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1.  Unravelling the structural and mechanistic basis of CRISPR–Cas systems 
Nature reviews. Microbiology  2014;12(7):479-492.
Bacteria and archaea have evolved sophisticated adaptive immune systems, known as CRISPR–Cas (clustered regularly interspaced short palindromic repeats–CRISPR-associated proteins) systems, which target and inactivate invading viruses and plasmids. Immunity is acquired by integrating short fragments of foreign DNA into CRISPR loci, and following transcription and processing of these loci, the CRISPR RNAs (crRNAs) guide the Cas proteins to complementary invading nucleic acid, which results in target interference. In this Review, we summarize the recent structural and biochemical insights that have been gained for the three major types of CRISPR–Cas systems, which together provide a detailed molecular understanding of the unique and conserved mechanisms of RNA-guided adaptive immunity in bacteria and archaea.
doi:10.1038/nrmicro3279
PMCID: PMC4225775  PMID: 24909109
2.  Bacterial Programmed Cell Death: Making Sense of a Paradox 
Nature reviews. Microbiology  2014;12(1):63-69.
Although the concept of programmed cell death (PCD) in bacteria has been met with skepticism, a growing body of evidence suggests that it can no longer be ignored. Several recent studies indicate that the phenotypic manifestations of apoptosis, processes associated with ordered cellular disassembly, are conserved in bacteria. In this Opinion article, I propose a model for the coordinated control of potential bacterial PCD effectors, and argue that the processes involved are functionally analogous to eukaryotic PCD systems.
doi:10.1038/nrmicro3136
PMCID: PMC4422510  PMID: 24336185
3.  Novel functions of viral anti-apoptotic factors 
Nature reviews. Microbiology  2014;13(1):7-12.
Cellular apoptosis is of major importance in the struggle between virus and host. Although many viruses use various strategies to control the cell death machinery by encoding anti-apoptotic virulence factors, it is now becoming clear that, in addition to their role in inhibiting apoptosis, these factors function in multiple immune and metabolic pathways to promote fitness and pathogenesis. In this Progress article, we discuss novel functions of viral anti-apoptotic factors in the regulation of autophagy in the nuclear factor-κB (NF-κB) pathway and in interferon signalling, with a focus on persistent and oncogenic gammaherpesviruses. If viral anti-apoptotic proteins are to be properly exploited as targets for antiviral drugs, their diverse and complex roles should be considered.
doi:10.1038/nrmicro3369
PMCID: PMC4420620  PMID: 25363821
4.  POXVIRUS TROPISM 
Nature reviews. Microbiology  2005;3(3):201-213.
Despite the success of the WHO-led smallpox eradication programme a quarter of a century ago, there remains considerable fear that variola virus, or other related pathogenic poxviruses such as monkeypox, could re-emerge and spread disease in the human population. Even today, we are still mostly ignorant about why most poxvirus infections of vertebrate hosts show strict species specificity, or how zoonotic poxvirus infections occur when poxviruses occasionally leap into novel host species. Poxvirus tropism at the cellular level seems to be regulated by intracellular events downstream of virus binding and entry, rather than at the level of specific host receptors as is the case for many other viruses. This review summarizes our current understanding of poxvirus tropism and host range, and discusses the prospects of exploiting host-restricted poxvirus vectors for vaccines, gene therapy or tissue-targeted oncolytic viral therapies for the treatment of human cancers.
doi:10.1038/nrmicro1099
PMCID: PMC4382915  PMID: 15738948
6.  Rab11-mediated trafficking in host-pathogen interactions 
Nature reviews. Microbiology  2014;12(9):624-634.
doi:10.1038/nrmicro3325
PMCID: PMC4274738  PMID: 25118884
7.  The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells 
Nature reviews. Microbiology  2014;12(3):159-167.
For the successful treatment of pulmonary tuberculosis, drugs need to penetrate complex lung lesions and permeate the mycobacterial cell wall in order to reach their intracellular targets. However, most currently used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic and pharmacodynamic properties that influence drug distribution, and this has contributed to the long duration and limited success of current therapies. In this Progress article, I describe new methods to quantify and image drug distribution in infected lung tissue and in mycobacterial cells, and I explore how this technology could be used to design optimized multidrug regimens.
doi:10.1038/nrmicro3200
PMCID: PMC4341982  PMID: 24487820
8.  Dengue: a continuing global threat 
Nature reviews. Microbiology  2010;8(12 0):S7-16.
Dengue fever and dengue haemorrhagic fever are important arthropod-borne viral diseases. Each year, there are ~50 million dengue infections and ~500,000 individuals are hospitalized with dengue haemorrhagic fever, mainly in Southeast Asia, the Pacific and the Americas. Illness is produced by any of the four dengue virus serotypes. A global strategy aimed at increasing the capacity for surveillance and outbreak response, changing behaviours and reducing the disease burden using integrated vector management in conjunction with early and accurate diagnosis has been advocated. Antiviral drugs and vaccines that are currently under development could also make an important contribution to dengue control in the future.
doi:10.1038/nrmicro2460
PMCID: PMC4333201  PMID: 21079655
9.  Animal models for HIV/AIDS research 
Nature reviews. Microbiology  2012;10(12):852-867.
The AIDS pandemic continues to present us with unique scientific and public health challenges. Although the development of effective antiretroviral therapy has been a major triumph, the emergence of drug resistance requires active management of treatment regimens and the continued development of new antiretroviral drugs. Moreover, despite nearly 30 years of intensive investigation, we still lack the basic scientific knowledge necessary to produce a safe and effective vaccine against HIV-1. Animal models offer obvious advantages in the study of HIV/AIDS, allowing for a more invasive investigation of the disease and for preclinical testing of drugs and vaccines. Advances in humanized mouse models, non-human primate immunogenetics and recombinant challenge viruses have greatly increased the number and sophistication of available mouse and simian models. Understanding the advantages and limitations of each of these models is essential for the design of animal studies to guide the development of vaccines and antiretroviral therapies for the prevention and treatment of HIV-1 infection.
doi:10.1038/nrmicro2911
PMCID: PMC4334372  PMID: 23154262
10.  Exploring bacterial cell biology with single-molecule tracking and super-resolution imaging 
Nature reviews. Microbiology  2014;12(1):9-22.
The ability to detect single molecules in live bacterial cells enables us to probe biological events one molecule at a time and thereby gain knowledge of the activities of intracellular molecules that remain obscure in conventional ensemble-averaged measurements. Single-molecule fluorescence tracking and super-resolution imaging are thus providing a new window into bacterial cells and facilitating the elucidation of cellular processes at an unprecedented level of sensitivity, specificity and spatial resolution. In this Review, we consider what these technologies have taught us about the bacterial cytoskeleton, nucleoid organization and the dynamic processes of transcription and translation, and we also highlight the methodological improvements that are needed to address a number of experimental challenges in the field.
doi:10.1038/nrmicro3154
PMCID: PMC3934628  PMID: 24336182
11.  Motility and more: the flagellum of Trypanosoma brucei 
Nature reviews. Microbiology  2014;12(7):505-518.
A central feature of trypanosome cell biology and life cycle is the parasite’s single flagellum, which is an essential and multifunctional organelle involved in cell propulsion, morphogenesis and cytokinesis. The flagellar membrane is also a specialized subdomain of the cell surface that harbors multiple parasite virulence factors with roles in signaling and host-parasite interactions. In this review, we discuss the structure, assembly and function of the trypanosome flagellum, including canonical roles in cell motility as well as novel and emerging roles in cell morphogenesis and host-parasite interaction.
doi:10.1038/nrmicro3274
PMCID: PMC4278896  PMID: 24931043
12.  Type VI secretion effectors: poisons with a purpose 
Nature reviews. Microbiology  2014;12(2):137-148.
The type VI secretion system (T6SS) mediates interactions between a diverse range of Gram-negative bacterial species. Recent studies have led to a drastic increase in the number of characterized T6SS effector proteins and produced a more complete and nuanced view of the adaptive significance of the system. While the system is most often implicated in antagonism, in this review we consider the case for its involvement in both antagonistic and non-antagonistic behaviors. Clarifying the roles that T6S plays in microbial communities will contribute to broader efforts to understand the importance of microbial interactions in maintaining human and environmental health, and will inform efforts to manipulate these interactions for therapeutic or environmental benefit.
doi:10.1038/nrmicro3185
PMCID: PMC4256078  PMID: 24384601
13.  Novel vaccine vectors for HIV-1 
Nature reviews. Microbiology  2014;12(11):765-771.
The ultimate solution to the global HIV-1 epidemic will probably require the development of a safe and effective vaccine. Multiple vaccine platforms have been evaluated in both preclinical and clinical trials, but, given the disappointing results of the clinical efficacy studies so far, novel vaccine approaches are needed. In this Opinion article, we discuss the scientific basis and clinical potential of novel adenovirus and cytomegalovirus vaccine vectors for HIV-1 as two contrasting, but potentially complementary, vector approaches. Both of these vector platforms have demonstrated partial protection against stringent simian immunodeficiency virus challenges in rhesus monkeys using different immunological mechanisms.
doi:10.1038/nrmicro3360
PMCID: PMC4237164  PMID: 25296195
14.  Tackling antibiotic resistance 
Nature reviews. Microbiology  2011;9(12):894-896.
The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable, but can nevertheless be controlled and must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of thirty scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, May 16-18, 2011. From these discussions emerged a priority list of steps that need to be taken to resolve this global crisis.
doi:10.1038/nrmicro2693
PMCID: PMC4206945  PMID: 22048738
15.  Bordetella pertussis pathogenesis: current and future challenges 
Nature reviews. Microbiology  2014;12(4):274-288.
Pertussis, or whooping cough, has recently reemerged as a major public health threat despite high levels of vaccination against the etiological agent, Bordetella pertussis. In this Review, we describe the pathogenesis of this disease, with a focus on recent mechanistic insights into virulence factor function. We also discuss the changing epidemiology of pertussis and the challenges of vaccine development. Despite decades of research, many aspects of B. pertussis physiology and pathogenesis remain poorly understood. We highlight knowledge gaps that must be addressed to develop improved vaccines and therapeutic strategies.
doi:10.1038/nrmicro3235
PMCID: PMC4205565  PMID: 24608338
16.  The Cryptic Sexual Strategies of Human Fungal Pathogens 
Nature reviews. Microbiology  2014;12(4):239-251.
doi:10.1038/nrmicro3236
PMCID: PMC4102497  PMID: 24625892
17.  The spectrum of latent tuberculosis: rethinking the goals of prophylaxis 
Nature reviews. Microbiology  2009;7(12):845-855.
Immunological tests provide evidence of latent tuberculosis in one third of the global population, more than two billion individuals. Latent tuberculosis is defined by the absence of clinical symptoms but carries a risk of subsequent progression to clinical disease, particularly in the context of co-infection with HIV. Here we discuss the biology of latent tuberculosis as part of a broad spectrum of responses that occur following infection with Mycobacterium tuberculosis, resulting in formation of a range of physiologically distinct granulomatous lesions that provide environments with differential ability to support or suppress persistence of viable bacteria. We go on to show how this model can be used to inform a rational programme to discover drugs that will be effective in the eradication of M. tuberculosis infection.
doi:10.1038/nrmicro2236
PMCID: PMC4144869  PMID: 19855401
18.  Rethinking vector immunology: the role of environmental temperature in shaping resistance 
Nature reviews. Microbiology  2012;10(12):869-876.
Recent ecological research has revealed that environmental factors can strongly affect insect immunity and influence the outcome of host–parasite interactions. To date, however, most studies examining immune function in mosquitoes have ignored environmental variability. We argue that one such environmental variable, temperature, influences both vector immunity and the parasite itself. As temperatures in the field can vary greatly from the ambient temperature in the laboratory, it will be essential to take temperature into account when studying vector immunology.
doi:10.1038/nrmicro2900
PMCID: PMC4142813  PMID: 23147703
19.  Molecular pathogenesis of the obligate intracellular bacterium Coxiella burnetii 
Nature reviews. Microbiology  2013;11(8):561-573.
The agent of Q fever, Coxiella burnetii, is an obligate intracellular bacterium that causes acute and chronic infections. The study of C. burnetii pathogenesis has benefited from two recent fundamental advances: improved genetic tools and the ability to grow the bacterium in extracellular media. In this Review, we describe how these recent advances have improved our understanding of C. burnetii invasion and host cell modulation, including the formation of replication-permissive Coxiella-containing vacuoles. Furthermore, we describe the Dot/Icm (defect in organelle trafficking/intracellular multiplication) system, which is used by C. burnetii to secrete a range of effector proteins into the host cell, and we discuss the role of these effectors in remodelling the host cell.
doi:10.1038/nrmicro3049
PMCID: PMC4134018  PMID: 23797173
20.  The changing face of pathogen discovery and surveillance 
Nature reviews. Microbiology  2013;11(2):133-141.
The pace of pathogen discovery is increasing dramatically. This reflects not only factors that enable the appearance and globalization of new microbial infections but also improvements in methods for ascertainment. New molecular diagnostic platforms; investments in pathogen surveillance in wildlife, domestic animals and humans; and the advent of social media tools that mine the world wide web for clues to outbreaks of infectious disease are proving invaluable in early recognition of threats to public health. Additionally, models of microbial pathogenesis are becoming more complex, providing insights into the mechanisms by which microorganisms can contribute to chronic illnesses like cancer, peptic ulcer disease and mental illness. Here we review the contributions of each of these elements to infectious disease emergence and strategies for addressing the challenges of pathogen surveillance and discovery.
doi:10.1038/nrmicro2949
PMCID: PMC4098826  PMID: 23268232
21.  New viruses for cancer therapy: meeting clinical needs 
Nature reviews. Microbiology  2013;12(1):23-34.
Early-stage clinical trials of oncolytic virotherapy have reported the safety of several virus platforms, and viruses from three families have progressed to advanced efficacy trials. In addition, preclinical studies have established proof-of-principle for many new genetic engineering strategies. Thus, the virotherapy field now has available a diverse collection of viruses that are equipped to address unmet clinical needs owing to improved systemic administration, greater tumour specificity and enhanced oncolytic efficacy. The current key challenge for the field is to develop viruses that replicate with greater efficiency within tumours while achieving therapeutic synergy with currently available treatments.
doi:10.1038/nrmicro3140
PMCID: PMC4002503  PMID: 24292552
22.  Molecular mechanisms of varicella zoster virus pathogenesis 
Nature reviews. Microbiology  2014;12(3):197-210.
Varicella zoster virus (VZV) is the causative agent of varicella (chickenpox) and zoster (shingles). Investigating VZV pathogenesis is challenging as VZV is a human-specific virus and infection does not occur, or is highly restricted, in other species. However, the use of human tissue xenografts in mice with severe combined immunodeficiency (SCID) enables the analysis of VZV infection in differentiated human cells in their typical tissue microenvironment. Xenografts of human skin, dorsal root ganglia or foetal thymus that contains T cells can be infected with mutant viruses or in the presence of inhibitors of viral or cellular functions to assess the molecular mechanisms of VZV–host interactions. In this Review, we discuss how these models have improved our understanding of VZV pathogenesis.
doi:10.1038/nrmicro3215
PMCID: PMC4066823  PMID: 24509782
23.  SYSTEMS VIROLOGY: HOST-DIRECTED APPROACHES TO VIRAL PATHOGENESIS AND DRUG TARGETING 
Nature reviews. Microbiology  2013;11(7):455-466.
Preface
High-throughput molecular profiling and computational biology are changing the face of virology, providing a new appreciation of the importance of the host in viral pathogenesis and offering unprecedented opportunities for better diagnostics, therapeutics and vaccines. Here, we provide a snapshot of the evolution of systems virology, from global gene expression profiling and signatures of disease outcome, to geometry-based computational methods that promise to yield novel therapeutic targets, personalized medicine and adeeper understanding of how viruses cause disease. To realize these goals, pipets and petri dishes need to join forces with the powers of mathematics and computational biology.
doi:10.1038/nrmicro3036
PMCID: PMC4028060  PMID: 23728212
24.  The molecular mechanisms and physiological consequences of oxidative stress: lessons from a model bacterium 
Nature reviews. Microbiology  2013;11(7):443-454.
Oxic environments are hazardous. Molecular oxygen adventitiously abstracts electrons from many redox enzymes, continuously forming intracellular superoxide and hydrogen peroxide. These species can destroy the activities of metalloenzymes and the integrity of DNA, which forces organisms to protect themselves with scavenging enzymes and repair systems. Nevertheless, elevated levels of oxidants quickly poison bacteria, and both microbial competitors and hostile eukaryotic hosts exploit this vulnerability by assaulting them with peroxides or superoxide-forming antibiotics. In response, bacteria activate elegant adaptive strategies. In this Review, I summarize our current knowledge of oxidative stress in Escherichia coli, the model organism for which our understanding of damage and defence is most well-developed.
doi:10.1038/nrmicro3032
PMCID: PMC4018742  PMID: 23712352
25.  How glycan metabolism shapes the human gut microbiota 
Nature reviews. Microbiology  2012;10(5):323-335.
Preface
Symbiotic microorganisms that reside in the human intestine are adept at foraging glycans and polysaccharides, including those in dietary plants (starch, hemicellulose, pectin), animal-derived cartilage and tissue (glycosaminoglycans and N-linked glycans), and endogenous glycans from host mucus (O-linked glycans). Fluctuations in the abundance of dietary and endogenous glycans, combined with the immense chemical variation among these molecules, create a dynamic and heterogeneous environment in which gut microorganisms proliferate. In this review, we describe how glycans shape the composition of the gut microbiota over various lengths of time, the mechanisms by which individual microorganisms degrade these glycans, and potential opportunities to intentionally influence this ecosystem for better health and nutrition.
doi:10.1038/nrmicro2746
PMCID: PMC4005082  PMID: 22491358

Results 1-25 (141)