The Molecular Pathophysiology of Psoriatic Arthritis—The Complex Interplay Between Genetic Predisposition, Epigenetics Factors, and the Microbiome

Psoriasis is a symmetric autoimmune/inflammatory disease that primarily affects the skin. In a significant proportion of cases, it is accompanied by arthritis that can affect any joint, the spine, and/or include enthesitis. Psoriasis and psoriatic arthritis are multifactor disorders characterized by aberrant immune responses in genetically susceptible individuals in the presence of additional (environmental) factors, including changes in microbiota and/or epigenetic marks. Epigenetic changes can be heritable or acquired (e.g., through changes in diet/microbiota or as a response to therapeutics) and, together with genetic factors, contribute to disease expression. In psoriasis, epigenetic alterations are mainly related to cell proliferation, cytokine signaling and microbial tolerance. Understanding the complex interplay between heritable and acquired pathomechanistic factors contributing to the development and maintenance of psoriasis is crucial for the identification and validation of diagnostic and predictive biomarkers, and the introduction of individualized effective and tolerable new treatments. This review summarizes the current understanding of immune activation, genetic, and environmental factors that contribute to the pathogenesis of psoriatic arthritis. Particular focus is on the interactions between these factors to propose a multifactorial disease model.

Engineering prokaryotic regulator IrrE to enhance stress tolerance in budding yeast

Background Stress tolerance is one of the important desired microbial traits for industrial bioprocesses, and global regulatory protein engineering is an efficient approach to improve strain tolerance. In our study, IrrE, a global regulatory protein from the prokaryotic organism Deinococcus radiodurans, was engineered to confer yeast improved tolerance to the inhibitors in lignocellulose hydrolysates or high temperatures. Results Three IrrE mutations were developed through directed evolution, and the expression of these mutants could improve the yeast fermentation rate by threefold or more in the presence of multiple inhibitors. Subsequently, the tolerance to multiple inhibitors of single-site mutants based on the mutations from the variants were then evaluated, and 11 mutants, including L65P, I103T, E119V, L160F, P162S, M169V, V204A, R244G, Base 824 Deletion, V299A, and A300V were identified to be critical for the improved representative inhibitors, i.e., furfural, acetic acid and phenol (FAP) tolerance. Further studies indicated that IrrE caused genome-wide transcriptional perturbation in yeast, and the mutant I24 led to the rapid growth of Saccharomyces cerevisiae by primarily regulating the transcription level of transcription activators/factors, protecting the intracellular environment and enhancing the antioxidant capacity under inhibitor environments, which reflected IrrE plasticity. Meanwhile, we observed that the expression of the wild-type or mutant IrrE could also protect Saccharomyces cerevisiae from the damage caused by thermal stress. The recombinant yeast strains were able to grow with glucose at 42 ℃. Conclusions IrrE from Deinococcus radiodurans can be engineered as a tolerance-enhancer for Saccharomyces cerevisiae. Systematic research on the regulatory model and mechanism of a prokaryotic global regulatory factor IrrE to increase yeast tolerance provided valuable insights for the improvements in microbial tolerance to complex industrial stress conditions.

Engineering prokaryotic regulator IrrE to enhance stress tolerance in budding yeast

BackgroundStress tolerance is one of the important desired microbial traits for industrial bioprocesses, and global regulatory protein engineering is an efficient approach to improve strain tolerance. In our study, IrrE, a global regulatory protein from the prokaryotic organism Deinococcus radiodurans, was engineered to confer yeast the improved tolerances to the inhibitors in lignocellulose hydrolysates or high temperatures.ResultsThree IrrE mutations were developed through directed evolution, and the expression of these mutants could improve the yeast fermentation rate by 3-fold or more in the presence of multiple inhibitors. Subsequently, the tolerance to multiple inhibitors of single-site mutants based on the mutations from the variants were then evaluated, and eleven mutants, including L65P, I103T, E119V, L160F, P162S, M169V, V204A, R244G, Base 824 Deletion, V299A, and A300V were identified to be critical for the improved representative inhibitors, i.e., furfural, acetic acid and phenol (FAP) tolerance. Further studies indicated that IrrE caused genome-wide transcriptional perturbation in yeast, and the mutant I24 led to the rapid growth of Saccharomyces cerevisiae by primarily regulating the transcription level of transcription activators/factors, protecting the intracellular environment and enhancing the antioxidant capacity under inhibitor environments, which reflected IrrE plasticity. Meanwhile, we observed that the expression of the wild-type or mutant IrrE could also protect Saccharomyces cerevisiae from the damage caused by thermal stress. The recombinant yeast strains were able to grow with glucose at 42 ºC.ConclusionsIrrE from Deinococcus radiodurans can be engineered as a tolerance-enhancer for Saccharomyces cerevisiae. Systematic research on the regulatory model and mechanism of a prokaryotic global regulatory factor IrrE to increase yeast tolerance provided valuable insights for the improvements in microbial tolerance to complex industrial stress conditions.

Survival and growth of soil microbial communities under influence of sodium perchlorates

Previously conducted space missions revealed the presence of perchlorates, which are known to have a high oxidizing potential in Martian regolith, at the level of 0.5%. Due to hygroscopic properties and crystallization features of perchlorate-containing solutions, assumptions leading to the possibility of the existence of liquid water in the form of brines, which can contribute to the vital activity of microorganisms, have been made. At the same time, high concentrations of perchlorates can inhibit the growth of microorganisms and cause their death. Previously performed studies have discovered the presence of highly diverse microbial communities in terrestrial perchlorate-containing soils and have also demonstrated the stability and activity of some prokaryotes cultured on highly concentrated perchlorates media (over 10%). Nevertheless, the limits of microbial tolerance to perchlorates and whether microbial communities are able to withstand the effects of high concentrations of perchlorates remain uncertain. The aim of this research was to study the reaction of microbial communities of hot-arid and cryo-arid soils and sedimentary rocks to the adding of a highly concentrated solution of sodium perchlorate (5%) in situ. An increase in the total number of prokaryotes, the number of metabolically active Bacteria and Archaea, and the variety of the consumed substrates were revealed. It was observed that in samples incubated with sodium perchlorate, a high taxonomic diversity of the microbial community is preserved at a level comparable to control sample. The study shows that the presence of high concentrations of sodium perchlorate (5%) in the soil does not lead to the death or significant inhibition of microbial communities.

Engineering prokaryotic regulator IrrE to enhance stress tolerance in budding yeast

Background: Stress tolerance is one of the important desired microbial traits for industrial bioprocess and global regulatory protein engineering is an efficient approach to improve strain tolerance. In our study, IrrE, a global regulatory protein from prokaryotic organism Deinococcus radiodurans, was engineered to confer yeast the improved tolerance to the inhibitors in lignocellulose hydrolysates or high temperature.Results: Three IrrE mutants were developed through directed evolution and the expression of these mutants could improve the yeast fermentation rate by 3- to 4-fold in the presence of multiple inhibitors. Subsequently, the tolerance to multiple inhibitors of single-site mutants based on the mutations from the variants was then evaluated, and eleven mutants including L65P, I103T, E119V, L160F, P162S, M169V, V204A, R244G, Base 824 Deletion, V299A and A300V were identified to be critical for the improved FAP tolerance. Further studies indicated that IrrE caused genome-wide transcriptional perturbation in yeast, and the mutant I24 led to the rapid growth of Saccharomyces cerevisiae mainly by regulating the transcription level of transcription activators/factors, protecting the intracellular environment and enhancing the antioxidant capacity under inhibitor environment, which reflected the plasticity of IrrE. Meanwhile, we observed that the expression of the wild-type or mutant IrrE could also protect Saccharomyces cerevisiae from the damage caused by thermal stress. The recombinant yeast strains were able to grow with glucose at 42 ºC.Conclusions: IrrE from Deinococcus radiodurans can be engineered as a tolerance-enhancer for Saccharomyces cerevisiae. Systematic research on the regulatory model and mechanism of a prokaryotic global regulatory factor IrrE to increase yeast tolerance provided valuable insights for the improvement of microbial tolerance to complex industrial stress conditions.

Can heavy metal pollution induce bacterial tolerance to antibiotics in soils from ancient land-mines?

<p>Soil microbial communities play vital roles in the biogeochemical processes, and they are sensitive to environmental pressure induced by environmental pollutants, including heavy metal or antibiotic contaminants. It is well known that exposure to heavy metals can increase microbial tolerance in contaminated soil. Recently it was also discovered that heavy metal exposure in agricultural soils could induce microbial tolerance to antibiotics, thus yielding human health concerns. To date, it remains unknown how wide-spread this co-tolerance is in the environment. The aim of this study was to determine the microbial tolerance under different heavy metal concentration levels, and to investigate whether increasing tolerance to metals will co-select for tolerance to antibiotic. We hypothesized that microbial tolerance to both heavy metals and antibiotics would increase with metal pollutant concentrations. The tolerance to pollutants was determined by the pollution induced community tolerance (PICT) approach and the concentration for 50% inhibition (IC<sub>50</sub>) values.</p><p>To address our hypothesis, we collected soil samples from an ancient open cast land-mine in North Wales, UK, called Parys Mountain, known as the ‘Copper Kingdom’, where the soils cover a very wide span concentrations (c. 50 µg – 4000 µg g<sup>-1</sup> soil) of copper (Cu), lead (Pb) and zinc (Zn) alone or in combination. The soils were very acidic with pH range from 3.49 to 4.96, and soil organic matter contents very variable, from 5 to 46 %, yielding a wide range of water holding capacities, from 0.45 to 3.47 g water g<sup>-1 </sup>dry soil. We determined basal soil respiration, SIR-biomass, microbial growth and community composition, and bacterial tolerance to Cu, Pb, Zn, tetracycline and vancomycin.</p><p>We found that bacterial growth rates significantly decreased with increasing available Cu (R² = 0.26) and decreasing pH (R² = 0.39), but did not show any regressions against with total metal concentrations, and total microbial biomass and respiration showed similar patterns. It was possible to reliably establish accurate dose-response relationships for bacterial tolerance to metals with average R<sup>2</sup> values of 0.96 for Cu, 0.93 for Pb, and 0.92 for Zn with logistic curve fits. Based on these, we estimated that bacterial tolerance to heavy metals varied substantially across the sites, with average log(IC<sub>50</sub>) value was c. 4 log-unit Cu, 3.4 log-unit Pb, and 3.8 log-unit Zn. Metal tolerance was weakly linked to soil metal concentrations, as shown by limited linear relationship built between tolerance and soil concentrations (R<sup>2</sup>= 0.25, 0.44, 0.20 for Cu, Pb and Zn, respectively). The substantial variance in heavy metal tolerance among the sampled mining soils provided a high power to assess if metal tolerance could induce tolerance also to antibiotics. To assess this, we established dose response relationships between bacterial growth and a common and widely used antibiotic (tetracycline) as well as an antibiotic held in reserve for human therapy (vancomycin). The toxicity estimates are still awaiting analyses, but we hypothesize a strong link between bacterial tolerance to tetracycline and that for Cu, Zn, and Pb, while a weaker or non-existent pattern is expected for vancomycin, due to its limited environmental presence.</p><p> </p>

Aerobiología en hospitales de Guayaquil: microorganismos resistentes a cobre

The present work reports the presence of bacteria and fungi in particulate matter suspended in the exterior of three hospitals in Guayaquil, during the month of March 2019, winter time. The isolated microbial diversity was tolerant to a toxic copper concentration of 3.1 mM. From the particulate material, a greater number of bacterial than fungal species was isolated. However, the fungal species found are related to nosocomial diseases. This is a seed study that aims to lay the foundations for the characterization of microbial diversity through bioprospecting studies, based on aerodynamic factors (wind speed), climatic factors (temperature and relative humidity) and physical composition (content of dust in the air) to correlate the viability of formation of bioaerosols in particulate material in Guayaquil hospitals. Therefore, one of the objectives of the present work is the investigation of the influence of the heavy metal copper in the formulations of culture media to evaluate the microbial tolerance. And due to the potential risk of lack of air control in health institutions, the main objective of the present work is to evaluate the growth conditions of microorganisms present in the suspended particulate material surrounding three hospitals in Guayaquil. Index Terms—nosocomial, pathogens, airborne, SEM

Mechanism of Tolerance to the Lignin-Derived Inhibitor p-Benzoquinone and Metabolic Modification of Biorefinery Fermentation Strains

ABSTRACT p-Benzoquinone (BQ) is a lignin-derived inhibitor of biorefinery fermentation strains produced during pretreatment of lignocellulose. Unlike the well-studied inhibitors furan aldehydes, weak acids, and phenolics, the inhibitory properties of BQ, the microbial tolerance mechanism, and the detoxification strategy for this inhibitor have not been clearly elucidated. Here, BQ was identified as a by-product generated during acid pretreatment of various lignocellulose feedstocks, including corn stover, wheat straw, rice straw, tobacco stem, sunflower stem, and corncob residue. BQ at 20 to 200 mg/liter severely inhibited the cell growth and fermentability of various bacteria and yeast strains used in biorefinery fermentations. The BQ tolerance of the strains was found to be closely related to their capacity to convert BQ to nontoxic hydroquinone (HQ). To identify the key genes responsible for BQ tolerance, transcription levels of 20 genes potentially involved in the degradation of BQ in Zymomonas mobilis were investigated using real-time quantitative PCR in BQ-treated cells. One oxidoreductase gene, one hydroxylase gene, three reductase genes, and three dehydrogenase genes were found to be responsible for the conversion of BQ to HQ. Overexpression of the five key genes in Z. mobilis (ZMO1696, ZMO1949, ZMO1576, ZMO1984, and ZMO1399) accelerated its cell growth and cellulosic ethanol production in BQ-containing medium and lignocellulose hydrolysates. IMPORTANCE This study advances our understanding of BQ inhibition behavior and the mechanism of microbial tolerance to this inhibitor and identifies the key genes responsible for BQ detoxification. The insights here into BQ toxicity and tolerance provide the basis for future synthetic biology to engineer industrial fermentation strains with enhanced BQ tolerance.

Phospho-tuning immunity through Denisovan, modern human and mouse TNFAIP3 gene variants

Resisting or tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here, genomic analyses of anatomically modern humans, extinct Denisovan hominins, and mice revealed a series of missense variants in the immune response inhibitor A20 (encoded by TNFAIP3), substituting non-catalytic residues of the ubiquitin protease domain to diminish IκB-dependent phosphorylation and activation of A20. Two A20 variants with partial phosphorylation deficits appeared beneficial: one originating in Denisovans and introgressed in modern humans throughout Oceania, and another in a mouse strain resistant to Coxsackievirus. By contrast, a variant with 95% loss of phosphorylation caused spontaneous inflammatory disease in humans and mice. Analysis of the partial phosphorylation variant in mice revealed diminished tolerance of bacterial lipopolysaccharide or to poxvirus inoculation as trade-offs for enhanced immunity.One Sentence SummaryModern and ancient variants reveal a genetically tunable element for balancing immunity and microbial tolerance.