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1
Xiong, Lifeng, Jade Teng, Michael Botelho, Regina Lo, Susanna Lau, and Patrick Woo. "Arginine Metabolism in Bacterial Pathogenesis and Cancer Therapy." International Journal of Molecular Sciences 17, no. 3 (March 11, 2016): 363. http://dx.doi.org/10.3390/ijms17030363.
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Das, Mayashree, Arshiya Dewan, Somnath Shee, and Amit Singh. "The Multifaceted Bacterial Cysteine Desulfurases: From Metabolism to Pathogenesis." Antioxidants 10, no. 7 (June 23, 2021): 997. http://dx.doi.org/10.3390/antiox10070997.
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Living cells have developed a relay system to efficiently transfer sulfur (S) from cysteine to various thio-cofactors (iron-sulfur (Fe-S) clusters, thiamine, molybdopterin, lipoic acid, and biotin) and thiolated tRNA. The presence of such a transit route involves multiple protein components that allow the flux of S to be precisely regulated as a function of environmental cues to avoid the unnecessary accumulation of toxic concentrations of soluble sulfide (S2−). The first enzyme in this relay system is cysteine desulfurase (CSD). CSD catalyzes the release of sulfane S from L-cysteine by converting it to L-alanine by forming an enzyme-linked persulfide intermediate on its conserved cysteine residue. The persulfide S is then transferred to diverse acceptor proteins for its incorporation into the thio-cofactors. The thio-cofactor binding-proteins participate in essential and diverse cellular processes, including DNA repair, respiration, intermediary metabolism, gene regulation, and redox sensing. Additionally, CSD modulates pathogenesis, antibiotic susceptibility, metabolism, and survival of several pathogenic microbes within their hosts. In this review, we aim to comprehensively illustrate the impact of CSD on bacterial core metabolic processes and its requirement to combat redox stresses and antibiotics. Targeting CSD in human pathogens can be a potential therapy for better treatment outcomes.
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Kirthika, Perumalraja, Khristine Kaith Sison Lloren, Vijayakumar Jawalagatti, and John Hwa Lee. "Structure, Substrate Specificity and Role of Lon Protease in Bacterial Pathogenesis and Survival." International Journal of Molecular Sciences 24, no. 4 (February 8, 2023): 3422. http://dx.doi.org/10.3390/ijms24043422.
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Proteases are the group of enzymes that carry out proteolysis in all forms of life and play an essential role in cell survival. By acting on specific functional proteins, proteases affect the transcriptional and post-translational pathways in a cell. Lon, FtsH, HslVU and the Clp family are among the ATP-dependent proteases responsible for intracellular proteolysis in bacteria. In bacteria, Lon protease acts as a global regulator, governs an array of important functions such as DNA replication and repair, virulence factors, stress response and biofilm formation, among others. Moreover, Lon is involved in the regulation of bacterial metabolism and toxin–antitoxin systems. Hence, understanding the contribution and mechanisms of Lon as a global regulator in bacterial pathogenesis is crucial. In this review, we discuss the structure and substrate specificity of the bacterial Lon protease, as well as its ability to regulate bacterial pathogenesis.
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Abuawad, Alaa. "Treatment of Macrophages with Gram-Negative and -Positive Bacterial Secretomes Induce Distinct Metabolic Signatures." Jordan Journal of Pharmaceutical Sciences 16, no. 2 (July 24, 2023): 465. http://dx.doi.org/10.35516/jjps.v16i2.1508.
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Infectious diseases represent major health and economic challenges globally. Emergence of multiple drug-resistant bacteria in the community and hospital has become a worldwide concern that requires novel approaches for rapid diagnosis and treatment. Metabolomics approach is a powerful tool providing important chemical information about the cellular phenotype of living systems, and the changes in their metabolic pathways in response to various perturbations. Metabolomics has become an important tool to study host-pathogen interactions and to discover potential novel therapeutic targets. In this study, untargeted LC-MS metabolic profiling was applied to differentiate between the impact of the secretome of the Gram-positive S. aureus SH1000 and Gram-negative P. aeruginosa PAO1 bacterial pathogens on THP-1 macrophages. The results showed that S. aureus and P. aeruginosa secretome affected alanine, aspartate and glutamate metabolism; sphingolipid metabolism; glycine and serine metabolism; GL metabolism; and tryptophan metabolism with different trends in THP-1 macrophages. However, the impact of both bacterial secretome on arginine and proline metabolism was similar. These data could contribute to a better understanding of pathogenesis and resistance of these bacteria and could pave the way for developing new therapeutics that selectively targeting Gram-positive or Gram-negative bacteria.
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Chen, Jiezhong, and Luis Vitetta. "Gut Microbiota Metabolites in NAFLD Pathogenesis and Therapeutic Implications." International Journal of Molecular Sciences 21, no. 15 (July 23, 2020): 5214. http://dx.doi.org/10.3390/ijms21155214.
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Gut microbiota dysregulation plays a key role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through its metabolites. Therefore, the restoration of the gut microbiota and supplementation with commensal bacterial metabolites can be of therapeutic benefit against the disease. In this review, we summarize the roles of various bacterial metabolites in the pathogenesis of NAFLD and their therapeutic implications. The gut microbiota dysregulation is a feature of NAFLD, and the signatures of gut microbiota are associated with the severity of the disease through altered bacterial metabolites. Disturbance of bile acid metabolism leads to underactivation of bile acid receptors FXR and TGR5, causal for decreased energy expenditure, increased lipogenesis, increased bile acid synthesis and increased macrophage activity. Decreased production of butyrate results in increased intestinal inflammation, increased gut permeability, endotoxemia and systemic inflammation. Dysregulation of amino acids and choline also contributes to lipid accumulation and to a chronic inflammatory status. In some NAFLD patients, overproduction of ethanol produced by bacteria is responsible for hepatic inflammation. Many approaches including probiotics, prebiotics, synbiotics, faecal microbiome transplantation and a fasting-mimicking diet have been applied to restore the gut microbiota for the improvement of NAFLD.
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Bongaerts, Ger P. A., and David M. Lyerly. "Role of bacterial metabolism and physiology in the pathogenesis ofClostridium difficiledisease." Microbial Pathogenesis 22, no. 4 (April 1997): 253–56. http://dx.doi.org/10.1006/mpat.1996.0119.
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Enany, Shymaa. "Impact of Low pH on Microbial Growth Rate, ATP Production, and NADH to NAD+ ratio." Egyptian Journal of Medical Microbiology 29, no. 3 (July 1, 2020): 121–28. http://dx.doi.org/10.51429/ejmm29314.
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Background: Bacterial metabolism is the tendency of bacteria to live, function, and replicate fittingly under their current culture and varied environment conditions. Microorganisms have intricated metabolic regulatory mechanisms to ameliorate environmental stresses. Objectives: We examined the effect of acidic pH, as one of stresses, on growth rate and metabolism of five different microorganisms. Methodology: ATP level, as an indicator for microbial viability, and alterations in NADH/NAD+ ratio, which plays a critical role in microbial metabolism, were assessed. Results: Our results showed that alterations in pH influence metabolism of different bacterial species with different extent. The growth rate of Pseudomonas aeruginosa, Escherichia coli and Bacillus Subtilis were diminished with an elevation in ATP and NADH/NAD+ ratio at low pH. Contrary, MRSA and MSSA showed trivial alterations for ATP and NADH/NAD+ ratio. Conclusion: Ultimately, this study affirmed differences in metabolism between different species and confirmed that alterations in pH influenced the metabolism and hence the pathogenesis.
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Sumner, Sarah E., Rachel L. Markley, and Girish S. Kirimanjeswara. "Role of Selenoproteins in Bacterial Pathogenesis." Biological Trace Element Research 192, no. 1 (September 5, 2019): 69–82. http://dx.doi.org/10.1007/s12011-019-01877-2.
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Laborda-Illanes, Aurora, Lidia Sanchez-Alcoholado, María Emilia Dominguez-Recio, Begoña Jimenez-Rodriguez, Rocío Lavado, Iñaki Comino-Méndez, Emilio Alba, and María Isabel Queipo-Ortuño. "Breast and Gut Microbiota Action Mechanisms in Breast Cancer Pathogenesis and Treatment." Cancers 12, no. 9 (August 31, 2020): 2465. http://dx.doi.org/10.3390/cancers12092465.
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In breast cancer (BC) the employment of sequencing technologies for metagenomic analyses has allowed not only the description of the overall metagenomic landscape but also the specific microbial changes and their functional implications. Most of the available data suggest that BC is related to bacterial dysbiosis in both the gut microenvironment and breast tissue. It is hypothesized that changes in the composition and functions of several breast and gut bacterial taxa may contribute to BC development and progression through several pathways. One of the most prominent roles of gut microbiota is the regulation of steroid-hormone metabolism, such as estrogens, a component playing an important role as risk factor in BC development, especially in postmenopausal women. On the other hand, breast and gut resident microbiota are the link in the reciprocal interactions between cancer cells and their local environment, since microbiota are capable of modulating mucosal and systemic immune responses. Several in vivo and in vitro studies show remarkable evidence that diet, probiotics and prebiotics could exert important anticarcinogenic effects in BC. Moreover, gut microbiota have an important role in the metabolism of chemotherapeutic drugs and in the activity of immunogenic chemotherapies since they are a potential dominant mediator in the response to cancer therapy. Then, the microbiome impact in BC is multi-factorial, and the gut and breast tissue bacteria population could be important in regulating the local immune system, in tumor formation and progression and in therapy response and/or resistance.
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Prudhomme, N., R. Pastora, B. Muselius, M. D. McLean, D. Cossar, and J. Geddes-McAlister. "Exposure of Agrobacterium tumefaciens to agroinfiltration medium demonstrates cellular remodelling and may promote enhanced adaptability for molecular pharming." Canadian Journal of Microbiology 67, no. 1 (January 2021): 85–97. http://dx.doi.org/10.1139/cjm-2020-0239.
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Agroinfiltration is used to treat plants with modified strains of Agrobacterium tumefaciens for the purpose of transient in planta expression of genes transferred from the bacterium. These genes encode valuable recombinant proteins for therapeutic or industrial applications. Treatment of large quantities of plants for industrial-scale protein production exposes bacteria (harboring genes of interest) to agroinfiltration medium that is devoid of nutrients and carbon sources for prolonged periods of time (possibly upwards of 24 h). Such conditions may negatively influence bacterial viability, infectivity of plant cells, and target protein production. Here, we explored the role of timing in bacterial culture preparation for agroinfiltration using mass spectrometry-based proteomics to define changes in cellular processes. We observed distinct profiles associated with bacterial treatment conditions and exposure timing, including significant changes in proteins involved in pathogenesis, motility, and nutrient acquisition systems as the bacteria adapt to the new environment. These data suggest a progression towards increased cellular remodelling over time. In addition, we described changes in growth- and environment-specific processes over time, underscoring the interconnectivity of pathogenesis and chemotaxis-associated proteins with transport and metabolism. Overall, our results have important implications for the production of transiently expressed target protein products, as prolonged exposure to agroinfiltration medium suggests remodelling of the bacterial proteins towards enhanced infection of plant cells.
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Murros, Kari Erik. "Hydrogen Sulfide Produced by Gut Bacteria May Induce Parkinson’s Disease." Cells 11, no. 6 (March 12, 2022): 978. http://dx.doi.org/10.3390/cells11060978.
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Several bacterial species can generate hydrogen sulfide (H2S). Study evidence favors the view that the microbiome of the colon harbors increased amounts of H2S producing bacteria in Parkinson’s disease. Additionally, H2S can easily penetrate cell membranes and enter the cell interior. In the cells, excessive amounts of H2S can potentially release cytochrome c protein from the mitochondria, increase the iron content of the cytosolic iron pool, and increase the amount of reactive oxygen species. These events can lead to the formation of alpha-synuclein oligomers and fibrils in cells containing the alpha-synuclein protein. In addition, bacterially produced H2S can interfere with the body urate metabolism and affect the blood erythrocytes and lymphocytes. Gut bacteria responsible for increased H2S production, especially the mucus-associated species of the bacterial genera belonging to the Desulfovibrionaceae and Enterobacteriaceae families, are likely play a role in the pathogenesis of Parkinson’s disease. Special attention should be devoted to changes not only in the colonic but also in the duodenal microbiome composition with regard to the pathogenesis of Parkinson’s disease. Influenza infections may increase the risk of Parkinson’s disease by causing the overgrowth of H2S-producing bacteria both in the colon and duodenum.
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Spalding, Maroya D., and Sean T. Prigge. "Lipoic Acid Metabolism in Microbial Pathogens." Microbiology and Molecular Biology Reviews 74, no. 2 (June 2010): 200–228. http://dx.doi.org/10.1128/mmbr.00008-10.
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SUMMARY Lipoic acid [(R)-5-(1,2-dithiolan-3-yl)pentanoic acid] is an enzyme cofactor required for intermediate metabolism in free-living cells. Lipoic acid was discovered nearly 60 years ago and was shown to be covalently attached to proteins in several multicomponent dehydrogenases. Cells can acquire lipoate (the deprotonated charge form of lipoic acid that dominates at physiological pH) through either scavenging or de novo synthesis. Microbial pathogens implement these basic lipoylation strategies with a surprising variety of adaptations which can affect pathogenesis and virulence. Similarly, lipoylated proteins are responsible for effects beyond their classical roles in catalysis. These include roles in oxidative defense, bacterial sporulation, and gene expression. This review surveys the role of lipoate metabolism in bacterial, fungal, and protozoan pathogens and how these organisms have employed this metabolism to adapt to niche environments.
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Gétaz, Michael, Joanna Puławska, Theo H. M. Smits, and Joël F. Pothier. "Host–Pathogen Interactions between Xanthomonas fragariae and Its Host Fragaria × ananassa Investigated with a Dual RNA-Seq Analysis." Microorganisms 8, no. 8 (August 18, 2020): 1253. http://dx.doi.org/10.3390/microorganisms8081253.
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Strawberry is economically important and widely grown, but susceptible to a large variety of phytopathogenic organisms. Among them, Xanthomonas fragariae is a quarantine bacterial pathogen threatening strawberry productions by causing angular leaf spots. Using whole transcriptome sequencing, the gene expression of both plant and bacteria in planta was analyzed at two time points, 12 and 29 days post inoculation, in order to compare the pathogen and host response between the stages of early visible and of well-developed symptoms. Among 28,588 known genes in strawberry and 4046 known genes in X. fragariae expressed at both time points, a total of 361 plant and 144 bacterial genes were significantly differentially expressed, respectively. The identified higher expressed genes in the plants were pathogen-associated molecular pattern receptors and pathogenesis-related thaumatin encoding genes, whereas the more expressed early genes were related to chloroplast metabolism as well as photosynthesis related coding genes. Most X. fragariae genes involved in host interaction, recognition, and pathogenesis were lower expressed at late-phase infection. This study gives a first insight into the interaction of X. fragariae with its host. The strawberry plant changed gene expression in order to consistently adapt its metabolism with the progression of infection.
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Nogales, Juan, and Junkal Garmendia. "Bacterial metabolism and pathogenesis intimate intertwining: time for metabolic modelling to come into action." Microbial Biotechnology 15, no. 1 (October 21, 2021): 95–102. http://dx.doi.org/10.1111/1751-7915.13942.
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Wyatt, Elliott V., Karina Diaz, Amanda Griffin, Jed Rasmussen, Deborah Crane, Bradley Jones, and Catharine M. Bosio. "Optimal replication and suppression of inflammation by virulent Francisella tularensis is achieved through reprogramming of host glycolysis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 66.7. http://dx.doi.org/10.4049/jimmunol.196.supp.66.7.
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Abstract Francisella tularensis (Ft) is a gram negative, facultative intracellular bacterium that is the causative agent of pneumonic tularemia. Inhalation of as a few as 15 organisms can result in lethal infection. The virulence of Ft is attributed to the bacterium’s ability to both evade and suppress the activation of macrophages. However, the mechanisms and bacterial components required for evasion and suppression by Ft are unclear. Activation of macrophages and induction of antimicrobial responses requires a metabolic shift from oxidative phosphorylation to aerobic glycolysis. Thus, we postulated that Ft manipulates host metabolism as a mechanism of virulence. We established that virulent Ft suppresses induction of aerobic glycolysis among infected macrophages. Moreover, utilizing purified capsule and defined capsule mutants, we elucidated a novel role for Ft capsule as a component contributing to this suppression. The requirement for inhibition of host cell glycolysis in Ft pathogenesis was confirmed via direct inhibition of glycolysis using 2-deoxyglucose. Addition of 2-DG to macrophages infected with capsule mutants partially restored the early intracellular survival and replication of these bacteria, and impaired the secretion of pro-inflammatory cytokines that is typical of infection with these mutants. Together, our data demonstrate that manipulation of host metabolism is an important component of Ft pathogenesis and uncovers a previously unappreciated function of bacterial capsule in the virulence of Ft.
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Seitz, Helmut K., Bernardo Moreira, and Manuela G. Neuman. "Pathogenesis of Alcoholic Fatty Liver a Narrative Review." Life 13, no. 8 (July 30, 2023): 1662. http://dx.doi.org/10.3390/life13081662.
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Alcohol effect hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as dietary fat (saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)) may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferator activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c). The inhibition of AMPK, and thus of PPARα, results in an inhibition of FA oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1)-driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons. On the other side, the secretion of FAs via very-low-density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor α (TNF α), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver. Alcohol-induced gut dysbiosis contributes to the severity of ALD by increasing the metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen-associated molecular patterns (PAMPS) via specific Toll-like receptor (TLR) bacterial overgrowth leads to the translocation of bacteria. Endotoxins and toxic ethanol metabolites enter the enterohepatic circulation, reaching the liver and inducing the activation of the nuclear factor kappa-B (NFκB) pathway. Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in favour of necrosis.
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Wang, Yiwen, Yu Liu, Ruoping Chen, and Liang Qiao. "Metabolomic Characterization of Cerebrospinal Fluid from Intracranial Bacterial Infection Pediatric Patients: A Pilot Study." Molecules 26, no. 22 (November 15, 2021): 6871. http://dx.doi.org/10.3390/molecules26226871.
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Intracranial bacterial infection remains a major cause of morbidity and mortality in neurosurgical cases. Metabolomic profiling of cerebrospinal fluid (CSF) holds great promise to gain insights into the pathogenesis of central neural system (CNS) bacterial infections. In this pilot study, we analyzed the metabolites in CSF of CNS infection patients and controls in a pseudo-targeted manner, aiming at elucidating the metabolic dysregulation in response to postoperative intracranial bacterial infection of pediatric cases. Untargeted analysis uncovered 597 metabolites, and screened out 206 differential metabolites in case of infection. Targeted verification and pathway analysis filtered out the glycolysis, amino acids metabolism and purine metabolism pathways as potential pathological pathways. These perturbed pathways are involved in the infection-induced oxidative stress and immune response. Characterization of the infection-induced metabolic changes can provide robust biomarkers of CNS bacterial infection for clinical diagnosis, novel pathways for pathological investigation, and new targets for treatment.
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Price, Jordan, Lucian DiPeso, Daniel Nomura, and Russell E. Vance. "Metabolic barriers underlie interferon gamma-mediated restriction of intracellular bacterial pathogenesis." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 50.11. http://dx.doi.org/10.4049/jimmunol.200.supp.50.11.
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Abstract Interferon gamma (IFNγ) plays a critical role in controlling Legionella pneumophila (L. pneumophila) infection in vivo and in vitro. IFNγ and IFNγ receptor-deficient mice fail to clear L. pneumophila and eventually succumb to infection. In vitro, L. pneumophila replication is restricted in IFNγ-stimulated macrophages; however, the mechanism of IFNγ-dependent restriction of L. pneumophila remains mysterious and does not require most known IFNγ-driven antimicrobial pathways, including induction of autophagy and production of reactive nitrogen. As enhanced glycolysis is a notable metabolic characteristic of IFNγ and toll-like receptor-stimulated macrophages, we hypothesized that changes in macrophage metabolism are required for IFNγ-mediated restriction of L. pneumophila. Using a strain of L. pneumophila that is resistant to the glycolysis inhibitor 2-deoxyglucose (2DG), we were able to rescue bacterial growth in IFNγ-stimulated macrophages treated with 2DG. Interestingly, we observed that 2DG-mediated induction of the unfolded protein response appears to be more important than glycolysis inhibition in terms of interfering with IFNγ-mediated restriction of L. pneumophila. Our data suggest that metabolic shifts in IFNγ-stimulated macrophages could play a role in restriction of intracellular bacterial pathogen replication by altering the pool of available intracellular metabolites.
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Nuñez-Belmar, Josefa, Mauricio Morales-Olavarria, Emiliano Vicencio, Rolando Vernal, Juan P. Cárdenas, and Cristian Cortez. "Contribution of −Omics Technologies in the Study of Porphyromonas gingivalis during Periodontitis Pathogenesis: A Minireview." International Journal of Molecular Sciences 24, no. 1 (December 30, 2022): 620. http://dx.doi.org/10.3390/ijms24010620.
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Periodontitis is a non-communicable chronic inflammatory disease characterized by the progressive and irreversible breakdown of the soft periodontal tissues and resorption of teeth-supporting alveolar bone. The etiology of periodontitis involves dysbiotic shifts in the diversity of microbial communities inhabiting the subgingival crevice, which is dominated by anaerobic Gram-negative bacteria, including Porphyromonas gingivalis. Indeed, P. gingivalis is a keystone pathogen with a repertoire of attributes that allow it to colonize periodontal tissues and influence the metabolism, growth rate, and virulence of other periodontal bacteria. The pathogenic potential of P. gingivalis has been traditionally analyzed using classical biochemical and molecular approaches. However, the arrival of new techniques, such as whole-genome sequencing, metagenomics, metatranscriptomics, proteomics, and metabolomics, allowed the generation of high-throughput data, offering a suitable option for bacterial analysis, allowing a deeper understanding of the pathogenic properties of P. gingivalis and its interaction with the host. In the present review, we revise the use of the different −omics technologies and techniques used to analyze bacteria and discuss their potential in studying the pathogenic potential of P. gingivalis.
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Kotlyarov, Stanislav, and Anna Kotlyarova. "Molecular Mechanisms of Lipid Metabolism Disorders in Infectious Exacerbations of Chronic Obstructive Pulmonary Disease." International Journal of Molecular Sciences 22, no. 14 (July 17, 2021): 7634. http://dx.doi.org/10.3390/ijms22147634.
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Exacerbations largely determine the character of the progression and prognosis of chronic obstructive pulmonary disease (COPD). Exacerbations are connected with changes in the microbiological landscape in the bronchi due to a violation of their immune homeostasis. Many metabolic and immune processes involved in COPD progression are associated with bacterial colonization of the bronchi. The objective of this review is the analysis of the molecular mechanisms of lipid metabolism and immune response disorders in the lungs in COPD exacerbations. The complex role of lipid metabolism disorders in the pathogenesis of some infections is only beginning to be understood, however, there are already fewer and fewer doubts even now about its significance both in the pathogenesis of infectious exacerbations of COPD and in general in the progression of the disease. It is shown that the lipid rafts of the plasma membranes of cells are involved in many processes related to the detection of pathogens, signal transduction, the penetration of pathogens into the cell. Smoking disrupts the normally proceeded processes of lipid metabolism in the lungs, which is a part of the COPD pathogenesis.
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Wilburn, Kaley M., Christine R. Montague, Bo Qin, Ashley K. Woods, Melissa S. Love, Case W. McNamara, Peter G. Schultz, et al. "Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis." PLOS Pathogens 18, no. 2 (February 8, 2022): e1009862. http://dx.doi.org/10.1371/journal.ppat.1009862.
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There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3’, 5’-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required during cholesterol metabolism. Finally, the pharmacokinetic properties of Rv1625c agonists have been optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.
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Beebout, Connor J., Gabriella L. Robertson, Bradley I. Reinfeld, Alexandra M. Blee, Grace H. Morales, John R. Brannon, Walter J. Chazin, et al. "Uropathogenic Escherichia coli subverts mitochondrial metabolism to enable intracellular bacterial pathogenesis in urinary tract infection." Nature Microbiology 7, no. 9 (August 22, 2022): 1348–60. http://dx.doi.org/10.1038/s41564-022-01205-w.
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Lee, Jongan, Sung-hee Lee, Gyo Jeong Gu, Ji hyun Choi, Kyu-Tae Jeong, Jeom-Kyu Lee, and Seung Hyun Kim. "Alterations of lung microbial communities in obese allergic asthma and metabolic potential." PLOS ONE 16, no. 10 (October 28, 2021): e0256848. http://dx.doi.org/10.1371/journal.pone.0256848.
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In recent years, there has been a rapid increase in microbiome studies to explore microbial alterations causing disease status and unveil disease pathogenesis derived from microbiome environmental modifications. Convincing evidence of lung microbial changes involving asthma has been collected; however, whether lung microbial changes under obesity leads to severe asthma in a state of allergen exposure has not been studied sufficiently. Here, we measured bacterial alterations in the lung of an allergen mouse model induced by a high fat diet (HFD) by using 16S rRNA gene sequencing. A total of 33 pathogen‑free 3‑week‑old male C57BL/6 mice were used, and they divided randomly into two groups. The Chow diet (n = 16) and high fat diet (n = 17) was administrated for 70 days. Mice were sensitized with PBS or Dermatophagoides pteronyssinus extract (Der.p), and concentration levels of total IgE and Der.p-IgE in the blood were measured to quantify immune responses. Although there were no meaningful differences in bacterial species richness in the HFD mouse group, momentous changes of bacterial diversity in the HFD mouse group were identified after the mouse group was exposed to allergens. At a genus level, the fluctuations of taxonomic relative abundances in several bacteria such as Ralstonia, Lactobacillus, Bradyrhizobium, Gaiella, PAC001932_g, Pseudolabrys, and Staphylococcus were conspicuously observed in the HFD mouse group exposed to allergens. Also, we predicted metabolic signatures occurring under microbial alterations in the Chow group versus the Chow group exposed to allergens, as well as in the HFD mouse group versus the HFD group exposed to allergens. We then compared their similarities and differences. Metabolic functions associated with macrophages such as propanoate metabolism, butanoate metabolism, and glycine-serine-threonine metabolism were identified in the HFD group versus the Chow group. These results provide new insights into the understanding of a microbiome community of obese allergic asthma, and shed light on the functional roles of lung microbiota inducing the pathogenesis of severe asthma.
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de Macedo, Cristiana Santos, Flavio Alves Lara, Roberta Olmo Pinheiro, Veronica Schmitz, Marcia de Berrêdo-Pinho, Geraldo Moura Pereira, and Maria Cristina Vidal Pessolani. "New insights into the pathogenesis of leprosy: contribution of subversion of host cell metabolism to bacterial persistence, disease progression, and transmission." F1000Research 9 (January 31, 2020): 70. http://dx.doi.org/10.12688/f1000research.21383.1.
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Chronic infection by the obligate intracellular pathogen Mycobacterium leprae may lead to the development of leprosy. Of note, in the lepromatous clinical form of the disease, failure of the immune system to constrain infection allows the pathogen to reproduce to very high numbers with minimal clinical signs, favoring transmission. The bacillus can modulate cellular metabolism to support its survival, and these changes directly influence immune responses, leading to host tolerance, permanent disease, and dissemination. Among the metabolic changes, upregulation of cholesterol, phospholipids, and fatty acid biosynthesis is particularly important, as it leads to lipid accumulation in the host cells (macrophages and Schwann cells) in the form of lipid droplets, which are sites of polyunsaturated fatty acid–derived lipid mediator biosynthesis that modulate the inflammatory and immune responses. In Schwann cells, energy metabolism is also subverted to support a lipogenic environment. Furthermore, effects on tryptophan and iron metabolisms favor pathogen survival with moderate tissue damage. This review discusses the implications of metabolic changes on the course of M. leprae infection and host immune response and emphasizes the induction of regulatory T cells, which may play a pivotal role in immune modulation in leprosy.
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Oukala, Nadira, Victoria Pastor, and Kamel Aissat. "Bacterial Endophytes: The Hidden Actor in Plant Immune Responses against Biotic Stress." Plants 10, no. 5 (May 19, 2021): 1012. http://dx.doi.org/10.3390/plants10051012.
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Bacterial endophytes constitute an essential part of the plant microbiome and are described to promote plant health by different mechanisms. The close interaction with the host leads to important changes in the physiology of the plant. Although beneficial bacteria use the same entrance strategies as bacterial pathogens to colonize and enter the inner plant tissues, the host develops strategies to select and allow the entrance to specific genera of bacteria. In addition, endophytes may modify their own genome to adapt or avoid the defense machinery of the host. The present review gives an overview about bacterial endophytes inhabiting the phytosphere, their diversity, and the interaction with the host. Direct and indirect defenses promoted by the plant–endophyte symbiont exert an important role in controlling plant defenses against different stresses, and here, more specifically, is discussed the role against biotic stress. Defenses that should be considered are the emission of volatiles or antibiotic compounds, but also the induction of basal defenses and boosting plant immunity by priming defenses. The primed defenses may encompass pathogenesis-related protein genes (PR family), antioxidant enzymes, or changes in the secondary metabolism.
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Lubomski, Michal, Ai Huey Tan, Shen-Yang Lim, Andrew Holmes, Ryan L. Davis, and Carolyn M. Sue. "064 Parkinson’s disease and the gastrointestinal microbiome: clinicopathological correlations and controversies." Journal of Neurology, Neurosurgery & Psychiatry 90, e7 (July 2019): A21.1—A21. http://dx.doi.org/10.1136/jnnp-2019-anzan.56.
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IntroductionThere has been a recent surge in interest around the gastrointestinal microbiome (GM) and its association with Parkinson’s disease (PD). The GM mediates interactions between the brain and the gut via the ‘microbiota-gut-brain-axis’. Compelling studies suggest that a shift in GM composition may play an important role in the pathogenesis and progression of PD.MethodsWe conducted a literature review exploring the pathological association between the GM, α-synuclein spread and intestinal inflammation in PD. We also summarised patterns and correlations of gut microflora seen in clinical studies of the GM in PD.ResultsTo date 14 mainly cross-sectional studies from 7 countries have reported GM alterations in PD. All studies described significant alterations between PD and healthy control groups across multiple bacterial families, genera and species. Several studies suggested that putative ‘pro-inflammatory’ bacteria were significantly more abundant, while putative beneficial bacteria were less abundant in PD. Various complex microbiota-gut-brain-axis interactions have been proposed due to alterations in the GM, inferred by changes in gut mucosal integrity and permeability, short-chain-fatty-acid metabolism, oxidative stress and inflammation.ConclusionsAcross the recent GM studies in PD, alterations in bacterial taxa have been repeatedly associated with various clinicopathological features, endorsing a plausible biological link between the GM and PD. Mechanisms involved in the pathogenesis of PD due to GM changes are complex and require ongoing study.
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Joshi, Abhayraj S., Priyanka Singh, and Ivan Mijakovic. "Interactions of Gold and Silver Nanoparticles with Bacterial Biofilms: Molecular Interactions behind Inhibition and Resistance." International Journal of Molecular Sciences 21, no. 20 (October 16, 2020): 7658. http://dx.doi.org/10.3390/ijms21207658.
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Many bacteria have the capability to form a three-dimensional, strongly adherent network called ‘biofilm’. Biofilms provide adherence, resourcing nutrients and offer protection to bacterial cells. They are involved in pathogenesis, disease progression and resistance to almost all classical antibiotics. The need for new antimicrobial therapies has led to exploring applications of gold and silver nanoparticles against bacterial biofilms. These nanoparticles and their respective ions exert antimicrobial action by damaging the biofilm structure, biofilm components and hampering bacterial metabolism via various mechanisms. While exerting the antimicrobial activity, these nanoparticles approach the biofilm, penetrate it, migrate internally and interact with key components of biofilm such as polysaccharides, proteins, nucleic acids and lipids via electrostatic, hydrophobic, hydrogen-bonding, Van der Waals and ionic interactions. Few bacterial biofilms also show resistance to these nanoparticles through similar interactions. The nature of these interactions and overall antimicrobial effect depend on the physicochemical properties of biofilm and nanoparticles. Hence, study of these interactions and participating molecular players is of prime importance, with which one can modulate properties of nanoparticles to get maximal antibacterial effects against a wide spectrum of bacterial pathogens. This article provides a comprehensive review of research specifically directed to understand the molecular interactions of gold and silver nanoparticles with various bacterial biofilms.
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D’Antonio, Domenica Lucia, Simona Marchetti, Pamela Pignatelli, Adriano Piattelli, and Maria Cristina Curia. "The Oncobiome in Gastroenteric and Genitourinary Cancers." International Journal of Molecular Sciences 23, no. 17 (August 26, 2022): 9664. http://dx.doi.org/10.3390/ijms23179664.
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Early evidence suggests a strong association of microorganisms with several human cancers, and great efforts have been made to understand the pathophysiology underlying microbial carcinogenesis. Bacterial dysbiosis causes epithelial barrier failure, immune dysregulation and/or genotoxicity and, consequently, creates a tumor-permissive microenvironment. The majority of the bacteria in our body reside in the gastrointestinal tract, known as gut microbiota, which represents a complex and delicate ecosystem. Gut microbes can reach the pancreas, stomach and colon via the bloodstream. Oral bacterial translocations can also occur. In the stomach, pancreas and colon, low microbial diversity is associated with cancer, in particular with a bad prognosis. The urogenital tract also harbors unique microbiota, distinct from the gut microbiota, which might have a role in the urinary and female/male reproductive cancers’ pathogenesis. In healthy women, the majority of bacteria reside in the vagina and cervix and unlike other mucosal sites, the vaginal microbiota exhibits low microbial diversity. Genital dysbiosis might have an active role in the development and/or progression of gynecological malignancies through mechanisms including modulation of oestrogen metabolism. Urinary dysbiosis may influence the pathogenesis of bladder cancer and prostate cancer in males. Modulation of the microbiome via pre, pro and postbiotics, fecal or vaginal microbiota transplantation and engineering bacteria might prove useful in improving cancer treatment response and quality of life. Elucidating the complex host-microbiome interactions will result in prevention and therapeutic efficacy interventions.
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Wenzel, Björn E., Achim Peters, and Igor Zubaschev. "Bacterial virulence antigens and the pathogenesis of autoimmune thyroid diseases (AITD)." Experimental and Clinical Endocrinology & Diabetes 104, S 04 (July 15, 2009): 75–78. http://dx.doi.org/10.1055/s-0029-1211707.
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Halsey, Cortney R., Rochelle C. Glover, Maureen K. Thomason, and Michelle L. Reniere. "The redox-responsive transcriptional regulator Rex represses fermentative metabolism and is required for Listeria monocytogenes pathogenesis." PLOS Pathogens 17, no. 8 (August 16, 2021): e1009379. http://dx.doi.org/10.1371/journal.ppat.1009379.
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The Gram-positive bacterium Listeria monocytogenes is the causative agent of the foodborne disease listeriosis, one of the deadliest bacterial infections known. In order to cause disease, L. monocytogenes must properly coordinate its metabolic and virulence programs in response to rapidly changing environments within the host. However, the mechanisms by which L. monocytogenes senses and adapts to the many stressors encountered as it transits through the gastrointestinal (GI) tract and disseminates to peripheral organs are not well understood. In this study, we investigated the role of the redox-responsive transcriptional regulator Rex in L. monocytogenes growth and pathogenesis. Rex is a conserved canonical transcriptional repressor that monitors the intracellular redox state of the cell by sensing the ratio of reduced and oxidized nicotinamide adenine dinucleotides (NADH and NAD+, respectively). Here, we demonstrated that L. monocytogenes Rex represses fermentative metabolism and is therefore required for optimal growth in the presence of oxygen. We also show that in vitro, Rex represses the production of virulence factors required for survival and invasion of the GI tract, as a strain lacking rex was more resistant to acidified bile and invaded host cells better than wild type. Consistent with these results, Rex was dispensable for colonizing the GI tract and disseminating to peripheral organs in an oral listeriosis model of infection. However, Rex-dependent regulation was required for colonizing the spleen and liver, and L. monocytogenes lacking the Rex repressor were nearly sterilized from the gallbladder. Taken together, these results demonstrated that Rex functions as a repressor of fermentative metabolism and suggests a role for Rex-dependent regulation in L. monocytogenes pathogenesis. Importantly, the gallbladder is the bacterial reservoir during listeriosis, and our data suggest redox sensing and Rex-dependent regulation are necessary for bacterial survival and replication in this organ.
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Parra-Llorca, Anna, Alejandro Pinilla-Gonzlez, Laura Torrejón-Rodríguez, Inmaculada Lara-Cantón, Julia Kuligowski, María Carmen Collado, María Gormaz, et al. "Effects of Sepsis on Immune Response, Microbiome and Oxidative Metabolism in Preterm Infants." Children 10, no. 3 (March 22, 2023): 602. http://dx.doi.org/10.3390/children10030602.
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This is a narrative review about the mechanisms involved in bacterial sepsis in preterm infants, which is an illness with a high incidence, morbidity, and mortality. The role of the innate immune response and its relationship with oxidative stress in the pathogenesis are described as well as their potential implementation as early biomarkers. Moreover, we address the impact that all the mechanisms triggered by sepsis have on the dysbiosis and the changes on neonatal microbiota.
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Bhuiyan, Md Saruar, Felix Ellett, Gerald L. Murray, Xenia Kostoulias, Gustavo M. Cerqueira, Keith E. Schulze, Mohd Hafidz Mahamad Maifiah, et al. "Acinetobacter baumannii phenylacetic acid metabolism influences infection outcome through a direct effect on neutrophil chemotaxis." Proceedings of the National Academy of Sciences 113, no. 34 (August 9, 2016): 9599–604. http://dx.doi.org/10.1073/pnas.1523116113.
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Innate cellular immune responses are a critical first-line defense against invading bacterial pathogens. Leukocyte migration from the bloodstream to a site of infection is mediated by chemotactic factors that are often host-derived. More recently, there has been a greater appreciation of the importance of bacterial factors driving neutrophil movement during infection. Here, we describe the development of a zebrafish infection model to study Acinetobacter baumannii pathogenesis. By using isogenic A. baumannii mutants lacking expression of virulence effector proteins, we demonstrated that bacterial drivers of disease severity are conserved between zebrafish and mammals. By using transgenic zebrafish with fluorescent phagocytes, we showed that a mutation of an established A. baumannii global virulence regulator led to marked changes in neutrophil behavior involving rapid neutrophil influx to a localized site of infection, followed by prolonged neutrophil dwelling. This neutrophilic response augmented bacterial clearance and was secondary to an impaired A. baumannii phenylacetic acid catabolism pathway, which led to accumulation of phenylacetate. Purified phenylacetate was confirmed to be a neutrophil chemoattractant. These data identify a previously unknown mechanism of bacterial-guided neutrophil chemotaxis in vivo, providing insight into the role of bacterial metabolism in host innate immune evasion. Furthermore, the work provides a potentially new therapeutic paradigm of targeting a bacterial metabolic pathway to augment host innate immune responses and attenuate disease.
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Dahlen, Gunnar, Amina Basic, and Johan Bylund. "Importance of Virulence Factors for the Persistence of Oral Bacteria in the Inflamed Gingival Crevice and in the Pathogenesis of Periodontal Disease." Journal of Clinical Medicine 8, no. 9 (August 29, 2019): 1339. http://dx.doi.org/10.3390/jcm8091339.
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Periodontitis is a chronic inflammation that develops due to a destructive tissue response to prolonged inflammation and a disturbed homeostasis (dysbiosis) in the interplay between the microorganisms of the dental biofilm and the host. The infectious nature of the microbes associated with periodontitis is unclear, as is the role of specific bacterial species and virulence factors that interfere with the host defense and tissue repair. This review highlights the impact of classical virulence factors, such as exotoxins, endotoxins, fimbriae and capsule, but also aims to emphasize the often-neglected cascade of metabolic products (e.g., those generated by anaerobic and proteolytic metabolism) that are produced by the bacterial phenotypes that survive and thrive in deep, inflamed periodontal pockets. This metabolic activity of the microbes aggravates the inflammatory response from a low-grade physiologic (homeostatic) inflammation (i.e., gingivitis) into more destructive or tissue remodeling processes in periodontitis. That bacteria associated with periodontitis are linked with a number of systemic diseases of importance in clinical medicine is highlighted and exemplified with rheumatoid arthritis, The unclear significance of a number of potential “virulence factors” that contribute to the pathogenicity of specific bacterial species in the complex biofilm–host interaction clinically is discussed in this review.
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Candon, Heather L., Brenda J. Allan, Cresson D. Fraley, and Erin C. Gaynor. "Polyphosphate Kinase 1 Is a Pathogenesis Determinant in Campylobacter jejuni." Journal of Bacteriology 189, no. 22 (September 7, 2007): 8099–108. http://dx.doi.org/10.1128/jb.01037-07.
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ABSTRACT Campylobacter jejuni is the leading cause of bacterial gastroenteritis in the developed world. Despite its prevalence, relatively little is known about C. jejuni's precise pathogenesis mechanisms, particularly in comparison to other well-studied enteric organisms such as Escherichia coli and Salmonella spp. Altered expression of phosphate genes in a C. jejuni stringent response mutant, together with known correlations between the stringent response, polyphosphate (poly-P), and virulence in other bacteria, led us to investigate the role of poly-P in C. jejuni stress survival and pathogenesis. All sequenced C. jejuni strains harbor a conserved putative polyphosphate kinase 1 predicted to be principally responsible for poly-P synthesis. We generated a targeted ppk1 deletion mutant (Δppk1) in C. jejuni strain 81-176 and found that Δppk1, as well as the ΔspoT stringent response mutant, exhibited low levels of poly-P at all growth stages. In contrast, wild-type C. jejuni poly-P levels increased significantly as the bacteria transitioned from log to stationary phase. Phenotypic analyses revealed that the Δppk1 mutant was defective for survival during osmotic shock and low-nutrient stress. However, certain phenotypes associated with ppk1 deletion in other bacteria (i.e., motility and oxidative stress) were unaffected in the C. jejuni Δppk1 mutant, which also displayed an unexpected increase in biofilm formation. The C. jejuni Δppk1 mutant was also defective for the virulence-associated phenotype of intraepithelial cell survival in a tissue culture infection model and exhibited a striking, dose-dependent chick colonization defect. These results indicate that poly-P utilization and accumulation contribute significantly to C. jejuni pathogenesis and affect its ability to adapt to specific stresses and stringencies. Furthermore, our study demonstrates that poly-P likely plays both similar and unique roles in C. jejuni compared to its roles in other bacteria and that poly-P metabolism is linked to stringent response mechanisms in C. jejuni.
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Li, Haozhou, Yushan Xia, Zhenyang Tian, Yongxin Jin, Fang Bai, Zhihui Cheng, Wieslaw Swietnicki, Weihui Wu, and Xiaolei Pan. "Dihydrolipoamide Acetyltransferase AceF Influences the Type III Secretion System and Resistance to Oxidative Stresses through RsmY/Z in Pseudomonas aeruginosa." Microorganisms 10, no. 3 (March 21, 2022): 666. http://dx.doi.org/10.3390/microorganisms10030666.
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Carbon metabolism plays an important role in bacterial physiology and pathogenesis. The type III secretion system (T3SS) of Pseudomonas aeruginosa is a virulence factor that contributes to acute infections. It has been demonstrated that bacterial metabolism affects the T3SS. Meanwhile, expression of T3SS genes is negatively regulated by the small RNAs RsmY and RsmZ. In this study, we studied the relationship between the dihydrolipoamide acetyltransferase gene aceF and the T3SS. Our results reveal an upregulation of RsmY and RsmZ in the aceF mutant, which represses the expression of the T3SS genes. Meanwhile, the aceF mutant is more tolerant to hydrogen peroxide. We demonstrate that the expression levels of the catalase KatB and the alkyl hydroperoxide reductase AhpB are increased in the aceF mutant. The simultaneous deletion of rsmY and rsmZ in the aceF mutant restored the expression levels of katB and ahpB, as well as bacterial susceptibility to hydrogen peroxide. Thus, we identify a novel role of AceF in the virulence and oxidative response of P. aeruginosa.
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Roth, Alexa N., Katrina R. Grau, and Stephanie M. Karst. "Diverse Mechanisms Underlie Enhancement of Enteric Viruses by the Mammalian Intestinal Microbiota." Viruses 11, no. 8 (August 17, 2019): 760. http://dx.doi.org/10.3390/v11080760.
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Over the past two decades, there has been tremendous progress in understanding the impact of the intestinal microbiota on mammalian metabolism, physiology, and immune development and function. There has also been substantial advancement in elucidating the interplay between commensal and pathogenic bacteria. Relatively more recently, researchers have begun to investigate the effect of the intestinal microbiota on viral pathogenesis. Indeed, a growing body of literature has reported that commensal bacteria within the mammalian intestinal tract enhance enteric virus infections through a variety of mechanisms. Commensal bacteria or bacterial glycans can increase the stability of enteric viruses, enhance virus binding to host receptors, modulate host immune responses in a proviral manner, expand the numbers of host cell targets, and facilitate viral recombination. In this review, we will summarize the current literature exploring these effects of the intestinal microbiota on enteric virus infections.
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Elshikha, Ahmed Samir, Josephine Brown, Nathalie Kanda, Yong Ge, Xiangyu Teng, Georges Abboud, Seung-Chul Choi, et al. "The gut microbiota transfers the therapeutic effect of inhibiting glucose metabolism in lupus-prone mice." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 174.02. http://dx.doi.org/10.4049/jimmunol.208.supp.174.02.
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Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease in which autoantibodies induce tissue damage including the kidney. Gut microbial dysbiosis contributes to SLE pathogenesis. An abnormal metabolism is a characteristic feature of SLE in which the inflammatory functions of CD4+ T cells rely on glycolysis. We have shown that treatment with 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, reduced the expansion of germinal centers and eliminated the production of autoantibodies, ameliorating disease in lupus-prone mice, including (NZB × NZW)F1 and (NZW x BXSB)F1. Here we show that the 2DG treatment also maintained gut bacterial diversity, reduced the changes in bacterial populations that occurred as disease developed in these mice, and that it altered the distribution of fecal metabolites. We investigated the effect of fecal microbiota transplantation (FMT) from 2DG-treated or control mice into pre-autoimmune lupus-prone mice of the same strain. In both strains, FMT from 2DG-treated mice was highly protective, with a reduction or elimination of anti-dsDNA IgG production, immune cell activation, and renal pathology compared to FMT from control mice. Overall, our results demonstrated for the first time that the therapeutic effect of glucose inhibition in lupus is transferable through the gut microbiota. This implicates either a direct effect of glucose on pathogenic gut bacteria, or an indirect effect through the immune system normalized by glucose inhibition. Supported b R01 AI143313
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Lamichhane, Purushottam, Morgan Maiolini, Omar Alnafoosi, Sedra Hussein, Hasan Alnafoosi, Stewart Umbela, Tayanna Richardson, et al. "Colorectal Cancer and Probiotics: Are Bugs Really Drugs?" Cancers 12, no. 5 (May 5, 2020): 1162. http://dx.doi.org/10.3390/cancers12051162.
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Colorectal cancer (CRC) is one of the most common types of cancer worldwide. There are many factors that predispose a patient to the disease such as age, family history, ethnicity, and lifestyle. There are different genetic factors and diseases that also increase a person’s risk for developing CRC. Studies have found associations between gut microbiome and the risk for developing versus protection against CRC. Normal gut microbiome aid in daily functions of the human body such as absorption, metabolism, detoxification, and regulation of inflammation. While some species of bacteria prevent CRC development and aid in therapeutic responses to various treatment regiments, other species seem to promote CRC pathogenesis. In this regard, many studies have been conducted to not only understand the biology behind these opposing different bacterial species; but also to determine if supplementation of these tumor opposing bacterial species as probiotics lends toward decreased risk of CRC development and improved therapeutic responses in patients with CRC. In this literature review, we aim to discuss the basics on colorectal cancer (epidemiology, risk factors, targets, treatments), discuss associations between different bacterial strains and CRC, and discuss probiotics and their roles in CRC prevention and treatment.
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González, Enid T., and Caitilyn Allen. "Characterization of a Ralstonia solanacearum Operon Required for Polygalacturonate Degradation and Uptake of Galacturonic Acid." Molecular Plant-Microbe Interactions® 16, no. 6 (June 2003): 536–44. http://dx.doi.org/10.1094/mpmi.2003.16.6.536.
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The bacterial wilt pathogen Ralstonia solanacearum produces three extracellular polygalacturonases (PGs): PehA, PehB, and PehC. All three PGs hydrolyze pectin's polygalacturonic acid backbone, but each releases different reaction products. PehA and PehB contribute significantly to pathogen virulence, probably by facilitating root invasion and colonization. To determine the collective contribution of PGs to virulence and saprophytic survival, we cloned, characterized, and mutated the R. solanacearum pehC gene, which encodes a distinctive monogalacturonate-releasing exo-PG. The virulence of a pehC mutant on tomato was indistinguishable from that of its wild-type parent; thus, this exo-PG alone does not contribute significantly to wilt pathogenesis. Unexpectedly, a completely PG-deficient triple pehA/B/C mutant was slightly more virulent than a pehA/B mutant. PehC may degrade galacturonide elicitors of host defense, thereby protecting the pathogen from plant antimicrobial responses. A galacturonate transporter gene, exuT, is immediately downstream of pehC and the two genes are co-transcribed. It has been hypothesized that galacturonic acid released by PGs from plant cell walls nourishes bacteria during pathogenesis. To separate the pectolytic and nutrient-generating roles of the PGs, we made an exuT mutant, which still produces all three isozymes of PG but cannot uptake PG degradation products. This exuT mutant had wild-type virulence on tomato, demonstrating that metabolism of galacturonic acid does not contribute significantly to bacterial success inside the plant.
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Sankar, Poornima, Mohd Saqib, Tanvir Noor Nafiz, and Bibhuti B. Mishra. "M. tuberculosisinduced alterations in Siglecs’ expression on neutrophils predicts susceptibility to infection." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 156.03. http://dx.doi.org/10.4049/jimmunol.210.supp.156.03.
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Abstract The Presence of neutrophils in tuberculosis (TB) lung lesions is associated with bacterial growth. Despite being potent microbicidal cells, why neutrophils in TB lesions fail to control bacterial replication is poorly understood. By infecting mice with a hypervirulent replication reporter Mycobacterium tuberculosis(Mtb) W-Beijing Strain HN878, we found elevated neutrophils containing bacteria, associated with host susceptibility to infection. Phenotypic characterization of neutrophils from infected lungs revealed a downregulation of canonical neutrophil marker Siglec E (SigE) with concomitant upregulation of Siglec H (SigH), a marker generally used to define plasmacytoid dendritic cells. SigH expression on lung neutrophils increased with disease progression and predicts susceptibility to TB. Importantly, these non-conventional Ly6G+SigH+ neutrophils harbored more replicating bacteria compared to Ly6G+SigH-SigE+ lung neutrophils. In-vitroinfection of naïve bone marrow neutrophils showed enhanced SigH expression with increased infectivity, and this was dependent on glycolysis and fatty acid metabolism. Treatment of immunocompetent mice with neutralizing antibodies for SigH reduced live cell bacterial burden, neutrophil infiltration, restricted bacterial replication and increased neutrophil expression of SigE. Further, SigH neutralized mice also showed elevated T cell numbers, indicating protective immunity. Collectively, our data suggests a model where Mtb induces SigH expression on neutrophils to survive within them, as a potential immune evasion strategy. Our future studies will determine the functional significance of this alteration in Siglecs on neutrophils and its role in TB pathogenesis. R56 AI148239-01A1 and R21AI16359 (sub-award) from NIH/NIAID toDr. Bibhuti B Mishra
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Gridnyev, O. Y., G. D. Fadieienko, I. E. Kushnir, and S. V. Gridnieva. "Intestinal permeability and its role in the pathogenesis and progress of non-alcoholic fatty liver disease. Review." Modern Gastroenterology, no. 1 (February 27, 2023): 55–67. http://dx.doi.org/10.30978/mg-2023-1-55.
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Non‑alcoholic fatty liver disease (NAFLD) is a topical problem for the medicine worldwide, and its association with an «unhealthy» lifestyle and metabolic disorders is well established. The important role of dysbiosis of the intestinal microbiota in the NAFLD pathogenesis and the functioning of the intestine‑liver axis is emphasized. Data on the structure and functioning of the intestinal barrier in physiological conditions are presented. It has been proven that the presence of dysbiotic changes in the microbiota plays an important role in the disruption of the barrier function of the gastrointestinal tract, which in turn increases the level of physiological translocation of both bacteria and their toxins and their life products. Part of these harmful products comes to the liver through the portal vein (endotoxinemia). The antigens’ overload contributes to the development and progression of NAFLD (up to liver cirrhosis). The intestinal barrier is emphasized to be dynamic and sensitive to changes occurring in the intestine. The increased intestinal permeability and bacterial overgrowth syndrome (which is a source of increased endotoxemia) is observed in patients with NAFLD more frequently than in healthy subjects. Number of studies have revealed that the degree of intestinal permeability in NAFLD patients correlated with the steatosis severity. The factors that most significantly affect intestinal permeability in patients with NAFLD include microbial environment, bile acids, levels of fecal short‑chain fatty acids (mainly butyrate), the metabolism of the essential aromatic amino acid tryptophan, as well as the nature of nutrition, alcohol intake, medicinal preparations, stress, and level of physical activity, which act either directly or through the induction of intestinal microbiota dysbacteriosis. The increased intestinal permeability and its consequence — bacterial translocation, are noticed to be involved in the development of such complications as spontaneous bacterial peritonitis, hepatorenal syndrome, portal vein thrombosis, hepatic encephalopathy, hepatocellular carcinoma.
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Rahman, Md Aejazur, Bridgette M. Cumming, Kelvin W. Addicott, Hayden T. Pacl, Shannon L. Russell, Kievershen Nargan, Threnesan Naidoo, et al. "Hydrogen sulfide dysregulates the immune response by suppressing central carbon metabolism to promote tuberculosis." Proceedings of the National Academy of Sciences 117, no. 12 (March 5, 2020): 6663–74. http://dx.doi.org/10.1073/pnas.1919211117.
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The ubiquitous gasotransmitter hydrogen sulfide (H2S) has been recognized to play a crucial role in human health. Using cystathionine γ-lyase (CSE)-deficient mice, we demonstrate an unexpected role of H2S inMycobacterium tuberculosis(Mtb) pathogenesis. We showed thatMtb-infected CSE−/−mice survive longer than WT mice, and support reduced pathology and lower bacterial burdens in the lung, spleen, and liver. Similarly, in vitroMtbinfection of macrophages resulted in reduced colony forming units in CSE−/−cells. Chemical complementation of infected WT and CSE−/−macrophages using the slow H2S releaser GYY3147 and the CSE inhibitor DL-propargylglycine demonstrated that H2S is the effector molecule regulatingMtbsurvival in macrophages. Furthermore, we demonstrate that CSE promotes an excessive innate immune response, suppresses the adaptive immune response, and reduces circulating IL-1β, IL-6, TNF-α, and IFN-γ levels in response toMtbinfection. Notably,Mtbinfected CSE−/−macrophages show increased flux through glycolysis and the pentose phosphate pathway, thereby establishing a critical link between H2S and central metabolism. Our data suggest that excessive H2S produced by the infected WT mice reduce HIF-1α levels, thereby suppressing glycolysis and production of IL-1β, IL-6, and IL-12, and increasing bacterial burden. Clinical relevance was demonstrated by the spatial distribution of H2S-producing enzymes in human necrotic, nonnecrotic, and cavitary pulmonary tuberculosis (TB) lesions. In summary, CSE exacerbates TB pathogenesis by altering immunometabolism in mice and inhibiting CSE or modulating glycolysis are potential targets for host-directed TB control.
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Eliseev, M. S., E. N. Kharlamova, O. V. Zhelyabina, and A. M. Lila. "Microbiota as a new pathogenetic factor in the development of chronic hyperuricemia and gout. Part I: the current state of the problem." Modern Rheumatology Journal 16, no. 5 (October 18, 2022): 7–12. http://dx.doi.org/10.14412/1996-7012-2022-5-7-12.
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The gut microbiota plays a key role in metabolism and immune regulation, and imbalance in microbial composition can contribute to various diseases. We present up-to-date data on the role of the gut microbiota in the occurrence of chronic hyperuricemia (HU) and gout, which is associated with the influence of the microbiota on the synthesis of purine-metabolizing enzymes and pro-inflammatory cytokines. It has been shown that the gut microbiota plays an important role in the pathophysiology of gout and can serve as a new target for therapy. Currently, the microbial index of gout is considered as a potential method for early diagnosis of the disease, possibly already at the preclinical stage. The gut microbiota can be a starting point in the study of the pathogenesis of HU and gout. This makes it necessary to assess the pathogenetic relationship between individual specific microorganisms, the microbiota as a whole, and the development of uric acid (UA) metabolism disorders that contribute to the onset of HU and its transformation into gout. It is assumed that this approach will provide a more complete understanding of the gut microbiota participation in the synthesis of UA and its extrarenal excretion, as well as of bacteria and bacterial enzymes that can be used as a probiotic coadjuvant for the treatment and prevention of gout.
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Uruimagova, Ada T., Vera N. Prilepskaya, Elena A. Mezhevitinova, Andrei E. Donnikov, and Angelina A. Ivanova. "Bacterial vaginosis: modern concepts, approaches to diagnosis and treatment." Gynecology 23, no. 4 (September 22, 2021): 286–93. http://dx.doi.org/10.26442/20795696.2021.4.200954.
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Microbiota a set of human microorganisms that exist with him in normal and pathological conditions, are involved in physiological and pathophysiological reactions, metabolism. The classic manifestation of a violation of the vaginal microbiota is a clinical non-inflammatory syndrome bacterial vaginosis (BV), characterized by certain changes in the composition of the vaginal microbiota and excessive reproduction of microorganisms, which are normally present in small quantities. To date, literature data emphasize that the issues of the etiology, pathogenesis of BV, the reasons for the recurrence of the process are not fully understood, the reasons for the lack of long-term effectiveness of BV therapy are unknown. Further research in this area should be aimed at studying predictors and prognostic signs of recurrence and persistence of the process, differences in vaginal microbiota in patients with recurrent and persistent BV.
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Trent, Brandon J., Widian Jubair, Sabrina Fetchner, Meagan Chriswell, and Kristine Kuhn. "Promotion of Autoimmune Arthritis via Tryptophan Metabolism and Production of the Bacterial-Derived Tryptophan Metabolite Indole." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 105.12. http://dx.doi.org/10.4049/jimmunol.206.supp.105.12.
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Abstract Dysbiosis of gut bacterial communities in autoimmunity is a noted phenomenon in both murine models and human patients; however, the mechanisms of dysbiosis that promote disease pathogenesis remain unclear. In agreement with such studies, our lab has published that administration of antibiotics to deplete the microbiota late in the course of murine collagen-induced arthritis (CIA) significantly ameliorated disease. To understand the mechanisms by which microbiota depletion would significantly decrease CIA, we analyzed cecal metabolites by LC-MS during CIA and after antibiotic treatment and observed significant changes in various tryptophan metabolite levels. Interestingly, mice placed on a tryptophan-free diet had significantly decreased CIA development and increased in regulatory T cell (Treg) populations in the spleen. Further studies identified increases in indole, a bacterial-derived, tryptophan metabolite that strongly correlated with CIA progression. Direct administration of indole during CIA promoted disease and led to increases in T follicular cell (Tfh) and B cell populations in the peyer’s patches and mesenteric lymph nodes. Ex vivo stimulation of murine splenic B cells with indole resulted in significantly increased IgG production and a ≈10% increase in the frequency of CD23+ B cells. Our results suggest that gut dysbiosis due to CIA results in altered tryptophan metabolism and indole production, which promotes CIA pathogenesis via activation of T and B cell populations and antibody production. Precise understanding of which indole metabolites are involved and how they influence mucosal and systemic immune responses will help elucidate the role of intestinal dysbiosis in autoimmunity.
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Rohmer, Laurence, Didier Hocquet, and Samuel I. Miller. "Are pathogenic bacteria just looking for food? Metabolism and microbial pathogenesis." Trends in Microbiology 19, no. 7 (July 2011): 341–48. http://dx.doi.org/10.1016/j.tim.2011.04.003.
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Blohmke, Christoph J., Thomas C. Darton, Claire Jones, Nicolas M. Suarez, Claire S. Waddington, Brian Angus, Liqing Zhou, et al. "Interferon-driven alterations of the host’s amino acid metabolism in the pathogenesis of typhoid fever." Journal of Experimental Medicine 213, no. 6 (May 23, 2016): 1061–77. http://dx.doi.org/10.1084/jem.20151025.
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Enteric fever, caused by Salmonella enterica serovar Typhi, is an important public health problem in resource-limited settings and, despite decades of research, human responses to the infection are poorly understood. In 41 healthy adults experimentally infected with wild-type S. Typhi, we detected significant cytokine responses within 12 h of bacterial ingestion. These early responses did not correlate with subsequent clinical disease outcomes and likely indicate initial host–pathogen interactions in the gut mucosa. In participants developing enteric fever after oral infection, marked transcriptional and cytokine responses during acute disease reflected dominant type I/II interferon signatures, which were significantly associated with bacteremia. Using a murine and macrophage infection model, we validated the pivotal role of this response in the expression of proteins of the host tryptophan metabolism during Salmonella infection. Corresponding alterations in tryptophan catabolites with immunomodulatory properties in serum of participants with typhoid fever confirmed the activity of this pathway, and implicate a central role of host tryptophan metabolism in the pathogenesis of typhoid fever.
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Moszak, Małgorzata, Monika Szulińska, and Paweł Bogdański. "You Are What You Eat—The Relationship between Diet, Microbiota, and Metabolic Disorders—A Review." Nutrients 12, no. 4 (April 15, 2020): 1096. http://dx.doi.org/10.3390/nu12041096.
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The gut microbiota (GM) is defined as the community of microorganisms (bacteria, archaea, fungi, viruses) colonizing the gastrointestinal tract. GM regulates various metabolic pathways in the host, including those involved in energy homeostasis, glucose and lipid metabolism, and bile acid metabolism. The relationship between alterations in intestinal microbiota and diseases associated with civilization is well documented. GM dysbiosis is involved in the pathogenesis of diverse diseases, such as metabolic syndrome, cardiovascular diseases, celiac disease, inflammatory bowel disease, and neurological disorders. Multiple factors modulate the composition of the microbiota and how it physically functions, but one of the major factors triggering GM establishment is diet. In this paper, we reviewed the current knowledge about the relationship between nutrition, gut microbiota, and host metabolic status. We described how macronutrients (proteins, carbohydrates, fat) and different dietary patterns (e.g., Western-style diet, vegetarian diet, Mediterranean diet) interact with the composition and activity of GM, and how gut bacterial dysbiosis has an influence on metabolic disorders, such as obesity, type 2 diabetes, and hyperlipidemia.
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Lei, L., Y. Yang, Y. Yang, S. Wu, X. Ma, M. Mao, and T. Hu. "Mechanisms by Which Small RNAs Affect Bacterial Activity." Journal of Dental Research 98, no. 12 (September 23, 2019): 1315–23. http://dx.doi.org/10.1177/0022034519876898.
Full textAbstract:
The oral cavity contains a distinct habitat that supports diverse bacterial flora. Recent observations have provided additional evidence that sRNAs are key regulators of bacterial physiology and pathogenesis. These sRNAs have been divided into 5 functional groups: cis-encoded RNAs, trans-encoded RNAs, RNA regulators of protein activity, bacterial CRISPR (clustered regularly interspaced short palindromic repeat) RNAs, and a novel category of miRNA-size small RNAs (msRNAs). In this review, we discuss a critical group of key commensal and opportunistic oral pathogens. In general, supragingival bacterial sRNAs function synergistically to fine-tune the regulation of cellular processes and stress responses in adaptation to environmental changes. Particularly in the cariogenic bacteria Streptococcus mutans, both the antisense vicR RNA and msRNA1657 can impede the metabolism of bacterial exopolysaccharides, prevent biofilm formation, and suppress its cariogenicity. In Enterococcus faecalis, selected sRNAs control the expression of proteins involved in diverse cellular processes and stress responses. In subgingival plaques, sRNAs from periodontal pathogens can function as novel bacterial signaling molecules that mediate bacterial-human interactions in periodontal homeostasis. In Porphyromonas gingivalis, the expression profiles of putative sRNA101 and sRNA42 were found to respond to hemin availability after hemin starvation. Regarding Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans), a major periodontal pathogen associated with aggressive periodontitis, the predicted sRNAs interact with several virulence genes, including those encoding leukotoxin and cytolethal distending toxin. Furthermore, in clinical isolates, these associated RNAs could be explored not only as potential biomarkers for oral disease monitoring but also as alternative types of regulators for drug design. Thus, this emerging subspecialty of bacterial regulatory RNAs could reshape our understanding of bacterial gene regulation from their key roles of endogenous regulatory RNAs to their activities in pathologic processes.
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Urso, Andreacarola, and Alice Prince. "Anti-Inflammatory Metabolites in the Pathogenesis of Bacterial Infection." Frontiers in Cellular and Infection Microbiology 12 (June 15, 2022). http://dx.doi.org/10.3389/fcimb.2022.925746.
Full textAbstract:
Host and pathogen metabolism have a major impact on the outcome of infection. The microenvironment consisting of immune and stromal cells drives bacterial proliferation and adaptation, while also shaping the activity of the immune system. The abundant metabolites itaconate and adenosine are classified as anti-inflammatory, as they help to contain the local damage associated with inflammation, oxidants and proteases. A growing literature details the many roles of these immunometabolites in the pathogenesis of infection and their diverse functions in specific tissues. Some bacteria, notably P. aeruginosa, actively metabolize these compounds, others, such as S. aureus respond by altering their own metabolic programs selecting for optimal fitness. For most of the model systems studied to date, these immunometabolites promote a milieu of tolerance, limiting local immune clearance mechanisms, along with promoting bacterial adaptation. The generation of metabolites such as adenosine and itaconate can be host protective. In the setting of acute inflammation, these compounds also represent potential therapeutic targets to prevent infection.