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  • Antibiotic Killing through Incomplete DNA Repair
    Trends Microbiol. (IF 11.02) Pub Date : 2017-11-17
    Benno H. ter Kuile, Marloes Hoeksema

    Two recent studies show that incomplete repair of DNA damage due to oxidized nucleotides is crucial for reactive oxygen species (ROS)-related antimicrobial lethality. Using widely different experimental approaches they both reach the same conclusions on the role of downstream ROS production in cell killing upon exposure to bactericidal antimicrobials.

  • The Role of Interferon in Persistent Viral Infection: Insights from Murine Norovirus
    Trends Microbiol. (IF 11.02) Pub Date : 2017-11-17
    Timothy J. Nice, Bridget A. Robinson, Jacob A. Van Winkle

    Persistent viral infections result from evasion or avoidance of sterilizing immunity, extend the timeframe of virus transmission, and can trigger disease. Prior studies in mouse models of persistent infection have suggested that ineffective adaptive immune responses are necessary for persistent viral infection. However, recent work in the murine norovirus (MNV) model of persistent infection demonstrates that innate immunity can control both early and persistent viral replication independently of adaptive immune effector functions. Interferons (IFNs) are central to the innate control of persistent MNV, apart from a role in modulating adaptive immunity. Furthermore, subtypes of IFN play distinct tissue-specific roles in innate control of persistent MNV infection. Type I IFN (IFN-α/β) controls systemic replication, and type III IFN (IFN-λ) controls MNV persistence in the intestinal epithelium. In this article, we review recent findings in the MNV model, highlighting the role of IFNs and innate immunity in clearing persistent viral infection, and discussing the broader implications of these findings for control of persistent human infections.

  • Turning Over a New Leaf: Bacteriocins Going Green
    Trends Microbiol. (IF 11.02) Pub Date : 2017-11-14
    Maarten G.K. Ghequire, René De Mot

    Bacteriocins are potent antibacterial proteins that selectively kill phylogenetic relatives of the producer. Their polymorphic nature, most prominent in γ-Proteobacteria, offers potential for the design of customized bacteriocin cocktails targeting Gram-negative pathogens. As an alternative to recombinant production in bacteria, they are eligible for large-scale production in plants.

  • Not Just Antibiotics: Is Cancer Chemotherapy Driving Antimicrobial Resistance?
    Trends Microbiol. (IF 11.02) Pub Date : 2017-11-13
    Lito E. Papanicolas, David L. Gordon, Steve L. Wesselingh, Geraint B. Rogers

    The global spread of antibiotic-resistant pathogens threatens to increase the mortality of cancer patients significantly. We propose that chemotherapy contributes to the emergence of antibiotic-resistant bacteria within the gut and, in combination with antibiotics, drives pathogen overgrowth and translocation into the bloodstream. In our model, these processes are mediated by the effects of chemotherapy on bacterial mutagenesis and horizontal gene transfer, the disruption of commensal gut microbiology, and alterations to host physiology. Clinically, this model manifests as a cycle of recurrent sepsis, with each episode involving ever more resistant organisms and requiring increasingly broad-spectrum antimicrobial therapy. Therapies that restore the gut microbiota following chemotherapy or antibiotics could provide a means to break this cycle of infection and treatment failure.

  • Quorum-Sensing Systems as Targets for Antivirulence Therapy
    Trends Microbiol. (IF 11.02) Pub Date : 2017-11-10
    Tom Defoirdt

    The development of novel therapies to control diseases caused by antibiotic-resistant pathogens is one of the major challenges we are currently facing. Many important plant, animal, and human pathogens regulate virulence by quorum sensing, bacterial cell-to-cell communication with small signal molecules. Consequently, a significant research effort is being undertaken to identify and use quorum-sensing-interfering agents in order to control diseases caused by these pathogens. In this review, an overview of our current knowledge of quorum-sensing systems of Gram-negative model pathogens is presented as well as the link with virulence of these pathogens, and recent advances and challenges in the development of quorum-sensing-interfering therapies are discussed.

  • A Tale of Two Viruses: Does Heterologous Flavivirus Immunity Enhance Zika Disease?
    Trends Microbiol. (IF 11.02) Pub Date : 2017-11-06
    Carlos A. Sariol, Mauricio L. Nogueira, Nikos Vasilakis

    The rise of Zika virus (ZIKV) and its unusual clinical manifestations provided ground for speculative debate. The clinical severity of secondary dengue virus (DENV) infections is associated with antibody-dependent enhancement (ADE), and it was recently suggested that previous exposure to DENV may worsen ZIKV clinical outcomes. In this Opinion article we analyze the relationship among different flaviviruses and ADE. We discuss new evidence obtained in non-human primates and human cohorts demonstrating that there is no correlation to ADE when ZIKV infection occurs in the presence of pre-existing DENV immunity. We propose a redefinition of ADE in the context of complex immunological flavivirus interactions to provide a more objective perspective when translating in vitro or in vivo observations into the clinical setting.

  • A Call to Arms: Quest for a Cryptococcal Vaccine
    Trends Microbiol. (IF 11.02) Pub Date : 2017-11-02
    Marley C. Caballero Van Dyke, Floyd L. Wormley Jr

    Cryptococcosis remains a significant cause of morbidity and mortality world-wide, particularly among AIDS patients. Yet, to date, there are no licensed vaccines clinically available to treat or prevent cryptococcosis. In this review, we provide a rationale to support continued investment in Cryptococcus vaccine research, potential challenges that must be overcome along the way, and a literature review of the current progress underway towards developing a vaccine to prevent cryptococcosis.

  • Oral Biofilms: Pathogens, Matrix, and Polymicrobial Interactions in Microenvironments
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-30
    William H. Bowen, Robert A. Burne, Hui Wu, Hyun Koo

    Biofilms are microbial communities embedded within an extracellular matrix, forming a highly organized structure that causes many human infections. Dental caries (tooth decay) is a polymicrobial biofilm disease driven by the diet and microbiota–matrix interactions that occur on a solid surface. Sugars fuel the emergence of pathogens, the assembly of the matrix, and the acidification of the biofilm microenvironment, promoting ecological changes and concerted multispecies efforts that are conducive to acid damage of the mineralized tooth tissue. Here, we discuss recent advances in the role of the biofilm matrix and interactions between opportunistic pathogens and commensals in the pathogenesis of dental caries. In addition, we highlight the importance of matrix-producing organisms in fostering a pathogenic habitat where interspecies competition and synergies occur to drive the disease process, which could have implications to other infections associated with polymicrobial biofilms.

  • Predictive Modeling of Influenza Shows the Promise of Applied Evolutionary Biology
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-30
    Dylan H. Morris, Katelyn M. Gostic, Simone Pompei, Trevor Bedford, Marta Łuksza, Richard A. Neher, Bryan T. Grenfell, Michael Lässig, John W. McCauley

    Seasonal influenza is controlled through vaccination campaigns. Evolution of influenza virus antigens means that vaccines must be updated to match novel strains, and vaccine effectiveness depends on the ability of scientists to predict nearly a year in advance which influenza variants will dominate in upcoming seasons. In this review, we highlight a promising new surveillance tool: predictive models. Developed through data-sharing and close collaboration between the World Health Organization and academic scientists, these models use surveillance data to make quantitative predictions regarding influenza evolution. Predictive models demonstrate the potential of applied evolutionary biology to improve public health and disease control. We review the state of influenza predictive modeling and discuss next steps and recommendations to ensure that these models deliver upon their considerable biomedical promise.

  • Anti-HIV Passive Immunization: New Weapons in the Arsenal
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-30
    Ruth M. Ruprecht

    Anti-HIV passive immunization with human neutralizing monoclonal antibodies (nmAbs) has made exciting gains: (i) identification of the HIV envelope V2 apex as a new in vivo protective epitope, (ii) a novel clade C SHIV for challenge studies, and (iii) a highly protective, trispecific nmAb. Potent, broad-spectrum protection by nmAbs holds promise.

  • Small RNA, Big Effect: Control of Flagellin Production
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-30
    Aleksandra A. Miranda-CasoLuengo, Stefani C. Kary, Marc Erhardt, Carsten Kröger

    Many bacteria move in their environment using a remarkable, rotating nanomachine – the flagellum. In a recent publication, Choi et al. report a new addition to the group of flagellar regulators, a trans-acting small RNA (sRNA).

  • Glycan Utilization and Cross-Feeding Activities by Bifidobacteria
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-28
    Francesca Turroni, Christian Milani, Sabrina Duranti, Jennifer Mahony, Douwe van Sinderen, Marco Ventura

    Bifidobacteria represent one of the first colonizers of the mammalian gut, where such colonization is facilitated by their saccharolytic capabilities. Genomic analyses of bifidobacteria have revealed intriguing genetic strategies employed by these bacteria to access a variety of dietary and host-produced glycans. Bifidobacterial genome evolution therefore represents a fascinating example of how their chromosomes were molded to contain a large number of genes involved in carbohydrate metabolism. One of the reasons as to why bifidobacteria are such dominant and prevalent members of the (early) microbiota is that they may access glycans in the gut through mutualistic cross-feeding or resource-sharing activities, which is indicative of ‘social behavior’ among bifidobacterial strains.

  • Breach: Host Membrane Penetration and Entry by Nonenveloped Viruses
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-25
    Chandra Shekhar Kumar, Debajit Dey, Sukanya Ghosh, Manidipa Banerjee

    Disruption of host membranes by nonenveloped viruses, which allows the nucleocapsid or genome to enter the cytosol, is a mechanistically diverse process. Although the membrane-penetrating agents are usually small, hydrophobic or amphipathic peptides deployed from the capsid interior during entry, their manner of membrane interaction varies substantially. In this review, we discuss recent data about the molecular pathways for externalization of viral peptides amidst conformational alterations in the capsid, as well as mechanisms of membrane penetration, which is influenced by structural features of the peptides themselves as well as physicochemical properties of membranes, and other host factors. The membrane-penetrating components of nonenveloped viruses constitute an interesting class of cell-penetrating peptides, and may have potential therapeutic value for gene transfer.

  • Infection’s Sweet Tooth: How Glycans Mediate Infection and Disease Susceptibility
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-24
    Steven L. Taylor, Michael A. McGuckin, Steve Wesselingh, Geraint B. Rogers

    Glycans form a highly variable constituent of our mucosal surfaces and profoundly affect our susceptibility to infection and disease. The diversity and importance of these surface glycans can be seen in individuals who lack a functional copy of the fucosyltransferase gene, FUT2. Representing around one-fifth of the population, these individuals have an altered susceptibility to many bacterial and viral infections and diseases. The mediation of host–pathogen interactions by mucosal glycans, such as those added by FUT2, is poorly understood. We highlight, with specific examples, important mechanisms by which host glycans influence infection dynamics, including by: acting as pathogen receptors (or receptor-decoys), promoting microbial stability, altering the physical characteristics of mucus, and acting as immunological markers. We argue that the effect glycans have on infection dynamics has profound implications for many aspects of healthcare and policy, including clinical management, outbreak control, and vaccination policy.

  • The Molecular Basis of Noncanonical Bacterial Morphology
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-19
    Paul D. Caccamo, Yves V. Brun

    Bacteria come in a wide variety of shapes and sizes. The true picture of bacterial morphological diversity is likely skewed due to an experimental focus on pathogens and industrially relevant organisms. Indeed, most of the work elucidating the genes and molecular processes involved in maintaining bacterial morphology has been limited to rod- or coccal-shaped model systems. The mechanisms of shape evolution, the molecular processes underlying diverse shapes and growth modes, and how individual cells can dynamically modulate their shape are just beginning to be revealed. Here we discuss recent work aimed at advancing our knowledge of shape diversity and uncovering the molecular basis for shape generation in noncanonical and morphologically complex bacteria.

  • Clinical Potential of Prefusion RSV F-specific Antibodies
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-17
    Iebe Rossey, Jason S. McLellan, Xavier Saelens, Bert Schepens

    Human respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in the very young. The RSV fusion protein (F) is essential for virus entry because it mediates viral and host membrane fusion. During this fusion process F is converted from a metastable prefusion conformation into an energetically favored postfusion state. Antibodies that target F can prevent viral entry and reduce disease caused by RSV. During recent years, many prefusion F-specific antibodies have been described. These antibodies typically have stronger RSV-neutralizing activity compared to those that also bind F in the postfusion conformation. Here, we describe how F-specific antibodies protect against RSV and why specifically targeting prefusion F could have great clinical potential.

  • Transfer of Antibiotic Resistance in Staphylococcus aureus
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-20
    Jakob Haaber, José R. Penadés, Hanne Ingmer

    Staphylococcus aureus is a serious human pathogen with remarkable adaptive powers. Antibiotic-resistant clones rapidly emerge mainly by acquisition of antibiotic-resistance genes from other S. aureus strains or even from other genera. Transfer is mediated by a diverse complement of mobile genetic elements and occurs primarily by conjugation or bacteriophage transduction, with the latter traditionally being perceived as the primary route. Recent work on conjugation and transduction suggests that transfer by these mechanisms may be more extensive than previously thought, in terms of the range of plasmids that can be transferred by conjugation and the efficiency with which transduction occurs. Here, we review the main routes of antibiotic resistance gene transfer in S. aureus in the context of its biology as a human commensal and a life-threatening pathogen.

  • The Emerging Roles of STING in Bacterial Infections
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-15
    Fabio V. Marinho, Sulayman Benmerzoug, Sergio C. Oliveira, Bernhard Ryffel, V.F.J. Quesniaux

    The STING (Stimulator of Interferon Genes) protein connects microorganism cytosolic sensing with effector functions of the host cell by sensing directly cyclic dinucleotides (CDNs), originating from pathogens or from the host upon DNA recognition. Although STING activation favors effective immune responses against viral infections, its role during bacterial diseases is controversial, ranging from protective to detrimental effects for the host. In this review, we summarize important features of the STING activation pathway and recent highlights about the role of STING in bacterial infections by Chlamydia, Listeria, Francisella, Brucella, Shigella, Salmonella, Streptococcus, and Neisseria genera, with a special focus on mycobacteria.

  • Perinatal Group B Streptococcal Infections: Virulence Factors, Immunity, and Prevention Strategies
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-17
    Jay Vornhagen, Kristina M. Adams Waldorf, Lakshmi Rajagopal

    Group B streptococcus (GBS) or Streptococcus agalactiae is a β-hemolytic, Gram-positive bacterium that is a leading cause of neonatal infections. GBS commonly colonizes the lower gastrointestinal and genital tracts and, during pregnancy, neonates are at risk of infection. Although intrapartum antibiotic prophylaxis during labor and delivery has decreased the incidence of early-onset neonatal infection, these measures do not prevent ascending infection that can occur earlier in pregnancy leading to preterm births, stillbirths, or late-onset neonatal infections. Prevention of GBS infection in pregnancy is complex and is likely influenced by multiple factors, including pathogenicity, host factors, vaginal microbiome, false-negative screening, and/or changes in antibiotic resistance. A deeper understanding of the mechanisms of GBS infections during pregnancy will facilitate the development of novel therapeutics and vaccines. Here, we summarize and discuss important advancements in our understanding of GBS vaginal colonization, ascending infection, and preterm birth.

  • The Role of ErbB Receptors in Infection
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-15
    Jemima Ho, David L. Moyes, Mahvash Tavassoli, Julian R. Naglik

    Members of the epidermal growth factor receptor family (ErbB family) possess a wide distribution and diverse functions ranging from cellular growth to migration and apoptosis. Though highly implicated in a variety of cancers, their involvement in infectious disease is less recognised. A growing body of evidence now highlights the importance of the ErbB family in a variety of infections. Their role as growth factor receptors, along with other characteristics, such as surface expression and continuous intracellular trafficking, make this receptor family ideally placed for exploitation by pathogens. Herein, we review our current understanding of the role of the ErbB family in the context of infectious disease, exploring the mechanisms that govern pathogen exploitation of this system.

  • Antibiotic-Resistance Genes in Waste Water
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-13
    Antti Karkman, Thi Thuy Do, Fiona Walsh, Marko P.J. Virta

    Waste water and waste water treatment plants can act as reservoirs and environmental suppliers of antibiotic resistance. They have also been proposed to be hotspots for horizontal gene transfer, enabling the spread of antibiotic resistance genes between different bacterial species. Waste water contains antibiotics, disinfectants, and metals which can form a selection pressure for antibiotic resistance, even in low concentrations. Our knowledge of antibiotic resistance in waste water has increased tremendously in the past few years with advances in the molecular methods available. However, there are still some gaps in our knowledge on the subject, such as how active is horizontal gene transfer in waste water and what is the role of the waste water treatment plant in the environmental resistome? The purpose of this review is to briefly describe some of the main methods for studying antibiotic resistance in waste waters and the latest research and main knowledge gaps on the issue. In addition, some future research directions are proposed.

  • Transmissible Viral Vaccines
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-13
    James J. Bull, Mark W. Smithson, Scott L. Nuismer

    Genetic engineering now enables the design of live viral vaccines that are potentially transmissible. Some designs merely modify a single viral genome to improve on the age-old method of attenuation whereas other designs create chimeras of viral genomes. Transmission has the benefit of increasing herd immunity above that achieved by direct vaccination alone but also increases the opportunity for vaccine evolution, which typically undermines vaccine utility. Different designs have different epidemiological consequences but also experience different evolution. Approaches that integrate vaccine engineering with an understanding of evolution and epidemiology will reap the greatest benefit from vaccine transmission.

  • In Silico Vaccine Strain Prediction for Human Influenza Viruses
    Trends Microbiol. (IF 11.02) Pub Date : 2017-10-09
    Thorsten R. Klingen, Susanne Reimering, Carlos A. Guzmán, Alice C. McHardy

    Vaccines preventing seasonal influenza infections save many lives every year; however, due to rapid viral evolution, they have to be updated frequently to remain effective. To identify appropriate vaccine strains, the World Health Organization (WHO) operates a global program that continually generates and interprets surveillance data. Over the past decade, sophisticated computational techniques, drawing from multiple theoretical disciplines, have been developed that predict viral lineages rising to predominance, assess their suitability as vaccine strains, link genetic to antigenic alterations, as well as integrate and visualize genetic, epidemiological, structural, and antigenic data. These could form the basis of an objective and reproducible vaccine strain-selection procedure utilizing the complex, large-scale data types from surveillance. To this end, computational techniques should already be incorporated into the vaccine-selection process in an independent, parallel track, and their performance continuously evaluated.

  • Personalized Medicine and Infectious Disease Management
    Trends Microbiol. (IF 11.02) Pub Date : 2017-09-29
    Slade O. Jensen, Sebastiaan J. van Hal

    A recent study identified pathogen factors associated with an increased mortality risk in Staphylococcus aureus bacteremia, using predictive modelling and a combination of genotypic, phenotypic, and clinical data. This study conceptually validates the benefit of personalized medicine and highlights the potential use of whole genome sequencing in infectious disease management.

  • Roles of Endogenous Retroviruses in Early Life Events
    Trends Microbiol. (IF 11.02) Pub Date : 2017-09-29
    Gkikas Magiorkinis, Aris Katzourakis, Pagona Lagiou

    A retrovirus that infected our ancestors 100 million years ago became a human gene that is expressed in embryos and cancers, and can be detected in the blood of pregnant women. Accumulating evidence suggests potential roles for endogenous retroviruses in early life events, which may affect adult health.

  • A Delicate Connection: c-di-AMP Affects Cell Integrity by Controlling Osmolyte Transport
    Trends Microbiol. (IF 11.02) Pub Date : 2017-09-28
    Fabian M. Commichau, Johannes Gibhardt, Sven Halbedel, Jan Gundlach, Jörg Stülke

    Bacteria use second-messenger molecules to adapt to their environment. Several second messengers, among them cyclic di-AMP (c-di-AMP), have been discovered and intensively studied. Interestingly, c-di-AMP is essential for growth of Gram-positive bacteria such as Bacillus subtilis, Listeria monocytogenes, and Staphylococcus aureus. Many studies demonstrated that perturbation of c-di-AMP metabolism affects the integrity of the bacterial cell envelope. Therefore, it has been assumed that the nucleotide is essential for proper cell envelope synthesis. In this Opinion paper, we propose that the cell envelope phenotypes caused by perturbations of c-di-AMP metabolism can be interpreted differently: c-di-AMP might indirectly control cell envelope integrity by modulating the turgor, a physical variable that needs to be tightly adjusted. We also discuss open questions related to c-di-AMP metabolism that need to be urgently addressed by future studies.

  • Black Truffle, a Hermaphrodite with Forced Unisexual Behaviour
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-13
    Marc-André Selosse, Laure Schneider-Maunoury, Elisa Taschen, François Rousset, Franck Richard

    The life cycle of the black truffle (Tuber melanosporum) includes a mating before sporulation: although the species is hermaphroditic, mating turns out to involve parents with very different features, that mostly behave as male or female only, suggesting that this species undergoes forced dioecism.

  • Ecological Insights into the Dynamics of Plant Biomass-Degrading Microbial Consortia
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-22
    Diego Javier Jiménez, Francisco Dini-Andreote, Kristen M. DeAngelis, Steven W. Singer, Joana Falcão Salles, Jan Dirk van Elsas

    Plant biomass (PB) is an important resource for biofuel production. However, the frequent lack of efficiency of PB saccharification is still an industrial bottleneck. The use of enzyme cocktails produced from PB-degrading microbial consortia (PB-dmc) is a promising approach to optimize this process. Nevertheless, the proper use and manipulation of PB-dmc depends on a sound understanding of the ecological processes and mechanisms that exist in these communities. This Opinion article provides an overview of arguments as to how spatiotemporal nutritional fluxes influence the successional dynamics and ecological interactions (synergism versus competition) between populations in PB-dmc. The themes of niche occupancy, ‘sugar cheaters’, minimal effective consortium, and the Black Queen Hypothesis are raised as key subjects that foster our appraisal of such systems. Here we provide a conceptual framework that describes the critical topics underpinning the ecological basis of PB-dmc, giving a solid foundation upon which further prospective experimentation can be developed.

  • The Hsp90 Chaperone Network Modulates Candida Virulence Traits
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-23
    Teresa R. O’Meara, Nicole Robbins, Leah E. Cowen

    Hsp90 is a conserved molecular chaperone that facilitates the folding and function of client proteins. Hsp90 function is dynamically regulated by interactions with co-chaperones and by post-translational modifications. In the fungal pathogen Candida albicans, Hsp90 enables drug resistance and virulence by stabilizing diverse signal transducers. Here, we review studies that have unveiled regulators of Hsp90 function, as well as downstream effectors that govern the key virulence traits of morphogenesis and drug resistance. We highlight recent work mapping the Hsp90 genetic network in C. albicans under diverse environmental conditions, and how these interactions provide insight into circuitry important for drug resistance, morphogenesis, and virulence. Ultimately, elucidating the Hsp90 chaperone network will aid in the development of therapeutics to treat fungal disease.

  • At the Nexus of Antibiotics and Metals: The Impact of Cu and Zn on Antibiotic Activity and Resistance
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-17
    Keith Poole

    Environmental influences on antibiotic activity and resistance can wreak havoc with in vivo antibiotic efficacy and, ultimately, antimicrobial chemotherapy. In nature, bacteria encounter a variety of metal ions, particularly copper (Cu) and zinc (Zn), as contaminants in soil and water, as feed additives in agriculture, as clinically-used antimicrobials, and as components of human antibacterial responses. Importantly, there is a growing body of evidence for Cu/Zn driving antibiotic resistance development in metal-exposed bacteria, owing to metal selection of genetic elements harbouring both metal and antibiotic resistance genes, and metal recruitment of antibiotic resistance mechanisms. Many classes of antibiotics also form complexes with metal cations, including Cu and Zn, and this can hinder (or enhance) antibiotic activity. This review highlights the ways in which Cu/Zn influence antibiotic resistance development and antibiotic activity, and in so doing impact in vivo antibiotic efficacy.

  • Antiviral Goes Viral: Harnessing CRISPR/Cas9 to Combat Viruses in Humans
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-15
    Jasper Adriaan Soppe, Robert Jan Lebbink

    The clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated (Cas) systems are RNA-guided sequence-specific prokaryotic antiviral immune systems. In prokaryotes, small RNA molecules guide Cas effector endonucleases to invading foreign genetic elements in a sequence-dependent manner, resulting in DNA cleavage by the endonuclease upon target binding. A rewired CRISPR/Cas9 system can be used for targeted and precise genome editing in eukaryotic cells. CRISPR/Cas has also been harnessed to target human pathogenic viruses as a potential new antiviral strategy. Here, we review recent CRISPR/Cas9-based approaches to combat specific human viruses in humans and discuss challenges that need to be overcome before CRISPR/Cas9 may be used in the clinic as an antiviral strategy.

  • Gut Microbiota Dysbiosis in Postweaning Piglets: Understanding the Keys to Health
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-08
    Raphaële Gresse, Frédérique Chaucheyras-Durand, Mickaël Alain Fleury, Tom Van de Wiele, Evelyne Forano, Stéphanie Blanquet-Diot

    Weaning is a critical event in the pig’s life cycle, frequently associated with severe enteric infections and overuse of antibiotics; this raises serious economic and public health concerns. In this review, we explain why gut microbiota dysbiosis, induced by abrupt changes in the diet and environment of piglets, emerges as a leading cause of post-weaning diarrhea, even if the exact underlying mechanisms remain unclear. Then, we focus on nonantimicrobial alternatives, such as zinc oxide, essential oils, and prebiotics or probiotics, which are currently evaluated to restore intestinal balance and allow a better management of the crucial weaning transition. Finally, we discuss how in vitro models of the piglet gut could be advantageously used as a complement to ex vivo and in vivo studies for the development and testing of new feed additives.

  • Opening Pandora’s Box: Mechanisms of Mycobacterium tuberculosis Resuscitation
    Trends Microbiol. (IF 11.02) Pub Date : 2017-09-11
    Ashley V. Veatch, Deepak Kaushal

    Mycobacterium tuberculosis (Mtb) characteristically causes an asymptomatic infection. While this latent tuberculosis infection (LTBI) is not contagious, reactivation to active tuberculosis disease (TB) causes the patient to become infectious. A vaccine has existed for TB for a century, while drug treatments have been available for over 70 years; despite this, TB remains a major global health crisis. Understanding the factors which allow the bacillus to control responses to host stress and mechanisms leading to latency are critical for persistence. Similarly, molecular switches which respond to reactivation are important. Recently, research in the field has sought to focus on reactivation, employing system-wide approaches and animal models. Here, we describe the current work that has been done to elucidate the mechanisms of reactivation and stop reactivation in its tracks.

  • Horizontal Gene Transfer and Ecosystem Function Dynamics
    Trends Microbiol. (IF 11.02) Pub Date : 2017-07-24
    Maarten van de Guchte

    Horizontal gene transfer can provide bacteria with new functions that confer an important competitive advantage, and is therefore likely to affect the dynamics of bacterial ecosystems. Two studies by Wolfe et al. and Bonham et al. prepare the way to study this hypothesis in a model ecosystem with reproducible properties.

  • Zika Virus: Mechanisms of Infection During Pregnancy
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-31
    Nicholas J.C. King, Mauro M. Teixeira, Suresh Mahalingam

    Immune status changes during pregnancy, with pro-inflammatory and anti-inflammatory contexts at different stages, making pregnant women potentially more susceptible to various infections. Infection by Zika virus during pregnancy can cause developmental damage to the fetus, and the altered immune response during pregnancy could contribute to disease during Zika infection.

  • Metabolic Integration of Bacterial Endosymbionts through Antimicrobial Peptides
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-23
    Peter Mergaert, Yoshitomo Kikuchi, Shuji Shigenobu, Eva C.M. Nowack

    Antimicrobial peptides (AMPs) are massively produced by eukaryotic hosts during symbiotic interactions with bacteria. Among other roles, these symbiotic AMPs have the capacity to permeabilize symbiont membranes and facilitate metabolite flow across the host–symbiont interface. We propose that an ancestral role of these peptides is to facilitate metabolic exchange between the symbiotic partners through membrane permeabilization. This function may be particularly critical for integration of endosymbiont and host metabolism in interactions involving bacteria with strongly reduced genomes lacking most small metabolite transporters. Moreover, AMPs could have acted in a similar way at the onset of plastid and mitochondrion evolution, after a host cell took up a bacterium and needed to extract nutrients from it in the absence of dedicated solute transporters.

  • Epidemiology, Evolution, and Pathogenesis of H7N9 Influenza Viruses in Five Epidemic Waves since 2013 in China
    Trends Microbiol. (IF 11.02) Pub Date : 2017-07-19
    Shuo Su, Min Gu, Di Liu, Jie Cui, George F. Gao, Jiyong Zhou, Xiufan Liu

    H7N9 influenza viruses were first isolated in 2013 and continue to cause human infections. H7N9 infections represent an ongoing public health threat that has resulted in 1344 cases with 511 deaths as of April 9, 2017. This highlights the continued threat posed by the current poultry trade and live poultry market system in China. Until now, there have been five H7N9 influenza epidemic waves in China; however, the steep increase in the number of humans infected with H7N9 viruses observed in the fifth wave, beginning in October 2016, the spread into western provinces, and the emergence of highly pathogenic (HP) H7N9 influenza outbreaks in chickens and infection in humans have caused domestic and international concern. In this review, we summarize and compare the different waves of H7N9 regarding their epidemiology, pathogenesis, evolution, and characteristic features, and speculate on factors behind the recent increase in the number of human cases and sudden outbreaks in chickens. The continuous evolution of the virus poses a long-term threat to public health and the poultry industry, and thus it is imperative to strengthen prevention and control strategies.

  • ‘Omic’ Approaches to Study Uropathogenic Escherichia coli Virulence
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-24
    Alvin W. Lo, Danilo G. Moriel, Minh-Duy Phan, Benjamin L. Schulz, Timothy J. Kidd, Scott A. Beatson, Mark A. Schembri

    Uropathogenic Escherichia coli (UPEC) is a pathogen of major significance to global human health and is strongly associated with rapidly increasing antibiotic resistance. UPEC is the primary cause of urinary tract infection (UTI), a disease that involves a complicated pathogenic pathway of extracellular and intracellular lifestyles during interaction with the host. The application of multiple ‘omic’ technologies, including genomics, transcriptomics, proteomics, and metabolomics, has provided enormous knowledge to our understanding of UPEC biology. Here we outline this progress and present a view for future developments using these exciting forefront technologies to fully comprehend UPEC pathogenesis in the context of infection.

  • Capsid-Dependent Host Factors in HIV-1 Infection
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-18
    Masahiro Yamashita, Alan N. Engelman

    After invasion of a susceptible target cell, HIV-1 completes the early phase of its life cycle upon integration of reverse-transcribed viral DNA into host chromatin. The viral capsid, a conical shell encasing the viral ribonucleoprotein complex, along with its constitutive capsid protein, plays essential roles at virtually every step in the early phase of the viral life cycle. Recent work has begun to reveal how the viral capsid interacts with specific cellular proteins to promote these processes. At the same time, cellular restriction factors target the viral capsid to thwart infection. Comprehensive understanding of capsid–host interactions that promote or impede HIV-1 infection may provide unique insight to exploit for novel therapeutic interventions.

  • Antimycobacterial Metabolism: Illuminating Mycobacterium tuberculosis Biology and Drug Discovery
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-13
    Divya Awasthi, Joel S. Freundlich

    Bacteria are capable of performing a number of biotransformations that may activate or deactivate xenobiotics. Recent efforts have utilized metabolomics techniques to study the fate of small-molecule antibacterials within the targeted organism. Examples involving Mycobacterium tuberculosis are reviewed and analyzed with regard to the insights they provide as to both activation and deactivation of the antibacterial. The studies, in particular, shed light on biosynthetic transformations performed by M. tuberculosis while suggesting avenues for the evolution of chemical tools, highlighting potential areas for drug discovery, and mechanisms of approved drugs. A two-pronged approach investigating the metabolism of antibacterials within both the host and bacterium is outlined and will be of value to both the chemical biology and drug discovery fields.

  • Protein Acetylation and Its Role in Bacterial Virulence
    Trends Microbiol. (IF 11.02) Pub Date : 2017-04-24
    Jie Ren, Yu Sang, Jie Lu, Yu-Feng Yao

    Protein acetylation is a universal post-translational modification which is found in both eukaryotes and prokaryotes. This process is achieved enzymatically by the protein acetyltransferase Pat, and nonenzymatically by metabolic intermediates (e.g., acetyl phosphate) in bacteria. Protein acetylation plays a role in bacterial chemotaxis, metabolism, DNA replication, and other cellular processes. Recently, accumulating evidence has suggested that protein acetylation might be involved in bacterial virulence because a number of bacterial virulence factors are acetylated. In this review, we summarize the progress in understanding bacterial protein acetylation and discuss how it mediates bacterial virulence.

  • Variation, Indispensability, and Masking in the M protein
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-31
    Partho Ghosh

    The M protein is the major surface-associated virulence factor of group A Streptococcus (GAS) and an antigenically variable target of host immunity. How selection pressures to escape immune recognition, maintain indispensable functions, and mask vulnerabilities have shaped the sequences of the >220 M protein types is unclear. Recent experiments have shed light on this question by showing that, hidden within the antigenic variability of many M protein types, are sequence patterns conserved for recruiting human C4b-binding protein (C4BP). Other host factors may be recruited in a similar manner by conserved but hidden sequence patterns in the M protein. The identification of such patterns may be applicable to the development of a GAS vaccine.

  • Bacterial Tubulins: A Eukaryotic-Like Microtubule Cytoskeleton
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-28
    Sylvain Trépout, Anne Marie Wehenkel

    Ever since their discovery, bacterial tubulins, found in several Prosthecobacter species, have raised curiosity as they are closely related to eukaryotic tubulin. Deng and colleagues now present new evidence for the functional homology of the two cytoskeletal systems where in vitro reconstituted Btub-microtubules display eukaryote-like biochemical and dynamic properties.

  • Phagocytes, Antibiotics, and Self-Limiting Bacterial Infections
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-24
    Bruce R. Levin, Fernando Baquero, Peter (Pierre) Ankomah, Ingrid C. McCall

    Most antibiotic use in humans is to reduce the magnitude and term of morbidity of acute, community-acquired infections in immune competent patients, rather than to save lives. Thanks to phagocytic leucocytes and other host defenses, the vast majority of these infections are self-limiting. Nevertheless, there has been a negligible amount of consideration of the contribution of phagocytosis and other host defenses in the research for, and the design of, antibiotic treatment regimens, which hyper-emphasizes antibiotics as if they were the sole mechanism responsible for the clearance of infections. Here, we critically review this approach and its limitations. With the aid of a heuristic mathematical model, we postulate that if the rate of phagocytosis is great enough, for acute, normally self-limiting infections, then (i) antibiotics with different pharmacodynamic properties would be similarly effective, (ii) low doses of antibiotics can be as effective as high doses, and (iii) neither phenotypic nor inherited antibiotic resistance generated during therapy are likely to lead to treatment failure.

  • Women and Their Microbes: The Unexpected Friendship
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-23
    Jessica A. Younes, Elke Lievens, Ruben Hummelen, Rebecca van der Westen, Gregor Reid, Mariya I. Petrova

    Communities of microbiota have been associated with numerous health outcomes, and while much emphasis has been placed on the gastrointestinal niche, there is growing interest in the microbiome specific for female reproductive health and the health of their offspring. The vaginal microbiome plays an essential role not only in health and dysbiosis, but also potentially in successful fertilization and healthy pregnancies. In addition, microbial communities have been isolated from formerly forbidden sterile niches such as the placenta, breast, uterus, and Fallopian tubes, strongly suggesting an additional microbial role in women’s health. A combination of maternally linked prenatal, birth, and postnatal factors, together with environmental and medical interventions, influence early and later life through the microbiome. Here, we review the role of microbes in female health focusing on the vaginal tract and discuss how male and female reproductive microbiomes are intertwined with conception and how mother–child microbial transfer is a key determinant in infant health, and thus the next generation.

  • Visualization of IAV Genomes at the Single-Cell Level
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-23
    Dan Wang, Wenjun Ma

    Different influenza A viruses (IAVs) infect the same cell in a host, and can subsequently produce new viruses through genome reassortment. By combining padlock probe RNA labeling with a single-cell analysis, a new approach effectively captures IAV genome trafficking and defines a time window for genome reassortment from same-cell coinfections.

  • Archaea Are Interactive Components of Complex Microbiomes
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-18
    Christine Moissl-Eichinger, Manuela Pausan, Julian Taffner, Gabriele Berg, Corinna Bang, Ruth A. Schmitz

    Recent findings have shaken our picture of the biology of the archaea and revealed novel traits beyond archaeal extremophily and supposed ‘primitiveness’. The archaea constitute a considerable fraction of the Earth’s ecosystems, and their potential to shape their surroundings by a profound interaction with their biotic and abiotic environment has been recognized. Moreover, archaea have been identified as a substantial component, or even as keystone species, in complex microbiomes – in the environment or accompanying a holobiont. Species of the Euryarchaeota (methanogens, halophiles) and Thaumarchaeota, in particular, have the capacity to coexist in plant, animal, and human microbiomes, where syntrophy allows them to thrive under energy-deficiency stress. Due to methodological limitations, the archaeome remains mysterious, and many questions with respect to potential pathogenicity, function, and structural interactions with their host and other microorganisms remain.

  • The HPV E6/E7 Oncogenes: Key Factors for Viral Carcinogenesis and Therapeutic Targets
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-17
    Karin Hoppe-Seyler, Felicitas Bossler, Julia A. Braun, Anja L. Herrmann, Felix Hoppe-Seyler

    Human papillomavirus (HPV)-induced cancers are expected to remain a major health problem worldwide for decades. The growth of HPV-positive cancer cells depends on the sustained expression of the viral E6 and E7 oncogenes which act in concert with still poorly defined cellular alterations. E6/E7 constitute attractive therapeutic targets since E6/E7 inhibition rapidly induces senescence in HPV-positive cancer cells. This cellular response is linked to the reconstitution of the antiproliferative p53 and pRb pathways, and to prosenescent mTOR signaling. Hypoxic HPV-positive cancer cells could be a major obstacle for treatment strategies targeting E6/E7 since they downregulate E6/E7 but evade senescence through hypoxia-induced mTOR impairment. Prospective E6/E7 inhibitors may therefore benefit from a combination with treatment strategies directed against hypoxic tumor cells.

  • Mechanisms of Hepatitis B Virus Persistence
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-16
    Kuen-Nan Tsai, Cheng-Fu Kuo, Jing-Hsiung James Ou

    Hepatitis B virus (HBV) chronically infects 250 million people worldwide, resulting in nearly one million deaths annually. Studies in recent years have significantly improved our knowledge on the mechanisms of HBV persistence. HBV uses multiple pathways to harness host innate immunity to enhance its replication. It can also take advantage of the developing immune system and the not-yet-stabilized gut microbiota of young children to facilitate its persistence, and use maternal viral e antigen to educate immunity of the offspring to support its persistence after vertical transmission. The knowledge gained from these recent studies paves the way for the development of new therapies for the treatment of chronic HBV infection, which has so far been very challenging.

  • Genomics and Ecology of Novel N2O-Reducing Microorganisms
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-10
    Sara Hallin, Laurent Philippot, Frank E. Löffler, Robert A. Sanford, Christopher M. Jones

    Microorganisms with the capacity to reduce the greenhouse gas nitrous oxide (N2O) to harmless dinitrogen gas are receiving increased attention due to increasing N2O emissions (and our need to mitigate climate change) and to recent discoveries of novel N2O-reducing bacteria and archaea. The diversity of denitrifying and nondenitrifying microorganisms with capacity for N2O reduction was recently shown to be greater than previously expected. A formerly overlooked group (clade II) in the environment include a large fraction of nondenitrifying N2O reducers, which could be N2O sinks without major contribution to N2O formation. We review the recent advances about fundamental understanding of the genomics, physiology, and ecology of N2O reducers and the importance of these findings for curbing N2O emissions.

  • Zika Virus Protease: An Antiviral Drug Target
    Trends Microbiol. (IF 11.02) Pub Date : 2017-08-05
    CongBao Kang, Thomas H. Keller, Dahai Luo

    The recent outbreak of Zika virus (ZIKV) infection has caused global concern due to its link to severe damage to the brain development of foetuses and neuronal complications in adult patients. A worldwide research effort has been undertaken to identify effective and safe treatment and vaccination options. Among the proposed viral and host components, the viral NS2B-NS3 protease represents an attractive drug target due to its essential role in the virus life cycle. Here, we outline recent progress in studies on the Zika protease. Biochemical, biophysical, and structural studies on different protease constructs provide new insight into the structure and activity of the protease. The unlinked construct displays higher enzymatic activity and better mimics the native state of the enzyme and therefore is better suited for drug discovery. Furthermore, the structure of the free enzyme adopts a closed conformation and a preformed active site. The availability of a lead fragment hit and peptide inhibitors, as well as the attainability of soakable crystals, suggest that the unlinked construct is a promising tool for drug discovery.

  • A Single Substitution Changes Zika Virus Infectivity in Mosquitoes
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-10
    Guan-Zhu Han

    Zika virus (ZIKV) has caused outbreaks in the Pacific and the Americas. The mechanism underlying the recent ZIKV epidemic remains obscure. A recent study reveals that an amino acid substitution is associated with increased infectivity of ZIKV in the Aedes aegypti mosquito.

  • What Does Not Kill You Makes You Stronger
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-26
    Miles T. Wetherington, Juan E. Keymer

    Colicin production is an extreme form of labor division; cells lyse after making the toxin! Stochastic phenotype switching allows producers to outcompete sensitive strains since colicin release frees up vacancy. If patch dynamics does not kill you, it stimulates adaptation to a dynamic habitat landscape which selects for rapid dispersal.

  • Micronutrient Deficiencies and the Human Gut Microbiota
    Trends Microbiol. (IF 11.02) Pub Date : 2017-06-20
    Núria Mach, Allison Clark

    Little is known about how micronutrient deficiencies affect the human gut microbiota. A study by Hibberd et al. illustrates how these deficiencies affect the composition and function of gut microbiota, and further, how different species realize changes in gene expression and cellular metabolism to cope with micronutrient shortages.

  • Microbiome-on-a-Chip: New Frontiers in Plant–Microbiota Research
    Trends Microbiol. (IF 11.02) Pub Date : 2017-05-24
    Claire E. Stanley, Marcel G.A. van der Heijden

    An enigmatic concoction of interactions between microbes and hosts takes place below ground, yet the function(s) of the individual components in this complex playground are far from understood. This Forum article highlights how microfluidic – or ‘Microbiome-on-a-Chip’ – technology could help to shed light on such relationships, opening new frontiers in plant–microbiota research.

  • Bacteria–Bacteriophage Coevolution in the Human Gut: Implications for Microbial Diversity and Functionality
    Trends Microbiol. (IF 11.02) Pub Date : 2017-03-22
    Pauline D. Scanlan

    Antagonistic coevolution (AC) between bacteria and bacteriophages plays a key role in driving and maintaining microbial diversity. Consequently, AC is predicted to affect all levels of biological organisation, from the individual to ecosystem scales. Nonetheless, we know nothing about bacteria–bacteriophage AC in perhaps the most important and clinically relevant microbial ecosystem known to humankind – the human gut microbiome. In this opinion piece I review current research on bacteria–phage AC in in vitro and natural populations of microbes. I then examine the evidence and discuss the potential role of AC in driving observed patterns of intra- and interindividual variation in the gut microbiome together with detailing the potential functional consequences of such AC-driven microbial variation for human health and disease.

  • Genome Surfing As Driver of Microbial Genomic Diversity
    Trends Microbiol. (IF 11.02) Pub Date : 2017-03-07
    Mallory J. Choudoir, Kevin Panke-Buisse, Cheryl P. Andam, Daniel H. Buckley

    Historical changes in population size, such as those caused by demographic range expansions, can produce nonadaptive changes in genomic diversity through mechanisms such as gene surfing. We propose that demographic range expansion of a microbial population capable of horizontal gene exchange can result in genome surfing, a mechanism that can cause widespread increase in the pan-genome frequency of genes acquired by horizontal gene exchange. We explain that patterns of genetic diversity within Streptomyces are consistent with genome surfing, and we describe several predictions for testing this hypothesis both in Streptomyces and in other microorganisms.

  • Cell Death Pathway That Monitors Spore Morphogenesis
    Trends Microbiol. (IF 11.02) Pub Date : 2017-04-10
    Amanda R. Decker, Kumaran S. Ramamurthi

    The use of quality control mechanisms to stall developmental pathways or completely remove defective cells from a population is a widespread strategy to ensure the integrity of morphogenetic programs. Endospore formation (sporulation) is a well conserved microbial developmental strategy in the Firmicutes phylum wherein a progenitor cell that faces starvation differentiates to form a dormant spore. Despite the conservation of this strategy, it has been unclear what selective pressure maintains the fitness of this developmental program, composed of hundreds of unique genes, during multiple rounds of vegetative growth when sporulation is not required. Recently, a quality control pathway was discovered in Bacillus subtilis which monitors the assembly of the spore envelope and specifically eliminates, through cell lysis, sporulating cells that assemble the envelope incorrectly. Here, we review the use of checkpoints that govern the entry into sporulation in B. subtilis and discuss how the use of regulated cell death pathways during bacterial development may help maintain the fidelity of the sporulation program in the species.

  • KSHV microRNAs: Tricks of the Devil
    Trends Microbiol. (IF 11.02) Pub Date : 2017-03-02
    Jie Qin, Wan Li, Shou-Jiang Gao, Chun Lu

    Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi’s sarcoma (KS), a vascular tumor frequently found in immunodeficient individuals. KSHV encodes 12 pre-microRNAs (pre-miRNAs), which are processed into 25 mature microRNAs (miRNAs). KSHV miRNAs maintain KSHV latency, enhance angiogenesis and dissemination of the infected cells, and interfere with the host immune system by regulating viral and cellular gene expression, ultimately contributing to KS development. In this review, we briefly introduce the biogenesis of miRNAs and then describe the recent advances in defining the roles and mechanisms of action of KSHV miRNAs in KS development.

  • Sweet New Roles for Protein Glycosylation in Prokaryotes
    Trends Microbiol. (IF 11.02) Pub Date : 2017-03-21
    Jerry Eichler, Michael Koomey

    Long-held to be a post-translational modification unique to Eukarya, it is now clear that both Bacteria and Archaea also perform protein glycosylation, namely the covalent attachment of mono- to polysaccharides to specific protein targets. At the same time, many of the roles assigned to this protein-processing event in eukaryotes, such as guiding protein folding/quality control, intracellular trafficking, dictating cellular recognition events and others, do not apply or are even irrelevant to prokaryotes. As such, protein glycosylation must serve novel functions in Bacteria and Archaea. Recent efforts have begun to elucidate some of these prokaryote-specific roles, which are addressed in this review.

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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