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At least 199 records · Page 11

Extensive cellular multi-tasking within Bacillus subtilis biofilms

Bacillus subtilis is a soil-dwelling bacterium that can form biofilms, or communities of cells surrounded by a self-produced extracellular matrix. In biofilms, genetically identical cells often exhibit heterogeneous transcriptional phenotypes, so that subpopulations of cells carry out essential yet costly cellular processes that allow the entire population to thrive. Surprisingly, the extent of phenotypic heterogeneity and the relationships between subpopulations of cells within biofilms of even in well-studied bacterial systems like B. subtilis remains largely unknown. To determine relationships between these subpopulations of cells, we created 182 strains containing pairwise combinations of fluorescent transcriptional reporters for the expression state of 14 different genes associated with potential cellular subpopulations. We determined the spatial organization of the expression of these genes within biofilms using confocal microscopy, which revealed that many reporters localized to distinct areas of the biofilm, some of which were co-localized. We used flow cytometry to quantify reporter co-expression, which revealed that many cells “multi-task,” simultaneously expressing two reporters. These data indicate that prior models describing B. subtilis cells as differentiating into specific cell types, each with a specific task or function, were oversimplified. Only a few subpopulations of cells, including surfactin and plipastatin producers, as well as sporulating and competent cells, appear to have distinct roles based on the set of genes examined here. These data will provide us with a framework with which to further study and make predictions about the roles of diverse cellular phenotypes in B. subtilis biofilms.

59 BASIC BIOLOGICAL SCIENCES↗

SourceFinder: a Machine-Learning-Based Tool for Identification of Chromosomal, Plasmid, and Bacteriophage Sequences from Assemblies

High-throughput genome sequencing technologies enable the investigation of complex genetic interactions, including the horizontal gene transfer of plasmids and bacteriophages. However, identifying these elements from assembled reads remains challenging due to genome sequence plasticity and the difficulty in assembling complete sequences. In this study, we developed a classifier, using random forest, to identify whether sequences originated from bacterial chromosomes, plasmids, or bacteriophages. The classifier was trained on a diverse collection of 23,211 chromosomal, plasmid, and bacteriophage sequences from hundreds of bacterial species. In order to adapt the classifier to incomplete sequences, each complete sequence was subsampled into 5,000 nucleotide fragments and further subdivided into k-mers. This three-class classifier succeeded in identifying chromosomes, plasmids, and bacteriophages using k-mer distributions of complete and partial genome sequences, including simulated metagenomic scaffolds with minimum performance of 0.939 area under the receiver operating characteristic curve (AUC). This classifier, implemented as SourceFinder, has been made available as an online web service to help the community with predicting the chromosomal, plasmid, and bacteriophage sources of assembled bacterial sequence data (https://cge.food.dtu.dk/services/SourceFinder/).

59 BASIC BIOLOGICAL SCIENCES↗

A Novel Signaling Pathway Connects Thiamine Biosynthesis, Bacterial Respiration, and Production of the Exopolysaccharide Amylovoran in Erwinia amylovora

Erwinia amylovora is a plant pathogen causing necrotrophic fire blight disease of apple, pear, and other rosaceous plants. This bacterium colonizes host vascular tissues via the production of exopolysaccharides (EPSs) including amylovoran. It is well-established that the nearly ubiquitous plasmid pEA29 of E. amylovora is an essential virulence factor, but the underlying mechanism remains uncharacterized. Here, we demonstrated that pEA29 was required for E. amylovora to produce amylovoran and to form a biofilm, and this regulation was dependent on the thiamine biosynthesis operon thiOSGF. We then conducted carbohydrate and genetic analyses demonstrating that the thiamine-mediated effect on amylovoran production was indirect, as cells lacking thiOSGF produced an EPS that did not contain glucuronic acid, one of the key components of amylovoran, whereas the transcriptional activity and RNA levels of the amylovoran biosynthesis genes were not altered. Alternatively, addition of exogenous thiamine restored amylovoran production in the pEA29-cured strain of E. amylovora and positively impacted amylovoran production in a dose-dependent manner. Individual deletion of several chromosomal thiamine biosynthesis genes also affected amylovoran production, implying that a complete thiamine biosynthesis pathway is required for the thiamine-mediated effect on amylovoran production in E. amylovora. Finally, we determined that an imbalanced tricarboxylic acid cycle negatively affected amylovoran production, which was restored by addition of exogenous thiamine or overexpression of the thiOSGF operon. In summary, our report revealed a novel signaling pathway that impacts E. amylovora virulence in which thiamine biosynthesis enhances bacterial respiration that provides energetic requirements for the biosynthesis of EPS amylovoran.

59 BASIC BIOLOGICAL SCIENCES↗

Significance of lysogeny for the metabolism of Desulfovibrio spp. strains isolated from aquatic environments of Georgia

Sulphate-reducing bacteria (SRB) are ecologically important group of anaerobic micro-organisms that can reduce sulphate to form hydrogen sulphide-a toxic gas causing iron corrosion on metal surfaces. In this work, SRB strains were isolated from aquatic environments in the country of Georgia to determine their lysogenicity and the role of temperate phages in host metabolism. SRB strains were isolated in samples from the Black Sea coast of Georgia. Based on their genetic, cytological and physiological properties of bacteria, 10 Georgian isolates were assigned to the genus Desulfovibrio. Temperate bacteriophages were induced from three out of ten strains by UV-exposure. Comparison of metal (Fe and Cr) reduction and utilization of various carbon sources by the wild-type (lysogenic) bacterial strains and their UV-irradiated counterparts was done. Temperate phage in the cells of SRB could alter significant functions of bacteria and may have a contribution in the acquisition of different traits by SRB. This article pointed to a significant role for temperate bacteriophages in the metabolism and metabolic potential of host strains of SRB, which were first isolated from the aquatic environment of Georgia.

temperate phage↗

Predicting antimicrobial susceptibility from the bacterial genome: A new paradigm for one health resistance monitoring

The laboratory identification of antibacterial resistance is a cornerstone of infectious disease medicine. In vitro antimicrobial susceptibility testing has long been based on the growth response of organisms in pure culture to a defined concentration of antimicrobial agents. By comparing individual isolates to wild type susceptibility patterns, strains with acquired resistance can be identified. Acquired resistance can also be detected genetically. After many decades of research, the inventory of genes underlying antimicrobial resistance (AMR) is well known for several pathogenic genera including zoonotic enteric organisms such as Salmonella and Campylobacter and continues to grow substantially for others. With the decline in costs for large scale DNA sequencing, it is now practicable to characterize bacteria using whole genome sequencing (WGS), including the carriage of resistance genes in individual microorganisms and those present in complex biological samples. With genomics we can generate comprehensive, detailed information on the bacterium, the mechanisms of antibiotic resistance, clues to its source, and the nature of mobile DNA elements by which resistance spreads. These developments point to a new paradigm for antimicrobial resistance detection and tracking for both clinical and public health purposes.

59 BASIC BIOLOGICAL SCIENCES↗

Macrophage-derived MLKL in alcohol-associated liver disease: Regulation of phagocytosis

Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3) -/- mice are completely protected from ethanol-induced liver injury, Mlkl -/- mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury. Bone marrow transplants between Mlkl -/- mice and littermates were conducted to distinguish the role of myeloid versus nonmyeloid Mlkl in the Gao-binge model of ALD. Ethanol-induced hepatic injury, steatosis, and inflammation were exacerbated in Mlkl -/- →wild-type (WT) mice, whereas Mlkl deficiency in nonmyeloid cells (WT→Mlkl -/- ) had no effect on Gao-binge ethanol-induced injury. Importantly, Mlkl deficiency in myeloid cells exacerbated ethanol-mediated bacterial burden and accumulation of immune cells in livers. Mechanistically, challenging macrophages with lipopolysaccharide (LPS) induced signal transducer and activator of transcription 1–mediated expression and phosphorylation of MLKL, as well as translocation and oligomerization of MLKL to intracellular compartments, including phagosomes and lysosomes but not plasma membrane. Importantly, pharmacological or genetic inhibition of MLKL suppressed the phagocytic capability of primary mouse Kupffer cells (KCs) at baseline and in response to LPS with/without ethanol as well as peripheral monocytes isolated from both healthy controls and patients with alcohol-associated hepatitis. Further, in vivo studies revealed that KCs of Mlkl -/- mice phagocytosed fewer bioparticles than KCs of WT mice. Together, these data indicate that myeloid MLKL restricts ethanol-induced liver inflammation and injury by regulating hepatic immune cell homeostasis and macrophage phagocytosis.

60 APPLIED LIFE SCIENCES↗

Soft X-ray tomography reveals variations in B. subtilis biofilm structure upon tasA deletion

Bacterial biofilms are complex cell communities within a self-produced extracellular matrix, crucial in various fields but challenging to analyze in 3D. We developed a "biofilm-in-capillary" growth method compatible with full-rotation soft X-ray tomography, enabling high-resolution 3D imaging of bacterial cells and their matrix during biofilm formation. This approach offers 50 nm isotropic spatial resolution, rapid imaging, and quantitative native analysis of biofilm structure. Using Bacillus subtilis biofilms, we detected coherent alignment and chaining of wild-type cells towards the oxygen-rich capillary tip. In contrast, the ΔtasA genetic knock-out showed a loss of cellular orientation and changes in the extracellular matrix. Adding TasA protein to the ΔtasA strain restored matrix density and led to cell assembly compaction, but without the chaining observed in wild-type biofilms. This scalable and transferable approach opens new avenues for examining biofilm structure and function across various species, including mixed biofilms, and response to genetic and environmental factors.

59 BASIC BIOLOGICAL SCIENCES↗

Bacterial Secondary Metabolite Biosynthetic Potential in Soil Varies with Phylum, Depth, and Vegetation Type

Microbes produce specialized compounds to compete or communicate with one another and their environment. Some of these compounds, such as antibiotics, are also useful in medicine and biotechnology. Historically, most antibiotics have come from soil bacteria which can be isolated and grown in the lab. Though the vast majority of soil bacteria cannot be isolated, we can extract their genetic information and search it for genes which produce these specialized compounds. These understudied soil bacteria offer a wealth of potential for the discovery of new and important microbial products. Here, we identified the ability to produce these specialized compounds in diverse and novel bacteria in a range of soil environments. This information will be useful to other researchers who wish to isolate certain products. Beyond their use to humans, understanding the distribution and function of microbial products is key to understanding microbial communities and their effects on biogeochemical cycles.

59 BASIC BIOLOGICAL SCIENCES↗

Efficient genetic code expansion tools enable in vivo study of lysine acetylation in non-model bacteria

Recent proteomic advancements have revealed widespread Nε-lysine acetylation in pathways governing pathogenicity, metabolism, and antibiotic resistance in bacteria. The spontaneous, non-specific nature of this modification in prokaryotes obscures its biological role, necessitating prokaryotic specific in vivo interrogation systems. Genetic Code Expansion (GCE) offers a powerful method to investigate the roles and regulation dynamics of acetyl-lysine in vivo with the precise incorporation of a suite of non-canonical amino acids, including acetyl-lysine analogs. However, its use has been largely restricted to E. coli strains due to challenges associated with implementation and optimization of the technology in more diverse bacterial strains. Here, we present a bacterial host-agnostic, readily optimizable GCE platform designed to site-specifically incorporate non-canonical amino acids into target proteins within living bacteria. We further demonstrate the versatility of this technology by showcasing, for the first time, the successful incorporation of acetyl-lysine in a non- E. coli bacterium.

59 BASIC BIOLOGICAL SCIENCES↗

Protecting honey bees through microbiome engineering

Honey bees are indispensable insects. Their pollination services support modern agriculture and natural ecosystems. Managed honey bee colonies face increasing threats to their survival, ranging from environmental stressors that include agrochemicals to infestations of arthropod pests and infections with microbial pathogens. Like humans, honey bees have a native gut microbiome that supports their health. However, the bee gut microbiome has a simpler composition than the gut microbiome of mammals, and its main constituent bacterial species can be easily cultured outside of the host. Furthermore, this experimental tractability and the need for new methods for protecting hive health have made honey bees a testbed for synthetic microbiomes augmented with probiotic bacteria and engineered DNA. Here, we discuss the natural benefits of bee gut bacteria, recent progress in genetically modifying these bacteria, and how symbiont-mediated RNA interference and other microbiome engineering approaches can boost bee immunity and suppress bee pathogens and parasites. Finally, we discuss how emerging methods for microbiome engineering and biocontainment could be applied to honey bees and used to address challenges in translating these proof-of-principle achievements into safe and effective technologies for field applications at scale.

Biological and medical sciences↗

Structural insights into mRNA reading frame regulation by tRNA modification and slippery codon–anticodon pairing

Modifications in the tRNA anticodon loop, adjacent to the three-nucleotide anticodon, influence translation fidelity by stabilizing the tRNA to allow for accurate reading of the mRNA genetic code. One example is the N1-methylguanosine modification at guanine nucleotide 37 (m 1 G37) located in the anticodon loop andimmediately adjacent to the anticodon nucleotides 34, 35, 36. The absence of m 1 G37 in tRNA Pro causes +1 frameshifting on polynucleotide, slippery codons. Here, we report structures of the bacterial ribosome containing tRNA Pro bound to either cognate or slippery codons to determine how the m 1 G37 modification prevents mRNA frameshifting. The structures reveal that certain codon–anticodon contexts and the lack of m 1 G37 destabilize interactions of tRNA Pro with the P site of the ribosome, causing large conformational changes typically only seen during EF-G-mediated translocation of the mRNA-tRNA pairs. These studies provide molecular insights into how m 1 G37 stabilizes the interactions of tRNA Pro with the ribosome in the context of a slippery mRNA codon.

59 BASIC BIOLOGICAL SCIENCES↗

Prevalence and diversity of TAL effector-like proteins in fungal endosymbiotic Mycetohabitans spp.

EndofungalMycetohabitans(formerlyBurkholderia) spp. rely on a type III secretion system to deliver mostly unidentified effector proteins when colonizing their host fungus,Rhizopus microsporus. The one known secreted effector family fromMycetohabitansconsists of homologues of transcription activator-like (TAL) effectors, which are used by plant pathogenicXanthomonasandRalstoniaspp. to activate host genes that promote disease. These ‘BurkholderiaTAL-like (Btl)’ proteins bind corresponding specific DNA sequences in a predictable manner, but their genomic target(s) and impact on transcription in the fungus are unknown. Recent phenotyping of Btl mutants of twoMycetohabitansstrains revealed that the single Btl in oneMycetohabitans endofungorumstrain enhances fungal membrane stress tolerance, while others in aMycetohabitans rhizoxinicastrain promote bacterial colonization of the fungus. The phenotypic diversity underscores the need to assess the sequence diversity and, given that sequence diversity translates to DNA targeting specificity, the functional diversity of Btl proteins. Using a dual approach to maximize capture of Btl protein sequences for our analysis, we sequenced and assembled nineMycetohabitansspp. genomes using long-read PacBio technology and also mined available short-read Illumina fungal–bacterial metagenomes. We show thatbtlgenes are present across diverseMycetohabitansstrains from Mucoromycota fungal hosts yet vary in sequences and predicted DNA binding specificity. Phylogenetic analysis revealed distinct clades of Btl proteins and suggested thatMycetohabitansmight contain more species than previously recognized. Within our data set, Btl proteins were more conserved acrossM. rhizoxinicastrains than acrossM. endofungorum, but there was also evidence of greater overall strain diversity within the latter clade. Overall, the results suggest that Btl proteins contribute to bacterial–fungal symbioses in myriad ways.

Genetics & Heredity↗

Redefining fundamental concepts of transcription initiation in bacteria

Despite enormous progress in understanding the fundamentals of bacterial gene regulation, our knowledge remains limited when compared with the number of bacterial genomes and regulatory systems to be discovered. Derived from a small number of initial studies, classic definitions for concepts of gene regulation have evolved as the number of characterized promoters has increased. Together with discoveries made using new technologies, this knowledge has led to revised generalizations and principles. In this Expert Recommendation, we suggest precise, updated definitions that support a logical, consistent conceptual framework of bacterial gene regulation, focusing on transcription initiation. The resulting concepts can be formalized by ontologies for computational modelling, laying the foundation for improved bioinformatics tools, knowledge-based resources and scientific communication. Furthermore, this work will help researchers construct better predictive models, with different formalisms, that will be useful in engineering, synthetic biology, microbiology and genetics.

59 BASIC BIOLOGICAL SCIENCES↗

Non-target RNA depletion strategy to improve sensitivity of next-generation sequencing for the detection of RNA viruses in poultry

PCR-based assays have become the benchmark for detecting pathogens of poultry and other livestock; however, these techniques are limited in their ability to detect multiple infecting agents, provide limited genetic information on the pathogen, and, for RNA viruses, must be reviewed frequently to assure high sensitivity and specificity. In contrast, untargeted, high-throughput sequencing can rapidly detect all infecting agents in a sample while providing genomic sequence information to allow more in-depth characterization of viruses. Although next-generation sequencing (NGS) offers many advantages, one of its primary limitations is low sensitivity to pathogens given the abundance of host and other non-target sequences in sequencing libraries. We explored methods for improving the sensitivity of NGS to detect respiratory and enteric viruses in poultry from RNA extracts of swab samples. We employed commercial and custom-designed negative enrichment strategies to selectively deplete the most abundant rRNA reads from the host and non-target bacteria; host RNA was diminished from up to 40% of total reads to as low as 3%, and the total number of reads assigned to abundant bacterial classes were reduced greatly. Our treatment resulted in up to a 700-fold increase in the number of viral reads, detection of a greater number of viral agents, and higher average genome coverage for pathogens. Depletion assays added only 2 h to the NGS library preparation workflow. Custom depletion probe design offered significant cost savings (US$7–12 per sample) compared to commercial kits (US$30–50 per sample).

Parris, D. Joshua↗

The Impact of Carotenoid Energy Levels on the Exciton Dynamics and Singlet–Triplet Annihilation in Isolated Bacterial Light-Harvesting 2 Complexes

The light-harvesting 2 (LH2) complex of purple phototrophic bacteria plays a critical role in absorbing solar energy and distributing the excitation energy. Exciton dynamics within LH2 complexes are controlled by the structural arrangement and energy levels of the bacteriochlorophyll (BChl) and carotenoid (Car) pigments. However, there is still debate over the competing light-harvesting versus energy-dissipation pathways. In this work, we compared five variants of the LH2 complex from genetically modified strains of Rhodobacter sphaeroides, all containing the same BChls but different Cars with increasing conjugation: zeta-carotene (N = 7; LH2 Zeta ), neurosporene (N = 9; LH2 Neu ), spheroidene (N = 10; LH2 Spher ), lycopene (N = 11; LH2 Lyco ), and spirilloxanthin (N = 13; LH2 Spir ). Absorption measurements confirmed that the Car excited-state energy decreased with increasing conjugation. Similarly, fluorescence spectra showed that the B850 BChl emission peak had an increasing red shift from LH2 Zeta →(LH2 Neu /LH2 Spher )→LH2 Lyco →LH2 Spir . In contrast, time-resolved fluorescence and ultrafast transient absorption (fs-TA) revealed similar excited-state lifetimes (∼1 ns) for all complexes except LH2 Spir (∼0.7 ns). From fs-TA analysis, an additional ∼7 ps nonradiative dissipation step from B850 BChl was observed for LH2 Zeta . Further, singlet− singlet and singlet−triplet annihilation studies showed a ∼50% average fluorescence lifetime reduction in LH2Zeta at high laser power and high repetition rate, compared to ∼10−15% reductions in LH2 Neu /LH2 Spher /LH2 Lyco and minimal lifetime change in LH2 Spir . In LH2 Zeta , the fastest decay component (<50 ps) became prominent at high repetition rates, consistent with strong singlet−triplet annihilation. Nanosecond TA measurements revealed long-lived (>40 μs) BChl triplet states in LH2 Zeta and signs of damage caused by singlet oxygen, whereas other LH2s showed faster triplet quenching (∼18 ns) by Cars. These findings highlight a key design principle of LH2 complexes: the Car triplet energy must be significantly lower than the BChl triplet energy to efficiently quench BChl triplets that otherwise act as potent “trap states,” causing exciton annihilation in laser-based experiments or photodamage in native membranes.

Absorption↗

Development of Strong Anaerobic Fluorescent Reporters for Clostridium acetobutylicum and Clostridium ljungdahlii Using HaloTag and SNAP-tag Proteins

One of the biggest limitations in the study and engineering of anaerobic Clostridium organisms is the lack of strong fluorescent reporters capable of strong and real-time fluorescence. Recently, we developed a strong fluorescent reporter system for Clostridium organisms based on the FAST protein. Here, we report the development of two new strong fluorescent reporter systems for Clostridium organisms based on the HaloTag and SNAP-tag proteins, which produce strong fluorescent signals when covalently bound to fluorogenic ligands. These new fluorescent reporters are orthogonal to the FAST ligands and to each other, allowing for simultaneous labeling and visualization. We used HaloTag and SNAP-tag to label the strictly anaerobic organisms Clostridium acetobutylicum and Clostridium ljungdahlii. We have also identified a new strong promoter for protein expression in C. acetobutylicum, based on the phosphotransacetylase gene (pta) from C. ljungdahlii. Furthermore, the HaloTag and the SNAP-tag, in combination with the previously described FAST system, were successfully used to measure cell populations in bacterial mixed cultures and showed the simultaneous orthogonal labeling of HaloTag and SNAP-tag together with the FAST protein reporter. Finally, we show the expression of recombinant fusion protein of FAST and the ZapA division protein (from C. acetobutylicum) in C. ljungdahlii. The availability of multiple strong fluorescent reporters is a major addition to the genetic toolkit of Here, Clostridium and other anaerobes that will lead to better understanding of these unique organisms.

59 BASIC BIOLOGICAL SCIENCES↗

Bacterial xylan utilization regulons: systems for coupling depolymerization of methylglucuronoxylans with assimilation and metabolism

Abstract Bioconversion of lignocellulosic resources offers an economically promising path to renewable energy. Technological challenges to achieving bioconversion include the development of cost-effective processes that render the cellulose and hemicellulose components of these resources to fermentable hexoses and pentoses. Natural bioprocessing of the hemicellulose fraction of lignocellulosic biomass requires depolymerization of methylglucuronoxylans. This requires secretion of endoxylanases that release xylooligosaccharides and aldouronates. Physiological, biochemical, and genetic studies with selected bacteria support a process in which a cell-anchored multimodular GH10 endoxylanase catalyzes release of the hydrolysis products, aldotetrauronate, xylotriose, and xylobiose, which are directly assimilated and metabolized. Gene clusters encoding intracellular enzymes, including α-glucuronidase, endoxylanase, β-xylosidase, ABC transporter proteins, and transcriptional regulators, are coordinately responsive to substrate induction or repression. The rapid rates of glucuronoxylan utilization and microbial growth, along with the absence of detectable products of depolymerization in the medium, indicate that assimilation and depolymerization are coupled processes. Genomic comparisons provide evidence that such systems occur in xylanolytic species in several genera, including Clostridium, Geobacillus, Paenibacillus, and Thermotoga. These systems offer promise, either in their native configurations or through gene transfer to other organisms, to develop biocatalysts for efficient production of fuels and chemicals from the hemicellulose fractions of lignocellulosic resources.

Biotechnology & Applied Microbiology↗