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At least 379 records · Page 21

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DOE OSTI2022

Assembly of ordered DNA-curli fibril complexes during Salmonella biofilm formation correlates with strengths of the type I interferon and autoimmune responses

Deposition of human amyloids is associated with complex human diseases such as Alzheimer’s and Parkinson’s. Amyloid proteins are also produced by bacteria. The bacterial amyloid curli, found in the extracellular matrix of both commensal and pathogenic enteric bacterial biofilms, forms complexes with extracellular DNA, and recognition of these complexes by the host immune system may initiate an autoimmune response. Here, we isolated early intermediate, intermediate, and mature curli fibrils that form throughout the biofilm development and investigated the structural and pathogenic properties of each. Early intermediate aggregates were smaller than intermediate and mature curli fibrils, and circular dichroism, tryptophan, and thioflavin T analyses confirmed the establishment of a beta-sheet secondary structure as the curli conformations matured. Intermediate and mature curli fibrils were more immune stimulatory than early intermediate fibrils in vitro . The intermediate curli was cytotoxic to macrophages independent of Toll-like receptor 2. Mature curli fibrils had the highest DNA content and induced the highest levels of Isg15 expression and TNFα production in macrophages. In mice, mature curli fibrils induced the highest levels of anti-double-stranded DNA autoantibodies. The levels of autoantibodies were higher in autoimmune-prone NZBWxF/1 mice than wild-type C57BL/6 mice. Chronic exposure to all curli forms led to significant histopathological changes and synovial proliferation in the joints of autoimmune-prone mice; mature curli was the most detrimental. In conclusion, curli fibrils, generated during biofilm formation, cause pathogenic autoimmune responses that are stronger when curli complexes contain higher levels of DNA and in mice predisposed to autoimmunity.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Technology Summary DNATRAX

DNATrax (DNA Tagged Reagents for Aerosol eXperiments) was developed to provide a safe simulant for understanding the transport and dispersion of pathogens. Specifically, it was developed as a safe surrogate for the Bacillus anthrasis spore bioagent, since most naturally occurring spores are not safe for public release. As DNA-tagged sugar particles, DNATrax aerosols are safe for public release. Scientists can add unique DNA barcode sequences to the sugar particles to produce a wide variety of test particles that can be easily differentiated, making it possible to release and test them simultaneously. The unique barcodes also eliminate the need to conduct decontamination between tests, dramatically reducing the cost and time to run experiments. Additionally, the surrogate offers a high-sensitivity detection method to understand key public health issues. We conducted both lab-based and largescale field studies using DNATrax to validate its capabilities for use as a pathogen surrogate. We have demonstrated the ability to produce DNATrax in a range of sizes, adjusting the microparticles to simulate different sized pathogens with ability to create unique sequences of DNA bases, enabling them to create a nearly unlimited variety of test particles.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Using Deep Mutational Data and Machine Learning to Guide Outbreak and Pandemic Response

A significant fraction of pathogens known to infect humans originate in non-human (zoonotic) hosts (Taylor, Latham, and Woolhouse 2001), and new and emerging pathogens continue to spill over into the human population more frequently at an alarming rate (e.g., SARS, MERS, Cholera, etc.). The recent outbreaks of Ebola virus in West Africa and the ongoing SARS-CoV-2 pandemic demonstrate the need for rapid and reliable assessments of viral phenotype information to help inform scientists and policy makers how best to control the spread of disease. Further understanding of the virus pathogenic evolutionary space and potential trajectory could guide appropriate control measures to limit the spread of a new virus throughout the local and global human population.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Characterizing the Defense Hierarchy of Populus trichocarpa

The U.S. Departments of Energy and Agriculture are developing bioenergy crops as a sustainable alternative to traditional fossil fuels. Plant disease threatens this effort by inhibiting the efficient production of plant feedstocks for bioenergy. In particular, biotrophic Melampsora leaf rust pathogens can increase morbidity in Populus trichocarpa and its hybrids (aka poplars), the primary woody feedstocks for bioenergy. Controlling rust disease in plantations is thus critical to the success of the poplar bioenergy program. Current efforts to control rust disease focus on plant genetic resistance. However, with novel pathogenic variation generated by the global movement of pathogens and their hybridization, it is increasingly clear that controlling rust disease in a long-lived plant like Populus depends on our ability to understand and manage not only genes for rust resistance, but also short-lived plant microorganisms that contribute to defense against rust (aka “defense mutualists”). Our proposed research thus seeks to develop an integrative, hierarchical model of P. trichocarpa defense that integrates genetic resistance and defense mutualists. Our overarching hypothesis is that defense against Melampsora rust is biologically degenerate, with major and minor plant resistance genes, plant defense compounds, and defense mutualists within the microbiome each contributing to rust resistance under different circumstances. The specific aims of our study will test the placement of each of these factors in the defense hierarchy. Ultimately, it is our hope that disease management strategies harnessing both resistance genes and naturally occurring defense mutualists of P. trichocarpa, and an appreciation of the ecological circumstances in which each is effective, will maximize plant resistance and productivity while minimizing impacts on the surrounding ecological landscape.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Combined Imaging and RNA-Seq on a Microfluidic Platform for Viral Infection Studies

The goal of this work was to pioneer a novel, low-overhead protocol for simultaneously assaying cell-surface markers and intracellular gene expression in a single mammalian cell. The purpose of developing such a method is to be able to understand the mechanisms by which pathogens engage with individual mammalian cells, depending on their cell surface proteins, and how both host and pathogen gene expression changes are reflective of these mechanisms. The knowledge gained from such analyses of single cells will ultimately lead to more robust pathogen detection and countermeasures. Our method was aimed at streamlining both the upstream cell sample preparation using microfluidic methods, as well as the actual library making protocol. Specifically, we wanted to implement a random hexamer-based reverse transcription of all RNA within a single cell (as opposed to oligo dT-based which would only capture polyadenylated transcripts), and then use a CRISPR-based method called scDash to deplete ribosomal DNAs (since ribosomal RNAs make up the majority of the RNA in a mammalian cell). After significant troubleshooting, we demonstrate that we are able to prepare cDNA from RNA using the random hexamer primer, and perform the rDNA depletion. We also show that we can visualize individually stained cells, setting up the pipeline for connecting surface markers to RNA-sequencing profiles. Finally, we test a number of devices for various parts of the pipeline, including bead generation, optical barcoding and cell dispensing, and demonstrate that while some of these have potential, more work is needed to optimize this part of the pipeline.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Conserved genetic mechanisms for biotic stress in sorghum (Final report)

Developing durable disease resistance for biofuel crops is crucial, particularly as the range of biofuel crop production expands and pathogens of other plant species evolve to cause diseases of bioenergy feedstocks. Setosphaeria species are significant pathogens of the Andropogonae, and S. turcica can infect both maize and sorghum. Sorghum leaf blight (SLB), caused by S. turcica, is widespread and can decrease grain yields up to 50%, reduce forage quantity and quality, and predispose plants to other diseases, such as anthracnose. Our overall objective was to gain a systems-level understanding of the pathosystem by leveraging natural genetic variation, host specificity of the pathogen, and transcriptome analysis to improve biotic stress resistance in sorghum. We proposed three specific goals: 1) Identify sorghum alleles conferring resistance to S. turcica using natural genetic variation. 2) Characterize genes associated with biotic stress response in sorghum. 3) Identify fungal genes responsible for host specificity.

09 BIOMASS FUELS↗

DOE OSTI2024

Conserved genetic mechanisms for biotic stress in sorghum (Final Report)

09 BIOMASS FUELS↗

DOE OSTI2025

Controlling Host Responses to Infection

Pathogen invasion of host cells causes a myriad of functional changes including alterations of chromatin accessibility often limiting defense responses, shunting of cellular resources to centers of viral replication, and rearrangement of intracellular membranes to facilitate genome reproduction and progeny release. Systems biology approaches provide global snapshots of pathogen induced changes following infection and provide a variety of tools to begin to define how cellular homeostasis is disrupted, but improvements on these tools are required to determine how cellular functions are altered post infection. Chromatin accessibility techniques, biochemical assays to assess the activity of epigenetic enzymes, scalable sample collection platforms, and activity-based probes were used to characterize how human respiratory viruses modify host responses in infected human lungs over time. These studies enhanced our knowledge of how pathogens usurp the host environment during infection and identify additional targets for future evaluations of medical countermeasures.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

PNNL DataHub NIAID Program Project: Modeling Host Responses to Understand Severe Human Virus Infections, Multi-Omic Viral Dataset Catalog Collection

The National Institute of Allergy and Infectious Diseases (NIAID) "Modeling Host Responses to Understand Severe Human Virus Infections" program project was a highly integrated and comprehensive systems biology research core, funded by the National Institute of Health (U19AI106772) from 2013-06-01 to 2018-05-31, investigating the complex host response to category A, B, and C priority pathogen infections. Resulting project deliverables include an extensive comprehensive collections of linked primary and secondary transformation viral experimental infection data. Here we provide a never before released comprehensive infectious disease collection of primary and secondary transformation multi-Omics data profiling a series of priority pathogen primary experimental studies for enhanced open access to viral Omics lifecycle datasets and project metadata. Using a highly integrated and multidisciplinary approach, linked primary data and metadata supporting secondary normalization datasets, provide critical information necessary for research reproducibility and long-term preservation. Enabling on-demand data access for research community consumption and developer reuse, serves to support new mechanistic insights and discoveries into host-pathogen interactions for aiding future biohazard data preparedness efforts in emergency response to global health crises involving viral infection.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Application of multi-criteria decision analysis techniques and decision support framework for informing plant select agent designation and decision making

The United States Department of Agriculture (USDA) Division of Agricultural Select Agents and Toxins (DASAT) established a list of biological agents (Select Agents List) that threaten crops of economic importance to the United States and regulates the procedures governing containment, incident response, and the security of entities working with them. Every 2 years the USDA DASAT reviews their select agent list, utilizing assessments by subject matter experts (SMEs) to rank the agents. We explored the applicability of multi-criteria decision analysis (MCDA) techniques and a decision support framework (DSF) to support the USDA DASAT biennial review process. The evaluation includes both current and non-select agents to provide a robust assessment. We initially conducted a literature review of 16 pathogens against 9 criteria for assessing plant health and bioterrorism risk and documented the findings to support this analysis. Technical review of published data and associated scoring recommendations by pathogen-specific SMEs was found to be critical for ensuring accuracy. Scoring criteria were adopted to ensure consistency. The MCDA supported the expectation that select agents would rank high on the relative risk scale when considering the agricultural consequences of a bioterrorism attack; however, application of analytical thresholds as a basis for designating select agents led to some exceptions to current designations. A second analytical approach used agent-specific data to designate key criteria in a DSF logic tree format to identify pathogens of low concern that can be ruled out for further consideration as select agents. Both the MCDA and DSF approaches arrived at similar conclusions, suggesting the value of employing the two analytical approaches to add robustness for decision making.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Feed status and skin injury modulate immunopathology, global gene expression, and survival in channel catfish during virulent Aeromonas hydrophila infection

Introduction VirulentAeromonas hydrophilais a major pathogen in channel catfish (Ictalurus punctatus), that causes motileAeromonassepticemia and significant economic losses. We investigated the effect of feeding status and skin integrity on the host immune response, disease survival, and gastrointestinal pathology following a vAh challenge. Methods Using a bath immersion model, channel catfish were divided into four treatment groups: fin clipped and fed (FCF), fin clipped but not fed (FCN), not fin clipped but fed (NCF), and not fin clipped nor fed (NCN) alongside non-challenged control groups The FCF and NCF groups were fed 2 h prior to the challenge, but the FCN and NCN groups were not. Survival analysis, histopathological assessment, and RNA sequencing were conducted across groups at different time intervals throughout the vAh challenge. Results Survival rates were lowest in the FCF and FCN groups (30% and 23% survival, respectively), suggesting that both feeding and skin damage contributed to disease severity. Histopathological analyses revealed more severe intestinal and gastric lesions in fed groups, characterized by epithelial necrosis, hemorrhage, and edema. Transcriptomic analysis among the groups identified significant differentially expressed genes associated with inflammation, apoptosis, and metabolic stress, with notable upregulation of interleukin 1-beta (il-1β), and complement C3 (c3). Gene ontology enrichment highlighted distinct immune activation patterns between fed and unfed groups, with enhanced pathogen recognition and pro-inflammatory responses in unfed fish. Discussion These findings suggest feeding prior to infection may exacerbate disease pathology, potentially by creating a physiological state conducive to facilitate pathogen proliferation and dampened early immune responses, whereas short-term fasting appears to promote early immune activation. This study provides novel insights into the complex interplay between feed status, physical injury, and immune response to vAh infection.

Immunology↗

DOE OSTI2020

Microbiome Variation Across Two Hemlock Species With Hemlock Woolly Adelgid Infestation

The hemlock woolly adelgid ( Adelges tsugae , HWA), an invasive insect, is devastating native hemlock populations in eastern North America, and management outcomes have so far had limited success. While many plant microbiomes influence and even support plant immune responses to insect herbivory, relatively little is known about the hemlock microbiome and its interactions with pathogens or herbivores such as HWA. Using 16S rRNA and ITS gene amplicon sequencing, we characterized the needle, branch, root, and rhizosphere microbiome of two hemlock species, Tsuga canadensis and T. sieboldii , that displayed low and high levels of HWA populations. We found that both archaeal/bacterial and fungal needle communities, as well as the archaeal/bacterial branch and root communities, varied in composition in both hemlock species relative to HWA population levels. While host species and plant-associated habitats explained a greater proportion of the variance in the microbiome than did HWA population level, high HWA populations were associated with enrichment of 100 likely fungal pathogen sequence variants across the four plant-associated habitats (e.g., needle, branch, root, rhizosphere) compared to trees with lower HWA populations. This work contributes to a growing body of literature linking plant pathogens and pests with the changes in the associated plant microbiome and host health. Furthermore, this work demonstrates the need to further investigate plant microbiome effects across multiple plant tissues to understand their influences on host health.

16S rRNA↗

DOE OSTI2022

The secreted FoAPY1 peptidase promotes Fusarium oxysporum invasion

The secretion of peptidases from several pathogens has been reported, but the biological function of these proteins in plant-pathogen interactions is poorly understood. Fusarium oxysporum , a soil-borne plant pathogenic fungus that causes Fusarium wilt in its host, can secrete proteins into host plant cells during the infection process to interfere with the host plant defense response and promote disease occurrence. In this study, we identified a peptidase, FoAPY1, that could be secreted from F. oxysporum depending on the N-terminal signal peptide of the protein. FoAPY1 belongs to the peptidase M28 family and exerts peptidase activity in vitro . Furthermore, the FoAYP1 gene knockout strain (∆FoAYP1) presented reduced virulence to tomato plants, but its mycelial growth and conidiation were unchanged. Moreover, FoAYP1 overexpression tomato seedlings exhibited enhanced susceptibility to F. oxysporum and Botrytis cinerea strains. These data demonstrated that FoAYP1 contributes to the virulence of F. oxysporum may through peptidase activity against host plant proteins.

Qian, Hengwei↗

DOE OSTI2022

Landscape Topography and Regional Drought Alters Dust Microbiomes in the Sierra Nevada of California

Dust provides an ecologically significant input of nutrients, especially in slowly eroding ecosystems where chemical weathering intensity limits nutrient inputs from underlying bedrock. In addition to nutrient inputs, incoming dust is a vector for dispersing dust-associated microorganisms. While little is known about dust-microbial dispersal, dust deposits may have transformative effects on ecosystems far from where the dust was emitted. Using molecular analyses, we examined spatiotemporal variation in incoming dust microbiomes along an elevational gradient within the Sierra Nevada of California. We sampled throughout two dry seasons and found that dust microbiomes differed by elevation across two summer dry seasons (2014 and 2015), which corresponded to competing droughts in dust source areas. Dust microbial taxa richness decreased with elevation and was inversely proportional to dust heterogeneity. Likewise, dust phosphorus content increased with elevation. At lower elevations, early season dust microbiomes were more diverse than those found later in the year. The relative abundances of microbial groups shifted during the summer dry season. Furthermore, mutualistic fungal diversity increased with elevation, which may have corresponded with the biogeography of their plant hosts. Although dust fungal pathogen diversity was equivalent across elevations, elevation and sampling month interactions for the relative abundance, diversity, and richness of fungal pathogens suggest that these pathogens differed temporally across elevations, with potential implications for humans and wildlife. This study shows that landscape topography and droughts in source locations may alter the composition and diversity of ecologically relevant dust-associated microorganisms.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Bacterial Resistance Toward Antimicrobial Ionic Liquids Mediated by Multidrug Efflux Pumps

The effective elimination of foodborne pathogens through cleaning and disinfection measures is of great importance to the food processing industry. As food producers rely heavily on disinfectants to control pathogenic bacteria in their facilities, the increasing spread of tolerant, often even multidrug resistant, strains is of particular concern. In addition to efforts to prevent or at least reduce development and spread of strains resistant to disinfectants and sanitizers, there is an urgent need for new and effective antimicrobials. One new class of promising antimicrobials is ionic liquids (ILs), which have been reported to be effective against resistant strains as they interact with bacterial cells in multiple ways, but investigations of their effectivity against MDR bacteria or specific defense mechanisms are still limited. This study investigates the role of multidrug efflux pumps of the Resistance Nodulation-Division family (RND) on the resistance of bacterial pathogens Escherichia coli and Salmonella enterica serovar Typhimurium toward 10 antimicrobial active ILs. Results reveal that, while known structure–activity relationships (SARs), such as the side-chain effect, were found for all strains, antimicrobial ILs with one elongated alkyl side chain were significantly affected by the RND efflux pump, highlighting the importance of efflux pumps for future IL toxicity studies. In case of antimicrobial ILs with multiple side chains and different cationic head groups, two ILs were identified that were highly active against all investigated strains with little to no effect of the efflux pump. The results obtained in this study for RND efflux pumps can serve as a starting point for identifying and designing antimicrobial ILs as effective biocides against MDR bacteria.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

SARS-CoV-2 raw wastewater surveillance from student residences on an urban university campus

The COVID-19 pandemic brought about an urgent need to monitor the community prevalence of infection and detect the presence of SARS-CoV-2. Testing individual people is the most reliable method to measure the spread of the virus in any given community, but it is also the most expensive and time-consuming. Wastewater-based epidemiology (WBE) has been used since the 1960s when scientists implemented monitoring to measure the effectiveness of the Polio vaccine. Since then, WBE has been used to monitor populations for various pathogens, drugs, and pollutants. In August 2020, the University of Tennessee-Knoxville implemented a SARS-CoV-2 surveillance program that began with raw wastewater surveillance of the student residence buildings on campus, the results of which were shared with another lab group on campus that oversaw the pooled saliva testing of students. Sample collection began at 8 am, and the final RT-qPCR results were obtained by midnight. The previous day’s results were presented to the campus administrators and the Student Health Center at 8 am the following morning. The buildings surveyed included all campus dormitories, fraternities, and sororities, 46 buildings in all representing an on-campus community of over 8,000 students. The WBE surveillance relied upon early morning “grab” samples and 24-h composite sampling. Because we only had three Hach AS950 Portable Peristaltic Sampler units, we reserved 24-h composite sampling for the dormitories with the highest population of students. Samples were pasteurized, and heavy sediment was centrifuged and filtered out, followed by a virus concentration step before RNA extraction. Each sample was tested by RT-qPCR for the presence of SARS-CoV-2, using the CDC primers for N Capsid targets N1 and N3. The subsequent pooled saliva tests from sections of each building allowed lower costs and minimized the total number of individual verification tests that needed to be analyzed by the Student Health Center. Our WBE results matched the trend of the on-campus cases reported by the student health center. The highest concentration of genomic copies detected in one sample was 5.06 × 10 7 copies/L. Raw wastewater-based epidemiology is an efficient, economical, fast, and non-invasive method to monitor a large community for a single pathogen or multiple pathogen targets.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Shifts in the swine nasal microbiota following Bordetella bronchiseptica challenge in a longitudinal study

Bordetella bronchiseptica is a widespread, highly infectious bacterial pathogen that causes respiratory disease in swine and increases the severity of respiratory infections caused by other viral or bacterial pathogens. However, the impact of B. bronchiseptica infection on the swine respiratory microbiota has not been thoroughly investigated. Here, we aim to assess the influence of B. bronchiseptica infection on the community structure and abundance of members of the swine nasal microbiota. To do so, the nasal microbiota of a non-infected control group and a group infected with B. bronchiseptica (BB group) were characterized prior to B. bronchiseptica strain KM22 challenge (day 0) and on selected days in the weeks following B. bronchiseptica challenge (days 1, 3, 7, 10, 14, 21, 36, and 42). Bordetella bronchiseptica was cultured from nasal samples of the BB group to assess nasal colonization. The results showed that B. bronchiseptica colonization did not persistently affect the nasal bacterial diversity of either of the treatment groups (alpha diversity). However, the bacterial community structures (beta diversity) of the two treatment groups significantly diverged on day 7 when peak colonization levels of B. bronchiseptica were detected. This divergence continued through the last sampling time point. In addition, Pasteurella, Pasteurellaceae (unclassified), Mycoplasma, Actinobacillus, Streptococcus, Escherichia-Shigella, and Prevotellaceae (unclassified) showed increased abundances in the BB group relative to the control group at various time points. This study revealed that B. bronchiseptica colonization can disturb the upper respiratory tract microbiota, and further research is warranted to assess how these disturbances can impact susceptibility to secondary infections by other respiratory pathogens.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2023

Construction of nano slow-release systems for antibacterial active substances and its applications: A comprehensive review

At present, nano-carrier materials with antibacterial activity are of great significance. Due to the widespread resistance of many pathogenic microorganisms, it has seriously threatened human health. The natural antimicrobial substances extracted from fruits and vegetables can significantly improve their stability combined with nano-carrier materials. The resistance of pathogenic microorganisms will be substantially reduced, greatly enhancing the effect of active antimicrobial substances. Nanotechnology has excellent research prospects in the food industry, antibacterial preservation, food additives, food packaging, and other fields. This paper introduces nano-carrier materials and preparation techniques for loading and encapsulating active antibacterial substances in detail by constructing a nano-release system for active antibacterial substances. The antibacterial effect can be achieved by protecting them from adverse external conditions and destroying the membrane of pathogenic microorganisms. The mechanism of the slow release of the bacteriostatic active substance is also described. The mechanism of carrier loading and release is mainly through non-covalent forces between the bacteriostatic active substance and the carrier material, such as hydrogen bonding, π-π stacking, van der Waals forces, electrostatic interactions, etc., as well as the loading and adsorption of the bacteriostatic active substance by the chemical assembly. Finally, its wide application in food and medicine is introduced. It is hoped to provide a theoretical basis and technical support for the efficient utilization and product development of bacteriostatic active substances.

Cao, Jiayong↗