectrum of PNP variants that differ from PNPs in other species.
Microbiology needs champions on-screen Nat. Microbiol. Pub Date : 2018-01-22
Microbiology needs champions on-screen Microbiology needs champions on-screen, Published online: 22 January 2018; doi:10.1038/s41564-018-0112-z By sparking imagination and interest during childhood, and by finding and supporting champions to nurture microbial fascination through to adulthood, the fundamental importance of microorganisms can attain a justified and necessary place in the public psyche, but more on-screen time will be needed.
The structure of serum resistance-associated protein and its implications for human African trypanosomiasis Nat. Microbiol. Pub Date : 2018-01-22 Sebastian Zoll, Harriet Lane-Serff, Shahid Mehmood, Jonathan Schneider, Carol V. Robinson, Mark Carrington, Matthew K. Higgins
Only two trypanosome subspecies are able to cause human African trypanosomiasis. To establish an infection in human blood, they must overcome the innate immune system by resisting the toxic effects of trypanolytic factor 1 and trypanolytic factor 2 (refs. 1,2). These lipoprotein complexes contain an active, pore-forming component, apolipoprotein L1 (ApoL1), that causes trypanosome cell death3. One of the two human-infective subspecies, Trypanosoma brucei rhodesiense, differs from non-infective trypanosomes solely by the presence of the serum resistance-associated protein, which binds directly to ApoL1 and blocks its pore-forming capacity3,4,5. Since this interaction is the single critical event that renders T. b. rhodesiense human- infective, detailed structural information that allows identification of binding determinants is crucial to understand immune escape by the parasite. Here, we present the structure of serum resistance-associated protein and reveal the adaptations that occurred as it diverged from other trypanosome surface molecules to neutralize ApoL1. We also present our mapping of residues important for ApoL1 binding, giving molecular insight into this interaction at the heart of human sleeping sickness.
Even malaria parasites watch their host’s diet Nat. Microbiol. Pub Date : 2018-01-22 Kim C. Williamson, Rodney L. Levine, Louis H. Miller
Even malaria parasites watch their host’s diet Even malaria parasites watch their host’s diet, Published online: 22 January 2018; doi:10.1038/s41564-017-0105-3 In recent years, there has been a growing appreciation of the role metabolism plays in controlling nearly all aspects of cellular function. Three recent articles explore how host metabolic cues influence different aspects of Plasmodium biology during infection, including parasite growth and sexual differentiation.
Sieving through gut models of colonization resistance Nat. Microbiol. Pub Date : 2018-01-22 Caroline Mullineaux-Sanders, Jotham Suez, Eran Elinav, Gad Frankel
The development of innovative high-throughput genomics and metabolomics technologies has considerably expanded our understanding of the commensal microorganisms residing within the human body, collectively termed the microbiota. In recent years, the microbiota has been reported to have important roles in multiple aspects of human health, pathology and host–pathogen interactions. One function of commensals that has attracted particular interest is their role in protection against pathogens and pathobionts, a concept known as colonization resistance. However, pathogens are also able to sense and exploit the microbiota during infection. Therefore, obtaining a holistic understanding of colonization resistance mechanisms is essential for the development of microbiome-based and microbiome-targeting therapies for humans and animals. Achieving this is dependent on utilizing physiologically relevant animal models. In this Perspective, we discuss the colonization resistance functions of the gut microbiota and sieve through the advantages and limitations of murine models commonly used to study such mechanisms within the context of enteric bacterial infection.
Decoding glycan recognition by bacterial toxins Nat. Microbiol. Pub Date : 2018-01-22 Sandrine Bourdoulous, Emmanuel Lemichez
Decoding glycan recognition by bacterial toxins Decoding glycan recognition by bacterial toxins, Published online: 22 January 2018; doi:10.1038/s41564-018-0107-9 Functional and structural studies highlight the remarkable evolution and features of the typhoid toxin from Salmonella Typhi. This reveals that attachment of the toxin to specific N-glycan chains accounts for its tropism for selected human tissues.
Stability of the human faecal microbiome in a cohort of adult men Nat. Microbiol. Pub Date : 2018-01-15 Raaj S. Mehta, Galeb S. Abu-Ali, David A. Drew, Jason Lloyd-Price, Ayshwarya Subramanian, Paul Lochhead, Amit D. Joshi, Kerry L. Ivey, Hamed Khalili, Gordon T. Brown, Casey DuLong, Mingyang Song, Long H. Nguyen, Himel Mallick, Eric B. Rimm, Jacques Izard, Curtis Huttenhower, Andrew T. Chan
Characterizing the stability of the gut microbiome is important to exploit it as a therapeutic target and diagnostic biomarker. We metagenomically and metatranscriptomically sequenced the faecal microbiomes of 308 participants in the Health Professionals Follow-Up Study. Participants provided four stool samples—one pair collected 24–72 h apart and a second pair ~6 months later. Within-person taxonomic and functional variation was consistently lower than between-person variation over time. In contrast, metatranscriptomic profiles were comparably variable within and between subjects due to higher within-subject longitudinal variation. Metagenomic instability accounted for ~74% of corresponding metatranscriptomic instability. The rest was probably attributable to sources such as regulation. Among the pathways that were differentially regulated, most were consistently over- or under-transcribed at each time point. Together, these results suggest that a single measurement of the faecal microbiome can provide long-term information regarding organismal composition and functional potential, but repeated or short-term measures may be necessary for dynamic features identified by metatranscriptomics.
Metatranscriptome of human faecal microbial communities in a cohort of adult men Nat. Microbiol. Pub Date : 2018-01-15 Galeb S. Abu-Ali, Raaj S. Mehta, Jason Lloyd-Price, Himel Mallick, Tobyn Branck, Kerry L. Ivey, David A. Drew, Casey DuLong, Eric Rimm, Jacques Izard, Andrew T. Chan, Curtis Huttenhower
The gut microbiome is intimately related to human health, but it is not yet known which functional activities are driven by specific microorganisms' ecological configurations or transcription. We report a large-scale investigation of 372 human faecal metatranscriptomes and 929 metagenomes from a subset of 308 men in the Health Professionals Follow-Up Study. We identified a metatranscriptomic 'core' universally transcribed over time and across participants, often by different microorganisms. In contrast to the housekeeping functions enriched in this core, a 'variable' metatranscriptome included specialized pathways that were differentially expressed both across participants and among microorganisms. Finally, longitudinal metagenomic profiles allowed ecological interaction network reconstruction, which remained stable over the six-month timespan, as did strain tracking within and between participants. These results provide an initial characterization of human faecal microbial ecology into core, subject-specific, microorganism-specific and temporally variable transcription, and they differentiate metagenomically versus metatranscriptomically informative aspects of the human faecal microbiome.
A pathway for biological methane production using bacterial iron-only nitrogenase Nat. Microbiol. Pub Date : 2018-01-15 Yanning Zheng, Derek F. Harris, Zheng Yu, Yanfen Fu, Saroj Poudel, Rhesa N. Ledbetter, Kathryn R. Fixen, Zhi-Yong Yang, Eric S. Boyd, Mary E. Lidstrom, Lance C. Seefeldt, Caroline S. Harwood
Methane (CH4) is a potent greenhouse gas that is released from fossil fuels and is also produced by microbial activity, with at least one billion tonnes of CH4 being formed and consumed by microorganisms in a single year1. Complex methanogenesis pathways used by archaea are the main route for bioconversion of carbon dioxide (CO2) to CH4 in nature2,3,4. Here, we report that wild-type iron-iron (Fe-only) nitrogenase from the bacterium Rhodopseudomonas palustris reduces CO2 simultaneously with nitrogen gas (N2) and protons to yield CH4, ammonia (NH3) and hydrogen gas (H2) in a single enzymatic step. The amount of CH4 produced by purified Fe-only nitrogenase was low compared to its other products, but CH4 production by this enzyme in R. palustris was sufficient to support the growth of an obligate CH4-utilizing Methylomonas strain when the two microorganisms were grown in co-culture, with oxygen (O2) added at intervals. Other nitrogen-fixing bacteria that we tested also formed CH4 when expressing Fe-only nitrogenase, suggesting that this is a general property of this enzyme. The genomes of 9% of diverse nitrogen-fixing microorganisms from a range of environments encode Fe-only nitrogenase. Our data suggest that active Fe-only nitrogenase, present in diverse microorganisms, contributes CH4 that could shape microbial community interactions.
Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis Nat. Microbiol. Pub Date : 2018-01-15 Louis S. Ates, Anzaan Dippenaar, Roy Ummels, Sander R. Piersma, Aniek D. van der Woude, Kim van der Kuij, Fabien Le Chevalier, Dulce Mata-Espinosa, Jorge Barrios-Payán, Brenda Marquina-Castillo, Carolina Guapillo, Connie R. Jiménez, Arnab Pain, Edith N. G. Houben, Robin M. Warren, Roland Brosch, Rogelio Hernández-Pando, Wilbert Bitter
Mycobacterium tuberculosis requires a large number of secreted and exported proteins for its virulence, immune modulation and nutrient uptake. Most of these proteins are transported by the different type VII secretion systems1,2. The most recently evolved type VII secretion system, ESX-5, secretes dozens of substrates belonging to the PE and PPE families, which are named for conserved proline and glutamic acid residues close to the amino terminus3,4. However, the role of these proteins remains largely elusive1. Here, we show that mutations of ppe38 completely block the secretion of two large subsets of ESX-5 substrates, that is, PPE-MPTR and PE_PGRS, together comprising >80 proteins. Importantly, hypervirulent clinical M. tuberculosis strains of the Beijing lineage have such a mutation and a concomitant loss of secretion5. Restoration of PPE38-dependent secretion partially reverted the hypervirulence phenotype of a Beijing strain, and deletion of ppe38 in moderately virulent M. tuberculosis increased virulence. This indicates that these ESX-5 substrates have an important role in virulence attenuation. Phylogenetic analysis revealed that deletion of ppe38 occurred at the branching point of the ‘modern’ Beijing sublineage and is shared by Beijing outbreak strains worldwide, suggesting that this deletion may have contributed to their success and global distribution6,7.
Author Correction: Fluorescent d-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorus predation Nat. Microbiol. Pub Date : 2018-01-08 Erkin Kuru, Carey Lambert, Jonathan Rittichier, Rob Till, Adrien Ducret, Adeline Derouaux, Joe Gray, Jacob Biboy, Waldemar Vollmer, Michael VanNieuwenhze, Yves V. Brun, R. Elizabeth Sockett
Author Correction: Fluorescent d-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorus predation Author Correction: Fluorescent d-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorus predation, Published online: 08 January 2018; doi:10.1038/s41564-017-0087-1 Author Correction: Fluorescent d-amino-acids reveal bi-cellular cell wall modifications important for Bdellovibrio bacteriovorus predation
Publisher Correction: Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice Nat. Microbiol. Pub Date : 2018-01-08 Kellie A. Jurado, Laura J. Yockey, Patrick W. Wong, Sarah Lee, Anita J. Huttner, Akiko Iwasaki
Publisher Correction: Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice Publisher Correction: Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice, Published online: 08 January 2018; doi:10.1038/s41564-017-0101-7 Publisher Correction: Antiviral CD8 T cells induce Zika-virus-associated paralysis in mice
Dynamics of metatranscription in the inflammatory bowel disease gut microbiome Nat. Microbiol. Pub Date : 2018-01-08 Melanie Schirmer, Eric A. Franzosa, Jason Lloyd-Price, Lauren J. McIver, Randall Schwager, Tiffany W. Poon, Ashwin N. Ananthakrishnan, Elizabeth Andrews, Gildardo Barron, Kathleen Lake, Mahadev Prasad, Jenny Sauk, Betsy Stevens, Robin G. Wilson, Jonathan Braun, Lee A. Denson, Subra Kugathasan, Dermot P. B. McGovern, Hera Vlamakis, Ramnik J. Xavier, Curtis Huttenhower
Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn’s disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study’s results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD.
Ephrin receptor A2 is a functional entry receptor for Epstein–Barr virus Nat. Microbiol. Pub Date : 2018-01-01 Jia Chen, Karthik Sathiyamoorthy, Xianming Zhang, Samantha Schaller, Bethany E. Perez White, Theodore S. Jardetzky, Richard Longnecker
Epstein–Barr virus (EBV) is an oncogenic virus that infects more than 90% of the world’s population1. EBV predominantly infects human B cells and epithelial cells, which is initiated by fusion of the viral envelope with a host cellular membrane2. The mechanism of EBV entry into B cells has been well characterized3. However, the mechanism for epithelial cell entry remains elusive. Here, we show that the integrins αvβ5, αvβ6 and αvβ8 do not function as entry and fusion receptors for epithelial cells, whereas Ephrin receptor tyrosine kinase A2 (EphA2) functions well for both. EphA2 overexpression significantly increased EBV infection of HEK293 cells. Using a virus-free cell–cell fusion assay, we found that EphA2 dramatically promoted EBV but not herpes simplex virus (HSV) fusion with HEK293 cells. EphA2 silencing using small hairpin RNA (shRNA) or knockout by CRISPR–Cas9 blocked fusion with epithelial cells. This inhibitory effect was rescued by the expression of EphA2. Antibody against EphA2 blocked epithelial cell infection. Using label-free surface plasmon resonance binding studies, we confirmed that EphA2 but not EphA4 specifically bound to EBV gHgL and this interaction is through the EphA2 extracellular domain (ECD). The discovery of EphA2 as an EBV epithelial cell receptor has important implications for EBV pathogenesis and may uncover new potential targets that can be used for the development of novel intervention strategies.
Ephrin receptor A2 is an epithelial cell receptor for Epstein–Barr virus entry Nat. Microbiol. Pub Date : 2018-01-01 Hua Zhang, Yan Li, Hong-Bo Wang, Ao Zhang, Mei-Ling Chen, Zhi-Xin Fang, Xiao-Dong Dong, Shi-Bing Li, Yong Du, Dan Xiong, Jiang-Yi He, Man-Zhi Li, Yan-Min Liu, Ai-Jun Zhou, Qian Zhong, Yi-Xin Zeng, Elliott Kieff, Zhiqiang Zhang, Benjamin E. Gewurz, Bo Zhao, Mu-Sheng Zeng
Epstein–Barr virus (EBV) is causally associated with nasopharyngeal carcinoma, 10% of gastric carcinoma and various B cell lymphomas1. EBV infects both B cells and epithelial cells2. Recently, we reported that epidermal growth factor and Neuropilin 1 markedly enhanced EBV entry into nasopharyngeal epithelial cells3. However, knowledge of how EBV infects epithelial cells remains incomplete. To understand the mechanisms through which EBV infects epithelial cells, we integrated microarray and RNA interference screen analyses and found that Ephrin receptor A2 (EphA2) is important for EBV entry into the epithelial cells. EphA2 short interfering RNA knockdown or CRISPR–Cas9 knockout markedly reduced EBV epithelial cell infection, which was mostly restored by EphA2 complementary DNA rescue. EphA2 overexpression increased epithelial cell EBV infection. Soluble EphA2 protein, antibodies against EphA2, soluble EphA2 ligand EphrinA1, or the EphA2 inhibitor 2,5-dimethylpyrrolyl benzoic acid efficiently blocked EBV epithelial cell infection. Mechanistically, EphA2 interacted with EBV entry proteins gH/gL and gB to facilitate EBV internalization and fusion. The EphA2 Ephrin-binding domain and fibronectin type III repeats domain were essential for EphA2-mediated EBV infection, while the intracellular domain was dispensable. This is distinct from Kaposi’s sarcoma-associated herpesvirus infection through EphA24. Taken together, our results identify EphA2 as a critical player for EBV epithelial cell entry.
Sensing fungi at the oral epithelium Nat. Microbiol. Pub Date : 2017-12-18 Ivy M. Dambuza, Gordon D. Brown
Sensing fungi at the oral epithelium Sensing fungi at the oral epithelium, Published online: 18 December 2017; doi:10.1038/s41564-017-0086-2 The mechanisms involved in controlling Candida albicans at mucosal sites are not fully understood. Recent work identifies the EphA2 on epithelial cells as a fungal β-glucan receptor that is critical for mediating protective immunity during oral candidiasis.
Peer review is not broken Nat. Microbiol. Pub Date : 2017-12-18
Peer review is not broken Peer review is not broken, Published online: 18 December 2017; doi:10.1038/s41564-017-0093-3 Despite regular claims to the contrary, our peer review systems are not fundamentally broken, but they do suffer from stresses and strains that require journals to undertake ongoing maintenance, by trialling and adopting new practices while ensuring continued rigor.
Enterotypes in the landscape of gut microbial community composition Nat. Microbiol. Pub Date : 2017-12-18 Paul I. Costea, Falk Hildebrand, Arumugam Manimozhiyan, Fredrik Bäckhed, Martin J. Blaser, Frederic D. Bushman, Willem M. de Vos, S. Dusko Ehrlich, Claire M. Fraser, Masahira Hattori, Curtis Huttenhower, Ian B. Jeffery, Dan Knights, James D. Lewis, Ruth E. Ley, Howard Ochman, Paul W. O’Toole, Christopher Quince, David A. Relman, Fergus Shanahan, Shinichi Sunagawa, Jun Wang, George M. Weinstock, Gary D. Wu, Georg Zeller, Liping Zhao, Jeroen Raes, Rob Knight, Peer Bork
Enterotypes in the landscape of gut microbial community composition Enterotypes in the landscape of gut microbial community composition, Published online: 18 December 2017; doi:10.1038/s41564-017-0072-8 This Perspective debates the concept of enterotypes and their use to characterize the gut microbiome, and provides a classifier and standardized methodology to aid cross-study comparisons.
Archaeal cells share common size control with bacteria despite noisier growth and division Nat. Microbiol. Pub Date : 2017-12-18 Ye-Jin Eun, Po-Yi Ho, Minjeong Kim, Salvatore LaRussa, Lydia Robert, Lars D. Renner, Amy Schmid, Ethan Garner, Ariel Amir
Archaeal cells share common size control with bacteria despite noisier growth and division Archaeal cells share common size control with bacteria despite noisier growth and division, Published online: 18 December 2017; doi:10.1038/s41564-017-0082-6 Using a soft-lithography method that enables single-cell analysis of Halobacterium salinarum, this study shows that archaeal cells achieve homogeneity in cell size by growing a constant size between two cell cycle events (that is, the adder model).
Phaged and confused by biofilm matrix Nat. Microbiol. Pub Date : 2017-12-18 Janet E. Price, Matthew R. Chapman
Phaged and confused by biofilm matrix Phaged and confused by biofilm matrix, Published online: 18 December 2017; doi:10.1038/s41564-017-0078-2 Bacterial biofilms fabricate an extracellular amyloid fibre network that intimately links cells together and inhibits the ability of bacteriophages to penetrate the biofilm.
Assigning function to symbionts Nat. Microbiol. Pub Date : 2017-12-18 Thaddeus S. Stappenbeck
Assigning function to symbionts Assigning function to symbionts, Published online: 18 December 2017; doi:10.1038/s41564-017-0088-0 The development of tools to accelerate identification of causal microorganisms is crucial, and advances in microbial culture, bioinformatics and animal experimentation are currently driving these discoveries.
Dietary pectic glycans are degraded by coordinated enzyme pathways in human colonic Bacteroides Nat. Microbiol. Pub Date : 2017-12-18 Ana S. Luis, Jonathon Briggs, Xiaoyang Zhang, Benjamin Farnell, Didier Ndeh, Aurore Labourel, Arnaud Baslé, Alan Cartmell, Nicolas Terrapon, Katherine Stott, Elisabeth C. Lowe, Richard McLean, Kaitlyn Shearer, Julia Schückel, Immacolata Venditto, Marie-Christine Ralet, Bernard Henrissat, Eric C. Martens, Steven C. Mosimann, D. Wade Abbott, Harry J. Gilbert
Dietary pectic glycans are degraded by coordinated enzyme pathways in human colonic Bacteroides Dietary pectic glycans are degraded by coordinated enzyme pathways in human colonic Bacteroides , Published online: 18 December 2017; doi:10.1038/s41564-017-0079-1 This study describes the dynamic mechanisms driving utilization of pectins by Bacteroides thetaiotaomicron, where specific polysaccharide-utilization loci target specific pectin molecules with the products available for use by other bacteria.
Author Correction: Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life Nat. Microbiol. Pub Date : 2017-12-12 Donovan H. Parks, Christian Rinke, Maria Chuvochina, Pierre-Alain Chaumeil, Ben J. Woodcroft, Paul N. Evans, Philip Hugenholtz, Gene W. Tyson
Author Correction: Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life Author Correction: Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life, Published online: 12 December 2017; doi:10.1038/s41564-017-0083-5 Author Correction: Recovery of nearly 8,000 metagenome-assembled genomes substantially expands the tree of life
PASTA repeats of the protein kinase StkP interconnect cell constriction and separation of Streptococcus pneumoniae Nat. Microbiol. Pub Date : 2017-12-04 Laure Zucchini, Chryslène Mercy, Pierre Simon Garcia, Caroline Cluzel, Virginie Gueguen-Chaignon, Frédéric Galisson, Céline Freton, Sébastien Guiral, Céline Brochier-Armanet, Patrice Gouet, Christophe Grangeasse
Eukaryotic-like serine/threonine kinases (eSTKs) with extracellular PASTA repeats are key membrane regulators of bacterial cell division. How PASTA repeats govern eSTK activation and function remains elusive. Using evolution- and structural-guided approaches combined with cell imaging, we disentangle the role of each PASTA repeat of the eSTK StkP from Streptococcus pneumoniae. While the three membrane-proximal PASTA repeats behave as interchangeable modules required for the activation of StkP independently of cell wall binding, they also control the septal cell wall thickness. In contrast, the fourth and membrane-distal PASTA repeat directs StkP localization at the division septum and encompasses a specific motif that is critical for final cell separation through interaction with the cell wall hydrolase LytB. We propose a model in which the extracellular four-PASTA domain of StkP plays a dual function in interconnecting the phosphorylation of StkP endogenous targets along with septal cell wall remodelling to allow cell division of the pneumococcus.
In vivo tropism of Salmonella Typhi toxin to cells expressing a multiantennal glycan receptor Nat. Microbiol. Pub Date : 2017-12-04 Yi-An Yang, Sohyoung Lee, Jun Zhao, Andrew J. Thompson, Ryan McBride, Buyankhishig Tsogtbaatar, James C. Paulson, Ruth Nussinov, Lingquan Deng, Jeongmin Song
Typhoid fever is a life-threatening disease, but little is known about the molecular bases for its unique clinical presentation. Typhoid toxin, a unique virulence factor of Salmonella Typhi (the cause of typhoid fever), recapitulates in an animal model many symptoms of typhoid fever. Typhoid toxin binding to its glycan receptor Neu5Ac is central, but, due to the ubiquity of Neu5Ac, how typhoid toxin causes specific symptoms remains elusive. Here we show that typhoid toxin displays in vivo tropism to cells expressing multiantennal glycoprotein receptors, particularly on endothelial cells of arterioles in the brain and immune cells, which is in line with typhoid symptoms. Neu5Ac displayed by multiantennal N-glycans, rather than a single Neu5Ac, appears to serve as the high-affinity receptor, as typhoid toxin possesses five identical binding pockets per toxin. Human counterparts also express the multiantennal Neu5Ac receptor. Here we also show that mice immunized with inactive typhoid toxins and challenged with wild-type typhoid toxin presented neither the characteristic in vivo tropism nor symptoms. These mice were protected against a lethal-dose toxin challenge, but Ty21a-vaccinated mice were not. Cumulatively, these results reveal remarkable features describing how a bacterial exotoxin induces virulence exclusively in specific cells at the organismal level.
Activation of Vibrio cholerae quorum sensing promotes survival of an arthropod host Nat. Microbiol. Pub Date : 2017-11-27 Adam C. N. Wong, Afsar Ali, Alexandra E. Purdy, Audrey S. Vanhove, J. Glenn Morris Jr, John M. Asara, Katharine Kierek-Pearson, Layla Kamareddine, Paula I. Watnick, Saiyu Hang
Vibrio cholerae colonizes the human terminal ileum to cause cholera, and the arthropod intestine and exoskeleton to persist in the aquatic environment. Attachment to these surfaces is regulated by the bacterial quorum-sensing signal transduction cascade, which allows bacteria to assess the density of microbial neighbours. Intestinal colonization with V. cholerae results in expenditure of host lipid stores in the model arthropod Drosophila melanogaster. Here we report that activation of quorum sensing in the Drosophila intestine retards this process by repressing V. cholerae succinate uptake. Increased host access to intestinal succinate mitigates infection-induced lipid wasting to extend survival of V. cholerae-infected flies. Therefore, quorum sensing promotes a more favourable interaction between V. cholerae and an arthropod host by reducing the nutritional burden of intestinal colonization.
Intergenerational transfer of antibiotic-perturbed microbiota enhances colitis in susceptible mice Nat. Microbiol. Pub Date : 2017-11-27 Anjelique F. Schulfer, Arlin B. Rogers, Dan Knights, Laura M. Cox, Luc Bijnens, Martin J. Blaser, Melody Ho, R. Balfour Sartor, Serina Robinson, Thomas Battaglia, Tonya Ward, Victoria E. Ruiz, Yelina Alvarez
Antibiotic exposure in children has been associated with the risk of inflammatory bowel disease (IBD). Antibiotic use in children or in their pregnant mother can affect how the intestinal microbiome develops, so we asked whether the transfer of an antibiotic-perturbed microbiota from mothers to their children could affect their risk of developing IBD. Here we demonstrate that germ-free adult pregnant mice inoculated with a gut microbial community shaped by antibiotic exposure transmitted their perturbed microbiota to their offspring with high fidelity. Without any direct or continued exposure to antibiotics, this dysbiotic microbiota in the offspring remained distinct from controls for at least 21 weeks. By using both IL-10-deficient and wild-type mothers, we showed that both inoculum and genotype shape microbiota populations in the offspring. Because IL10−/− mice are genetically susceptible to colitis, we could assess the risk due to maternal transmission of an antibiotic-perturbed microbiota. We found that the IL10−/− offspring that had received the perturbed gut microbiota developed markedly increased colitis. Taken together, our findings indicate that antibiotic exposure shaping the maternal gut microbiota has effects that extend to the offspring, with both ecological and long-term disease consequences.
A radical way to die Nat. Microbiol. Pub Date : 2017-11-24 Philip J. Hastings, Susan M. Rosenberg
A radical way to die A radical way to die, Published online: 24 November 2017; doi:10.1038/s41564-017-0074-6 Recent work finds that reactive oxygen species are generated in cells starved for the nucleobase thymine and contribute to DNA-destructive “thymineless death” mechanisms, which underlie the activities of many drugs, including trimethoprim and sulfa-based antibiotics. Such mechanisms may also apply to cells across the tree of life.
Tackling host–circuit give and take Nat. Microbiol. Pub Date : 2017-11-24 Grant Gelderman, Mark P. Brynildsen, Sandra J. Aedo
Tackling host–circuit give and take Tackling host–circuit give and take, Published online: 24 November 2017; doi:10.1038/s41564-017-0058-6 The incorporation of additional gene circuits into hosts can often lead to unpredicted and undesirable behaviours. Recent work has developed a modelling framework that accounts for host–circuit interactions and can predict a variety of phenotypes at both single-cell and population levels.
Overcoming hurdles in sharing microbiome data Nat. Microbiol. Pub Date : 2017-11-24
Overcoming hurdles in sharing microbiome data Overcoming hurdles in sharing microbiome data, Published online: 24 November 2017; doi:10.1038/s41564-017-0077-3 Increasing research on microbial communities has resulted in massive amounts of data being generated and shared, yet data accessibility, accuracy and thoroughness remain problematic and can be a substantial obstacle for scientists looking to explore existing datasets.
Reply to ‘The population genetics of pangenomes’ Nat. Microbiol. Pub Date : 2017-11-24 Alan McNally, James O. McInerney, Mary J. O’Connell
Reply to ‘The population genetics of pangenomes’ Reply to ‘The population genetics of pangenomes’, Published online: 24 November 2017; doi:10.1038/s41564-017-0068-4 Reply to ‘The population genetics of pangenomes’
The development of cryo-EM and how it has advanced microbiology Nat. Microbiol. Pub Date : 2017-11-24 Catherine M. Oikonomou, Grant J. Jensen
The development of cryo-EM and how it has advanced microbiology The development of cryo-EM and how it has advanced microbiology, Published online: 24 November 2017; doi:10.1038/s41564-017-0073-7 The 2017 Nobel Prize in Chemistry was awarded to Jacques Dubochet, Richard Henderson and Joachim Frank for the development of cryo-electron microscopy, a technique for high-resolution structural determination of biomolecules in solution that has provided unprecedented insight into the biology of microorganisms.
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