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Letter to the Editor
Letter to the Editor | Host-Microbe BiologyGenomics and Chlamydial Persistence In Vivo
Author Reply
Author Reply | Host-Microbe BiologyReply to Rockey et al., “Genomics and Chlamydial Persistence In Vivo”
Opinion/Hypothesis
Opinion/Hypothesis | Therapeutics and PreventionEvolving Antibiotics against Resistance: a Potential Platform for Natural Product Development?To avoid an antibiotic resistance crisis, we need to develop antibiotics at a pace that matches the rate of evolution of resistance. However, the complex functions performed by antibiotics—combining, e.g., penetration of membranes, counteraction of resistance mechanisms, and interaction with molecular targets—have proven hard to achieve with current methods for drug development, including target-based screening and rational design....
Minireview
Minireview | Host-Microbe BiologyVomocytosis: Too Much Booze, Base, or Calcium?Macrophages are well known for their phagocytic activity and their role in innate immune responses. Macrophages eat non-self particles, via a variety of mechanisms, and typically break down internalized cargo into small macromolecules. However, some pathogenic agents have the ability to evade this endosomal degradation through a nonlytic exocytosis process termed vomocytosis.
Observations
Observation | Host-Microbe BiologyIntracellular Mycobacterium leprae Utilizes Host Glucose as a Carbon Source in Schwann CellsLeprosy remains a major problem in the world today, particularly affecting the poorest and most disadvantaged sections of society in the least developed countries of the world. The long-term aim of research is to develop new treatments and vaccines, and these aims are currently hampered by our inability to grow the pathogen in axenic culture. In this study, we probed the metabolism of...
Observation | Molecular Biology and PhysiologyCell Cycle-Dependent Flagellar Disassembly in a Firebug Trypanosomatid Leptomonas pyrrhocorisCurrent understanding of flagellum biogenesis during the cell cycle in trypanosomatids is limited to a few pathogenic species, including Trypanosoma brucei, Trypanosoma cruzi, and Leishmania spp. The most notable characteristics of trypanosomatid flagella studied so far are the extreme...
Observation | Molecular Biology and PhysiologyQuantitative Visualization of Gene Expression in Mucoid and Nonmucoid Pseudomonas aeruginosa Aggregates Reveals Localized Peak Expression of Alginate in the Hypoxic ZoneA goal for microbial ecophysiological research is to reveal microbial activities in natural environments, including sediments, soils, or infected human tissues. Here, we report the application of the hybridization chain reaction (HCR) v3.0 to quantitatively measure microbial gene expression in situ at single-cell resolution in bacterial aggregates. Using quantitative image analysis of thousands of...
Research Articles
Research Article | Host-Microbe BiologyReprogramming of Small Noncoding RNA Populations in Peripheral Blood Reveals Host Biomarkers for Latent and Active Mycobacterium tuberculosis InfectionTuberculosis is the infectious disease with the worldwide largest disease burden and there remains a great need for better diagnostic biomarkers to detect latent and active M. tuberculosis infection. RNA molecules hold great promise in this regard, as their levels of expression may differ considerably between infected and uninfected subjects. We have measured...
Research Article | Clinical Science and EpidemiologyEvolution and Global Transmission of a Multidrug-Resistant, Community-Associated Methicillin-Resistant Staphylococcus aureus Lineage from the Indian SubcontinentThe Bengal Bay clone (ST772) is a community-associated and multidrug-resistant Staphylococcus aureus lineage first isolated from Bangladesh and India in 2004. In this study, we showed that the Bengal Bay clone emerged from a virulent progenitor circulating on the Indian subcontinent. Its subsequent global transmission was associated with travel or family contact in...
Research Article | Molecular Biology and PhysiologyThe Toxin-Antitoxin MazEF Drives Staphylococcus aureus Biofilm Formation, Antibiotic Tolerance, and Chronic InfectionSurgical infections are one of the most common types of infections encountered in a hospital. Staphylococcus aureus is the most common pathogen associated with this infection. These infections are resilient and difficult to eradicate, as the bacteria form biofilm, a community of bacteria held together by an extracellular matrix. Compared to bacteria that are...
Research Article | Host-Microbe BiologyChanges in Aphid Host Plant Diet Influence the Small-RNA Expression Profiles of Its Obligate Nutritional Symbiont, BuchneraIn general, the genomes of intracellular bacterial symbionts are reduced compared to those of free-living relatives and lack many key regulatory genes. Many of these reduced genomes belong to obligate mutualists of insects that feed on a diet that is deficient in essential nutrients, such as essential amino acids. It is unclear if these symbionts respond with their host to changes in insect diet, because of their reduced regulatory...
Research Article | Molecular Biology and PhysiologyEmbryonic Cells Redistribute SUMO1 upon Forced SUMO1 OverexpressionEmbryonic stem (ES) cells exhibit unusual transcriptional, proteomic, and signal response profiles, reflecting their unusual needs for rapid differentiation and replication. The work reported here demonstrated that mouse embryonic cell lines did not tolerate the overexpression of SUMO1, the small ubiquitin-like modifier protein that is covalently attached to many substrates to alter their intracellular localization and functionality....
Research Article | Applied and Environmental ScienceDNA- and RNA-SIP Reveal Nitrospira spp. as Key Drivers of Nitrification in Groundwater-Fed BiofiltersWith this study we provide the first in situ evidence of ecologically relevant ammonia oxidation by comammox Nitrospira in a complex microbiome and document an unexpectedly high H13CO3− uptake and growth of proteobacterial and acidobacterial taxa under ammonia selectivity. This finding raises the question of whether comammox Nitrospira is an equally important ammonia oxidizer...
Research Article | Host-Microbe BiologyPaternal Grandmother Age Affects the Strength of Wolbachia-Induced Cytoplasmic Incompatibility in Drosophila melanogasterUnidirectional cytoplasmic incompatibility (CI) results in a postfertilization incompatibility between Wolbachia-infected males and uninfected females. CI contributes to reproductive isolation between closely related species and is used in worldwide vector control programs to drastically lower arboviral vector population sizes or to replace populations that transmit arboviruses with those resistant to transmission. Despite...
Editor's Pick Research Article | Therapeutics and PreventionA Mechanosensitive Channel Governs Lipid Flippase-Mediated Echinocandin Resistance in Cryptococcus neoformansCryptococcus neoformans is the leading cause of fungal meningitis, accounting for ∼15% of HIV/AIDS-related deaths, but treatment options for cryptococcosis are limited. Echinocandins are the newest fungicidal drug class introduced but are ineffective in treating cryptococcosis. Our previous study identified the lipid flippase subunit Cdc50 as a contributor to...
Research Article | Ecological and Evolutionary SciencePopulation Structure and Genetic Diversity among Isolates of Coccidioides posadasii in Venezuela and Surrounding RegionsValley Fever is a fungal disease caused by two species of fungi: Coccidioides immitis and C. posadasii. These fungi are found throughout the arid regions of North and South America; however, our understanding of genetic diversity and disease in South America is limited. In this report, we analyze 10 new genomes of Coccidioides posadasii from regions...
Editor's Pick Research Article | Host-Microbe BiologyBacteriophage Adherence to Mucus Mediates Preventive Protection against Pathogenic BacteriaThe mucosal surfaces of animals are habitat for microbes, including viruses. Bacteriophages—viruses that infect bacteria—were shown to be able to bind to mucus. This may result in a symbiotic relationship in which phages find bacterial hosts to infect, protecting the mucus-producing animal from bacterial infections in the process. Here, we studied phage binding on mucus and the effect of mucin on phage-bacterium interactions. The...
Research Article | Host-Microbe BiologyThe Metabolite Repair Enzyme Phosphoglycolate Phosphatase Regulates Central Carbon Metabolism and Fosmidomycin Sensitivity in Plasmodium falciparumThe malaria parasite has a voracious appetite, requiring large amounts of glucose and nutrients for its rapid growth and proliferation inside human red blood cells. The host cell is resource rich, but this is a double-edged sword; nutrient excess can lead to undesirable metabolic reactions and harmful by-products. Here, we demonstrate that the parasite possesses a metabolite repair enzyme (PGP) that suppresses harmful metabolic by-...
Research Article | Host-Microbe BiologyThe Human Cytomegalovirus Nonstructural Glycoprotein UL148 Reorganizes the Endoplasmic ReticulumPerturbations to endoplasmic reticulum (ER) morphology occur during infection with various intracellular pathogens and in certain genetic disorders. We identify that a human cytomegalovirus (HCMV) gene product, UL148, profoundly reorganizes the ER during infection and is sufficient to do so when expressed on its own. Our results reveal that UL148-dependent reorganization of the ER is a prominent feature of HCMV-infected cells. Moreover...
Research Article | Ecological and Evolutionary ScienceIntegrative Activity of Mating Loci, Environmentally Responsive Genes, and Secondary Metabolism Pathways during Sexual Development of Chaetomium globosumFungal diversity has amazed evolutionary biologists for decades. One societally important aspect of this diversity manifests in traits that enable pathogenicity. The opportunistic pathogen Chaetomium globosum is well adapted to a high-humidity environment and produces numerous secondary metabolites that defend it from predation. Many of these chemicals can threaten...
Research Article | Applied and Environmental ScienceUnusual Metabolism and Hypervariation in the Genome of a Gracilibacterium (BD1-5) from an Oil-Degrading CommunityCPR bacteria are generally predicted to be symbionts due to their extensive biosynthetic deficits. Although monophyletic, they are not monolithic in terms of their lifestyles. The organism described here appears to have evolved an unusual metabolic platform not reliant on glucose or pentose sugars. Its biology appears to be centered around bacterial host-derived compounds and/or cell detritus. Amino acids likely provide building blocks...
Research Article | Host-Microbe BiologyTranslational Regulation Promotes Oxidative Stress Resistance in the Human Fungal Pathogen Cryptococcus neoformansFungal survival in a mammalian host requires the coordinated expression and downregulation of a large cohort of genes in response to cellular stresses. Initial infection with C. neoformans occurs in the lungs, where it interacts with host macrophages. Surviving macrophage-derived cellular stresses, such as the production of reactive oxygen and nitrogen species, is...
Research Article | Host-Microbe BiologyA Heat-Killed Cryptococcus Mutant Strain Induces Host Protection against Multiple Invasive Mycoses in a Murine Vaccine ModelInvasive fungal infections kill more than 1.5 million people each year, with limited treatment options. There is no vaccine available in clinical use to prevent and control fungal infections. Our recent studies showed that a mutant of the F-box protein Fbp1, a subunit of the SCF(Fbp1) E3 ligase in Cryptococcus neoformans, elicited superior protective Th1 host immunity...
Research Article | Applied and Environmental ScienceGene Regulation Shifts Shed Light on Fungal Adaption in Plant Biomass DecomposersFungi dominate the turnover of wood, Earth’s largest pool of aboveground terrestrial carbon. Fungi first evolved this capacity by degrading lignin to access and hydrolyze embedded carbohydrates (white rot). Multiple lineages, however, adapted faster reactive oxygen species (ROS) pretreatments to loosen lignocellulose and selectively extract sugars (brown rot). This brown rot “shortcut” often coincided with losses (>60%) of...
Research Article | Molecular Biology and PhysiologyControl of Bacillus subtilis Replication Initiation during Physiological Transitions and PerturbationsHigh-throughput, quantitative approaches have enabled the discovery of fundamental principles describing bacterial physiology. These principles provide a foundation for predicting the behavior of biological systems, a widely held aspiration. However, these approaches are often exclusively applied to the best-known model organism, E. coli. In this report, we...
Research Article | Ecological and Evolutionary ScienceDiversity in lac Operon Regulation among Diverse Escherichia coli Isolates Depends on the Broader Genetic Background but Is Not Explained by Genetic RelatednessThe lac operon of Escherichia coli is a classic model for studying gene regulation. This study has uncovered features such as the environmental input logic controlling gene expression, as well as gene expression bistability and hysteresis. Most lac operon studies have focused on a few lab strains, and it is not known how generally those findings...
Research Article | Host-Microbe BiologyHost-Microbe Interactions in the Chemosynthetic Riftia pachyptila SymbiosisAll animals are associated with microorganisms; hence, host-microbe interactions are of fundamental importance for life on earth. However, we know little about the molecular basis of these interactions. Therefore, we studied the deep-sea Riftia pachyptila symbiosis, a model association in which the tubeworm host is associated with only one phylotype of endosymbiotic bacteria and completely depends on this sulfur-oxidizing...
Research Article | Therapeutics and PreventionThe Aminoalkylindole BML-190 Negatively Regulates Chitosan Synthesis via the Cyclic AMP/Protein Kinase A1 Pathway in Cryptococcus neoformansCryptococcus neoformans is a fungal pathogen that kills ∼200,000 people every year. The cell wall is an essential organelle that protects fungi from the environment. Chitosan, the deacetylated form of chitin, has been shown to be an essential component of the cryptococcal cell wall during infection of a mammalian host. In this study, we screened a set of 480 compounds...
Research Article | Host-Microbe BiologyStaphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during InfectionCaspase-3 controls the apoptotic pathway, a form of programmed cell death designed to be immunologically silent. Polymorphisms leading to reduced caspase-3 activity are associated with variable effects on tumorigenesis and yet arise frequently. Staphylococcus aureus is a human commensal and a frequent cause of soft tissue and bloodstream infections. Successful...
Research Article | Molecular Biology and PhysiologyMycobacterial OtsA Structures Unveil Substrate Preference Mechanism and Allosteric Regulation by 2-Oxoglutarate and 2-PhosphoglycerateMycobacterial infections are a significant source of mortality worldwide, causing millions of deaths annually. Trehalose is a multipurpose disaccharide that plays a fundamental structural role in these organisms as a component of mycolic acids, a molecular hallmark of the cell envelope of mycobacteria. Here, we describe the first mycobacterial OtsA structures. We show mechanisms of substrate preference and show that OtsA is regulated...
Research Article | Therapeutics and PreventionMultidrug Resistance in Neisseria gonorrhoeae: Identification of Functionally Important Residues in the MtrD Efflux ProteinWith over 78 million new infections globally each year, gonorrhea remains a frustratingly common infection. Continuous development and spread of antimicrobial-resistant strains of Neisseria gonorrhoeae, the causative agent of gonorrhea, have posed a serious threat to public health. One of the mechanisms in...
Research Article | Host-Microbe BiologyCharacteristics of Wetting-Induced Bacteriophage Blooms in Biological Soil CrustThis work forms part of an overarching research theme studying the effects of a changing climate on biological soil crust (biocrust) in the Southwestern United States. To our knowledge, this study was the first to characterize bacteriophages in biocrust and offers a view into the ecology of phages in response to a laboratory wetting experiment. The phages identified here represent lineages of Caudovirales, and we found that the...
Research Article | Host-Microbe BiologyThe Immune Protein Calprotectin Impacts Clostridioides difficile Metabolism through Zinc LimitationClostridioides difficile infection (CDI) is the leading cause of postantibiotic nosocomial infection. Antibiotic therapy can be successful, yet up to one-third of individuals suffer from recurrent infections. Understanding the mechanisms controlling C. difficile colonization is paramount in...
Research Article | Ecological and Evolutionary ScienceA New Lineage of Cryptococcus gattii (VGV) Discovered in the Central Zambezian Miombo WoodlandsCryptococcus gattii is an environmental pathogen that causes severe systemic infection in immunocompetent individuals more often than in immunocompromised humans. Over the past 2 decades, researchers have shown that C. gattii falls within four genetically distinct major lineages. By combining field...
Research Article | Host-Microbe BiologyIdentification of Key Determinants of Staphylococcus aureus Vaginal ColonizationStaphylococcus aureus is an opportunistic pathogen able to cause a wide variety of infections in humans. Recent reports have suggested an increasing prevalence of MRSA in pregnant and postpartum women, coinciding with the increased incidence of MRSA infections in neonatal intensive care units (NICUs) and newborn nurseries. Vertical transmission from mothers to infants...
Research Article | Host-Microbe BiologyIntestinal IgA Regulates Expression of a Fructan Polysaccharide Utilization Locus in Colonizing Gut Commensal Bacteroides thetaiotaomicronGiven the significant impact that gut microbes have on our health, it is essential to identify key host and environmental factors that shape this diverse community. While many studies have highlighted the impact of diet on gut microbiota, little is known about how the host regulates this critical diet-microbiota interaction. In our present study, we discovered that gut IgA targeted a protein complex involved in the utilization of an...
Editor's Pick Research Article | Host-Microbe BiologyA Novel Neuraminidase-Dependent Hemagglutinin Cleavage Mechanism Enables the Systemic Spread of an H7N6 Avian Influenza VirusThe identification of virulence markers in influenza viruses underpins risk assessment programs and the development of novel therapeutics. The cleavage of the influenza virus HA is a required step in the viral life cycle, and phenotypic differences in viruses can be caused by changes in this process. Here, we describe a novel mechanism for HA cleavage in an H7N6 influenza virus isolated from a mallard duck. The mechanism requires the N6...
Research Article | Clinical Science and EpidemiologyHigh-Risk International Clones of Carbapenem-Nonsusceptible Pseudomonas aeruginosa Endemic to Indonesian Intensive Care Units: Impact of a Multifaceted Infection Control Intervention Analyzed at the Genomic LevelIn low-to-middle-income countries such as Indonesia, work in intensive care units (ICUs) can be hampered by lack of resources. Conducting large epidemiological studies in such settings using genomic tools is rather challenging. Still, we were able to systematically study the transmissions of carbapenem-nonsusceptible strains of P. aeruginosa (CNPA) within and between...
Research Article | Host-Microbe BiologyCause and Effectors: Whole-Genome Comparisons Reveal Shared but Rapidly Evolving Effector Sets among Host-Specific Plant-Castrating FungiPlant pathogens use molecular weapons to successfully infect their hosts, secreting a large portfolio of various proteins and enzymes. Different plant species are often parasitized by host-specific pathogens; however, it is still unclear whether the molecular basis of such host specialization involves species-specific weapons or different variants of the same weapons. We therefore compared the genes encoding secreted proteins in three...
Research Article | Clinical Science and EpidemiologyA Single Salt Bridge in VIM-20 Increases Protein Stability and Antibiotic Resistance under Low-Zinc ConditionsAntibiotic resistance is a growing clinical threat. One of the most serious areas of concern is the ability of some bacteria to degrade carbapenems, drugs that are often reserved as last-resort antibiotics. Resistance to carbapenems can be conferred by a large group of related enzymes called metallo-β-lactamases that rely on zinc ions for function and for overall stability. Here, we studied an extensive panel of 45 different metallo-β-...
Research Article | Host-Microbe BiologyActivation of RNase L in Egyptian Rousette Bat-Derived RoNi/7 Cells Is Dependent Primarily on OAS3 and Independent of MAVS SignalingMany RNA viruses that are highly pathogenic in humans are relatively apathogenic in their bat reservoirs, making it important to compare innate immune responses in bats to those well characterized in humans. One such antiviral response is the OAS-RNase L pathway. OASs, upon sensing dsRNA, produce 2-5A, leading to activation of RNase L which degrades viral and host RNA, limiting viral replication. Analysis of Egyptian Rousette bat...
Research Article | Molecular Biology and PhysiologyMeasles Virus Ribonucleoprotein Complexes Rapidly Spread across Well-Differentiated Primary Human Airway Epithelial Cells along F-Actin RingsThe ability of viral particles to directly spread cell to cell within the airways without particle release is considered to be highly advantageous to many respiratory viruses. Our previous studies in well-differentiated, primary human airway epithelial cells suggest that measles virus (MeV) spreads cell to cell by eliciting the formation of intercellular membrane pores. Based on a newly generated ribonucleoprotein complex (RNP) “tracker...
Research Article | Molecular Biology and PhysiologyMining the Methylome Reveals Extensive Diversity in Staphylococcus epidermidis Restriction ModificationStaphylococcus epidermidis is a major cause of hospital-acquired infections, especially those related to implanted medical devices. Understanding how S. epidermidis causes disease and devising ways to combat these infections have been hindered by an inability to genetically manipulate clinically...
Research Article | Host-Microbe BiologyCell-to-Cell Spreading of HIV-1 in Myeloid Target Cells Escapes SAMHD1 RestrictionWe demonstrate that HIV-1 uses a common two-step cell-to-cell fusion mechanism for massive virus transfer from infected T lymphocytes and dissemination to myeloid target cells, including dendritic cells and macrophages as well as osteoclasts. This cell-to-cell infection process bypasses the restriction imposed by the SAMHD1 host cell restriction factor for HIV-1 replication, leading to the formation of highly virus-productive...
Research Article | Host-Microbe BiologyExpression of 9-O- and 7,9-O-Acetyl Modified Sialic Acid in Cells and Their Effects on Influenza VirusesSialic acids are key glycans that are involved in many different normal cellular functions, as well as being receptors for many pathogens. However, Sia come in diverse chemically modified forms. Here, we examined and manipulated the expression of 7,9-O- and 9-O-acetyl modified Sia on cells commonly used in influenza virus and other research by engineering the enzymes that produce or remove the acetyl groups.
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Research Article | Host-Microbe BiologyAnalysis of CA Content and CPSF6 Dependence of Early HIV-1 Replication Complexes in SupT1-R5 CellsThe HIV-1 capsid performs essential functions during early viral replication and is an interesting target for novel antivirals. Thus, understanding molecular and structural details of capsid function will be important for elucidating early HIV-1 (and retroviral in general) replication in relevant target cells and may also aid antiviral development. Here, we show that HIV-1 capsids stay largely intact during transport to the nucleus of...
Research Article | Host-Microbe BiologyCandida albicans rvs161Δ and rvs167Δ Endocytosis Mutants Are Defective in Invasion into the Oral CavityOropharyngeal candidiasis (OPC) is a common fungal infection that is associated with severe morbidity. Another concern is that patients at risk for developing OPC often take long courses of antifungal drugs, which can lead to the emergence of drug-resistant C. albicans strains. We therefore identified nine mutants with defects in undergoing invasive hyphal growth in...
Editor's Pick Research Article | Molecular Biology and PhysiologyComparative Genomics for the Elucidation of Multidrug Resistance in Candida lusitaniaeAntifungal resistance is an inevitable phenomenon when fungal pathogens are exposed to antifungal drugs. These drugs can be grouped in four distinct classes (azoles, candins, polyenes, and pyrimidine analogs) and are used in different clinical settings. Failures in therapy implicate the sequential or combined use of these different drug classes, which can result in some cases in the development of multidrug resistance (MDR). MDR is...
Research Article | Ecological and Evolutionary ScienceThe Emergence of Successful Streptococcus pyogenes Lineages through Convergent Pathways of Capsule Loss and Recombination Directing High Toxin ExpressionStreptococcus pyogenes is a genetically diverse pathogen, with over 200 different genotypes defined by emm typing, but only a minority of these genotypes are responsible for the majority of human infection in high-income countries. Two prevalent genotypes associated with disease rose to international dominance following recombination of a toxin locus that...
Research Article | Ecological and Evolutionary ScienceSingle-Cell Transcriptomics Reveal a Correlation between Genome Architecture and Gene Family Evolution in CiliatesCiliates, a eukaryotic clade that is over 1 billion years old, are defined by division of genome function between transcriptionally inactive germline micronuclei and functional somatic macronuclei. To date, most analyses of gene family evolution have been limited to cultivable model lineages (e.g., Tetrahymena, Paramecium, Oxytricha, and Stylonychia). Here, we focus on the uncultivable Karyorelictea...
Research Article | Host-Microbe BiologyEnterococcus faecalis Enhances Expression and Activity of the Enterohemorrhagic Escherichia coli Type III Secretion SystemThis work reveals a complex and multifaceted interaction between a human gut commensal, Enterococcus faecalis, and a pathogen, enterohemorrhagic E. coli. We demonstrate that E. faecalis enhances expression of the enterohemorrhagic...
Research Article | Host-Microbe BiologyPseudomonas aeruginosa Leucine Aminopeptidase Influences Early Biofilm Composition and Structure via Vesicle-Associated Antibiofilm ActivityBiofilm formation by the bacterial pathogen P. aeruginosa is known to contribute to drug resistance in nosocomial infections and chronic lung infections of cystic fibrosis patients. In order to treat these infections more successfully, the mechanisms of bacterial biofilm development must be elucidated. While both bacterially secreted aminopeptidase and outer membrane...
Research Article | Therapeutics and PreventionPreclinical Efficacy of a Lipooligosaccharide Peptide Mimic Candidate Gonococcal VaccineNeisseria gonorrhoeae has become resistant to most antibiotics. The incidence of gonorrhea is also sharply increasing. A safe and effective antigonococcal vaccine is urgently needed. Lipooligosaccharide (LOS), the most abundant outer membrane molecule, is indispensable for gonococcal pathogenesis. A glycan epitope on LOS that is recognized by monoclonal antibody (MAb...
Research Article | Molecular Biology and PhysiologyTransmembrane Prolines Mediate Signal Sensing and Decoding in Bacillus subtilis DesK Histidine KinaseSignal sensing and transduction is an essential biological process for cell adaptation and survival. Histidine kinases (HK) are the sensory proteins of two-component systems that control many bacterial responses to different stimuli, like environmental changes. Here, we focused on the HK DesK from Bacillus subtilis, a paradigmatic example of a transmembrane...
Research Article | Host-Microbe BiologyInterferon-Responsive Genes Are Targeted during the Establishment of Human Cytomegalovirus LatencyHuman cytomegalovirus (HCMV) is a ubiquitous herpesvirus which infects 50 to 100% of humans worldwide. HCMV causes a lifelong subclinical infection in immunocompetent individuals but is a serious cause of mortality and morbidity in the immunocompromised and neonates. In particular, reactivation of HCMV in the transplant setting is a major cause of transplant failure and related disease. Therefore, a molecular understanding of HCMV...
Research Article | Therapeutics and PreventionFluconazole Monotherapy Is a Suboptimal Option for Initial Treatment of Cryptococcal Meningitis Because of Emergence of ResistanceCryptococcal meningitis is a lethal disease with few treatment options. The incidence remains high and intricately linked with the HIV/AIDS epidemic. In many parts of the world, fluconazole is the only agent that is available for the initial treatment of cryptococcal meningitis despite considerable evidence that it is associated with suboptimal microbiological and clinical outcomes. Fluconazole has a fungistatic mode of action: it...
Research Article | Host-Microbe BiologyDrug-Resistant Epimutants Exhibit Organ-Specific Stability and Induction during Murine Infections Caused by the Human Fungal Pathogen Mucor circinelloidesThe emerging fungal pathogen Mucor circinelloides causes a severe infection, mucormycosis, which leads to considerable morbidity and mortality. Treatment of Mucor infection is challenging because Mucor is inherently resistant to nearly all clinical antifungal agents. An RNAi-dependent and reversible mechanism of antifungal resistance, epimutation,...
Research Article | Host-Microbe BiologyFunctional Multigenomic Screening of Human-Associated Bacteria for NF-κB-Inducing Bioactive EffectorsHuman-associated bacteria are thought to encode bioactive small molecules and proteins that play an intimate role in human health and disease. Here, we report on the creation and functional screening of a multigenomic library constructed using genomic DNA from 116 bacteria found at diverse sites across the human body. Individual clones were screened for genes capable of conferring NF-κB-inducing activity to...
Research Article | Host-Microbe BiologyTryptophan Metabolism Activates Aryl Hydrocarbon Receptor-Mediated Pathway To Promote HIV-1 Infection and ReactivationCellular metabolic pathways that are altered by HIV-1 infection may accelerate disease progression. Dysfunction in tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the mechanism responsible was not known. This study demonstrates that Trp metabolites augment the activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, to promote HIV-1 infection...
Research Article | Therapeutics and PreventionA Multicomponent Vaccine Provides Immunity against Local and Systemic Infections by Group A Streptococcus across SerotypesGAS is among the most common human pathogens and causes a wide variety of diseases, likely more than any other microorganism. The diverse clinical manifestations of GAS may be attributable to its large repertoire of virulence factors that are selectively and synergistically involved in streptococcal pathogenesis. To date, GAS vaccines have not been successful due to multiple serotypes and postinfection sequelae associated with...
Research Article | Host-Microbe BiologyA Novel Mouse Model of Enteric Vibrio parahaemolyticus Infection Reveals that the Type III Secretion System 2 Effector VopC Plays a Key Role in Tissue Invasion and GastroenteritisVibrio parahaemolyticus causes severe gastroenteritis following consumption of contaminated seafood. Global warming has allowed this pathogen to spread worldwide, contributing to recent outbreaks. Clinical isolates are known to harbor an array of virulence factors, including T3SS1 and T3SS2; however, the precise role these systems play in intestinal disease remains...
Research Article | Host-Microbe BiologyThe Cyclic AMP Receptor Protein Regulates Quorum Sensing and Global Gene Expression in Yersinia pestis during Planktonic Growth and Growth in BiofilmsBacterial pathogens have evolved extensive signaling pathways to translate environmental signals into changes in gene expression. While Crp has long been appreciated for its role in regulating metabolism of carbon sources in many bacterial species, transcriptional profiling has revealed that this protein regulates many other aspects of bacterial physiology. The plague pathogen...
Research Article | Molecular Biology and PhysiologyDevelopmentally Regulated Oscillations in the Expression of UV Repair Genes in a Soilborne Plant Pathogen Dictate UV Repair Efficiency and SurvivalFusarium oxysporum infects plants through the roots and therefore is not exposed to the sun regularly. However, the ability to survive sun exposure expands the distribution of the population. UV from the sun is toxic and mutagenic, and to survive sun exposure, fungi encode several DNA repair mechanisms. We found that...
Research Article | Therapeutics and PreventionTranscriptomic Signatures Predict Regulators of Drug Synergy and Clinical Regimen Efficacy against TuberculosisMultidrug combination therapy is an important strategy for treating tuberculosis, the world’s deadliest bacterial infection. Long treatment durations and growing rates of drug resistance have created an urgent need for new approaches to prioritize effective drug regimens. Hence, we developed a computational model called INDIGO-MTB that identifies synergistic drug regimens from an immense set of possible drug combinations using the...
Research Article | Host-Microbe BiologyIRG1 and Inducible Nitric Oxide Synthase Act Redundantly with Other Interferon-Gamma-Induced Factors To Restrict Intracellular Replication of Legionella pneumophilaLegionella pneumophila is one example among many species of pathogenic bacteria that replicate within mammalian macrophages during infection. The immune signaling factor interferon gamma (IFN-γ) blocks L. pneumophila replication in macrophages and is an essential component of the immune response to...
Research Article | Ecological and Evolutionary ScienceTime after Time: Temporal Variation in the Effects of Grass and Forb Species on Soil Bacterial and Fungal CommunitiesOur findings highlight how soil fungal and bacterial communities respond to time, season, and plant species identity. We found that succession shapes the soil bacterial community, while plant species and the type of plant species that grows in the soil drive the assembly of soil fungal communities. Future research on the effects of plants on soil microbes should take into consideration the relative roles of both time and plant growth on...
Research Article | Molecular Biology and PhysiologyTREM-1 Protects HIV-1-Infected Macrophages from Apoptosis through Maintenance of Mitochondrial FunctionThe major challenge to human immunodeficiency virus (HIV) treatment is the development of strategies that lead to viral eradication. A roadblock to accomplishing this goal is the lack of an approach that would safely eliminate HIV from all resting/latent reservoirs, including macrophages. Macrophages are a key part of the innate immune system and are responsible for recognizing invading microbes and sending appropriate signals to other...
Research Article | Host-Microbe BiologyShigella sonnei O-Antigen Inhibits Internalization, Vacuole Escape, and Inflammasome ActivationDiarrheal disease remains the second leading cause of death in children under five. Shigella remains a significant cause of diarrheal disease with two species, S. flexneri and S. sonnei, causing the majority of infections....
Research Article | Molecular Biology and PhysiologyNusG-Dependent RNA Polymerase Pausing and Tylosin-Dependent Ribosome Stalling Are Required for Tylosin Resistance by Inducing 23S rRNA Methylation in Bacillus subtilisAntibiotic resistance is a growing health concern. Resistance mechanisms have evolved that provide bacteria with a growth advantage in their natural habitat such as the soil. We determined that B. subtilis, a Gram-positive soil organism, has a mechanism of resistance to tylosin, a macrolide antibiotic commonly used in the meat industry. Tylosin induces expression of...
Research Article | Applied and Environmental SciencePhotoferrotrophs Produce a PioAB Electron Conduit for Extracellular Electron UptakeSome anoxygenic phototrophs use soluble iron, insoluble iron minerals (such as rust), or their proxies (poised electrodes) as electron donors for photosynthesis. However, the underlying electron uptake mechanisms are not well established. Here, we show that these phototrophs use a protein complex made of an outer membrane porin and a periplasmic decaheme cytochrome (electron transfer protein) to harvest electrons from both soluble iron...
Research Article | Molecular Biology and PhysiologyReassessing the Role of the Type II MqsRA Toxin-Antitoxin System in Stress Response and Biofilm Formation: mqsA Is Transcriptionally Uncoupled from mqsRThere is growing controversy regarding the role of chromosomal toxin-antitoxin systems in bacterial physiology. mqsRA is a peculiar toxin-antitoxin system, as the gene encoding the toxin precedes that of the antitoxin. This system was previously shown to play a role in stress response and biofilm formation. In this work, we identified two promoters specifically driving the constitutive expression of the antitoxin, thereby...
Research Article | Host-Microbe BiologyA Fungal Arrestin Protein Contributes to Cell Cycle Progression and PathogenesisTo survive under unpredictable conditions, all organisms must adapt to stressors by regulating adaptive cellular responses. Arrestin proteins are conserved regulators of adaptive cellular responses in eukaryotes. Studies that have been limited to mammals and model fungi have demonstrated that the disruption of arrestin-regulated pathways is detrimental for viability. The human fungal pathogen...
Research Article | Host-Microbe BiologyAntibody-Dependent Cellular Cytotoxicity-Competent Antibodies against HIV-1-Infected Cells in Plasma from HIV-Infected SubjectsHIV Env-specific nonneutralizing Abs (NnAbs) able to mediate ADCC have been implicated in protection from HIV infection. However, Env-specific NnAbs have the capacity to support ADCC of both HIV-infected and HIV-uninfected bystander cells, potentially leading to misinterpretations when the assay used to measure ADCC does not distinguish between the two target cell types present in HIV cultures. Using a novel ADCC assay, which...
Editor's Pick Research Article | Applied and Environmental ScienceBottom-Up Fabrication of Protein Nanowires via Controlled Self-Assembly of Recombinant Geobacter PilinsThe discovery in 2005 of conductive protein appendages (pili) in the metal-reducing bacterium Geobacter sulfurreducens challenged our understanding of biological electron transfer and pioneered studies in electromicrobiology that revealed the electronic basis of many microbial metabolisms and interactions. The protein nature of the pili afforded opportunities for...
Research Article | Host-Microbe BiologyThe Unfolded Protein Response Regulates Pathogenic Development of Ustilago maydis by Rok1-Dependent Inhibition of Mating-Type SignalingThe unfolded protein response (UPR) is crucial for endoplasmic reticulum (ER) homeostasis and disease development in fungal pathogens. In the plant-pathogenic fungus Ustilago maydis, the UPR supports fungal proliferation in planta and effector secretion for plant defense suppression. In this study, we uncovered that UPR activity, which is normally restricted...
Research Article | Host-Microbe BiologyInhibition of Neutrophil Primary Granule Release during Yersinia pestis Pulmonary InfectionYersinia pestis is the causative agent of plague and is one of the deadliest human pathogens. The pneumonic form of Y. pestis infection has played a critical role in the severity of both historical and modern plague outbreaks, yet the host-pathogen interactions that govern the lethality of...
Research Article | Host-Microbe BiologyCD71+ Erythroid Cells Exacerbate HIV-1 Susceptibility, Mediate trans-Infection, and Harbor Infective Viral ParticlesImmature red blood cells (erythroid precursors or CD71+ erythroid cells) have a wide range of immunomodulatory properties. In this study, we found that these erythroid precursors are abundant in the human cord blood/placental tissues, in the blood of HIV-infected and anemic individuals. We observed that these cells exacerbate HIV-1 replication/infection in target cells and even make HIV target cells more permissible to HIV...
Research Article | Host-Microbe BiologyThe Staphylococcus aureus Transcriptome during Cystic Fibrosis Lung InfectionAlthough bacteria have been studied in infection for over 100 years, the majority of these studies have utilized laboratory and animal models that often have unknown relevance to the human infections they are meant to represent. A primary challenge has been to assess bacterial physiology in the human host. To address this challenge, we performed transcriptomics of S. aureus...
Research Article | Host-Microbe BiologyInsect Hsp90 Chaperone Assists Bacillus thuringiensis Cry Toxicity by Enhancing Protoxin Binding to the Receptor and by Protecting Protoxin from Gut Protease DegradationBacillus thuringiensis took advantage of important insect cellular proteins, such as chaperones, involved in maintaining protein homeostasis, to enhance its insecticidal activity. This constitutes a positive loop where the concentrations of Hsp90 and Hsp70 in the gut lumen are likely to increase as midgut cells burst due to Cry1A pore formation action. Hsp90 protects...
Research Article | Host-Microbe BiologyUbiquitination of Listeria Virulence Factor InlC Contributes to the Host Response to InfectionThe pathogenic potential of Listeria monocytogenes relies on the production of an arsenal of virulence determinants that have been extensively characterized, including surface and secreted proteins of the internalin family. We have previously shown that the Listeria secreted internalin InlC interacts with IκB kinase α to interfere with the host immune...
Research Article | Molecular Biology and PhysiologyDiversity in Natural Transformation Frequencies and Regulation across Vibrio SpeciesNaturally transformable, or competent, bacteria are able to take up DNA from their environment, a key method of horizontal gene transfer for acquisition of new DNA sequences. Our research shows that Vibrio species that inhabit marine environments exhibit a wide diversity in natural transformation capability ranging from nontransformability to high transformation rates in which 10% of cells measurably incorporate new DNA. We...
Editor's Pick Research Article | Host-Microbe BiologySimian Immunodeficiency Virus Infection of Rhesus Macaques Results in Delayed Zika Virus ClearanceImmunocompromised individuals often become symptomatic with infections which are normally fairly asymptomatic in healthy individuals. The particular mechanisms that underlie susceptibility to coinfections in human immunodeficiency virus (HIV)-infected individuals are multifaceted. ZIKV and other flaviviruses are sensitive to neutralizing antibodies, whose production can be limited in HIV-infected individuals but are also sensitive to...
Research Article | Host-Microbe BiologyFunctionally Overlapping Variants Control Tuberculosis Susceptibility in Collaborative Cross MiceThe variable outcome of Mycobacterium tuberculosis infection observed in natural populations is difficult to model in genetically homogeneous small-animal models. The newly developed Collaborative Cross (CC) represents a reproducible panel of genetically diverse mice that display a broad range of phenotypic responses to infection. We explored the genetic basis of this...
Research Article | Host-Microbe BiologyA Porcine Ex Vivo Lung Perfusion Model To Investigate Bacterial PathogenesisThe implementation of infection models that approximate human disease is essential to understand infections and for testing new therapies before they enter into clinical stages. Rodents are used in most preclinical studies, although the differences between mice and humans have fueled the conclusion that murine studies are unreliable predictors of human outcomes. In this study, we have developed a whole-lung porcine model of infection...
Research Article | Host-Microbe BiologyLong-Term Effects of Early-Life Antibiotic Exposure on Resistance to Subsequent Bacterial InfectionThe gastrointestinal microbiota protects hosts from enteric infections; while antibiotics, by altering the microbiota, may diminish this protection. We show that after early-life exposure to antibiotics host susceptibility to enhanced Citrobacter rodentium-induced colitis is persistent and that this enhanced disease susceptibility is transferable by the antibiotic-...
Research Article | Molecular Biology and PhysiologyA Conserved Regulatory Circuit Controls Large Adhesins in Vibrio choleraeVibrio cholerae, the causative agent of the diarrheal disease cholera, benefits from a sessile biofilm lifestyle that enhances survival outside the host but also contributes to host colonization and infectivity. The bacterial second messenger c-di-GMP has been identified as a central regulator of biofilm formation, including in...
Research Article | Molecular Biology and PhysiologyRedox Regulation of a Light-Harvesting Antenna Complex in an Anoxygenic PhototrophAn essential aspect of the physiology of phototrophic bacteria is their ability to adjust the amount and composition of their light-harvesting apparatus in response to changing environmental conditions. The phototrophic purple bacterium R. palustris adapts its photosystem to a range of light intensities by altering the amount and composition of its peripheral LH...
Research Article | Molecular Biology and PhysiologyRefined Mechanism of Mycoplasma mobile Gliding Based on Structure, ATPase Activity, and Sialic Acid Binding of MachineryThe genus Mycoplasma is made up of the smallest parasitic and sometimes commensal bacteria; Mycoplasma pneumoniae, which causes human “walking pneumonia,” is representative. More than ten Mycoplasma species glide on host tissues by novel mechanisms, always in the direction of the distal side of the machinery....
Research Article | Host-Microbe BiologyG Protein Pathway Suppressor 1 Promotes Influenza Virus Polymerase Activity by Activating the NF-κB Signaling PathwayIn the present study, we identified G protein pathway suppressor 1 (GPS1) to be a host cellular protein that is important for influenza virus replication. We also found that GPS1 plays a role in viral genome transcription through the NF-κB signaling pathway. Moreover, downregulation of GPS1 also affected the growth of vesicular stomatitis virus. Therefore, GPS1 may be a host target for antiviral drugs against influenza virus and...
Research Article | Clinical Science and EpidemiologyUnbiased Metagenomic Sequencing for Pediatric Meningitis in Bangladesh Reveals Neuroinvasive Chikungunya Virus Outbreak and Other Unrealized PathogensGlobally, there are an estimated 10.6 million cases of meningitis and 288,000 deaths every year, with the vast majority occurring in low- and middle-income countries. In addition, many survivors suffer from long-term neurological sequelae. Most laboratories assay only for common bacterial etiologies using culture and directed PCR, and the majority of meningitis cases lack microbiological diagnoses, impeding institution of evidence-based...
Research Article | Molecular Biology and PhysiologyAlanyl-tRNA Synthetase Quality Control Prevents Global Dysregulation of the Escherichia coli ProteomeErrors in protein synthesis have historically been assumed to be detrimental to the cell. While there are many reports that translational errors are consequential, there is a growing body of evidence that some mistranslation events may be tolerated or even beneficial. Using two models of mistranslation, we compare the direct phenotypic effects of these events in Escherichia...
Research Article | Host-Microbe BiologyA Multiorgan Trafficking Circuit Provides Purifying Selection of Listeria monocytogenes Virulence GenesListeria monocytogenes maintains capabilities for free-living growth in the environment and for intracellular replication in a wide range of hosts, including livestock and humans. Here, we characterized an enterocolitis model of foodborne L. monocytogenes infection. This work highlights a multiorgan...
Research Article | Host-Microbe BiologyRIP1, RIP3, and MLKL Contribute to Cell Death Caused by Clostridium perfringens EnterotoxinC. perfringens type F strains are a common cause of food poisoning and antibiotic-associated diarrhea. Type F strain virulence requires production of C. perfringens enterotoxin (CPE). In Caco-2 cells, high CPE concentrations cause necrosis while low enterotoxin concentrations induce apoptosis. The...
Research Article | Therapeutics and PreventionVaccine Protection against Multidrug-Resistant Klebsiella pneumoniae in a Nonhuman Primate Model of Severe Lower Respiratory Tract InfectionMultidrug-resistant bacteria continue to be a major problem worldwide, especially among individuals with significant comorbidities and other risk factors for infection. K. pneumoniae is among the leading causes of health care-associated infections, and the organism is often resistant to multiple classes of antibiotics. A carbapenem-resistant...
Commentaries
Influenza A viruses are important pathogens for humans and for many birds and mammals. Hemagglutinin and neuraminidase are the major surface proteins of this enveloped RNA virus.
Domestication led to profound changes in human culture. During this period, humans used breeding strategies to select for desirable traits in crops and livestock. These practices led to genetic and phenotypic changes that are trackable through archaeological and genomic records. Bacteria, yeasts, and molds also experienced domestication during the agricultural revolution, but the effects of domestication on microbes are poorly...