# | Rank | Similarity | Title + Abs. | Year | PMID |
|---|---|---|---|---|---|
| 0 | 1 | 2 | 3 | 4 | 5 |
| 8283 | 0 | 0.9970 | Stress responses as determinants of antimicrobial resistance in Gram-negative bacteria. Bacteria encounter a myriad of potentially growth-compromising conditions in nature and in hosts of pathogenic bacteria. These 'stresses' typically elicit protective and/or adaptive responses that serve to enhance bacterial survivability. Because they impact upon many of the same cellular components and processes that are targeted by antimicrobials, adaptive stress responses can influence antimicrobial susceptibility. In targeting and interfering with key cellular processes, antimicrobials themselves are 'stressors' to which protective stress responses have also evolved. Cellular responses to nutrient limitation (nutrient stress), oxidative and nitrosative stress, cell envelope damage (envelope stress), antimicrobial exposure and other growth-compromising stresses, have all been linked to the development of antimicrobial resistance in Gram-negative bacteria - resulting from the stimulation of protective changes to cell physiology, activation of resistance mechanisms, promotion of resistant lifestyles (biofilms), and induction of resistance mutations. | 2012 | 22424589 |
| 8267 | 1 | 0.9969 | Why put up with immunity when there is resistance: an excursion into the population and evolutionary dynamics of restriction-modification and CRISPR-Cas. Bacteria can readily generate mutations that prevent bacteriophage (phage) adsorption and thus make bacteria resistant to infections with these viruses. Nevertheless, the majority of bacteria carry complex innate and/or adaptive immune systems: restriction-modification (RM) and CRISPR-Cas, respectively. Both RM and CRISPR-Cas are commonly assumed to have evolved and be maintained to protect bacteria from succumbing to infections with lytic phage. Using mathematical models and computer simulations, we explore the conditions under which selection mediated by lytic phage will favour such complex innate and adaptive immune systems, as opposed to simple envelope resistance. The results of our analysis suggest that when populations of bacteria are confronted with lytic phage: (i) In the absence of immunity, resistance to even multiple bacteriophage species with independent receptors can evolve readily. (ii) RM immunity can benefit bacteria by preventing phage from invading established bacterial populations and particularly so when there are multiple bacteriophage species adsorbing to different receptors. (iii) Whether CRISPR-Cas immunity will prevail over envelope resistance depends critically on the number of steps in the coevolutionary arms race between the bacteria-acquiring spacers and the phage-generating CRISPR-escape mutants. We discuss the implications of these results in the context of the evolution and maintenance of RM and CRISPR-Cas and highlight fundamental questions that remain unanswered. This article is part of a discussion meeting issue 'The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems'. | 2019 | 30905282 |
| 9240 | 2 | 0.9968 | CRISPR-Cas-Mediated Phage Resistance Enhances Horizontal Gene Transfer by Transduction. A powerful contributor to prokaryotic evolution is horizontal gene transfer (HGT) through transformation, conjugation, and transduction, which can be advantageous, neutral, or detrimental to fitness. Bacteria and archaea control HGT and phage infection through CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) adaptive immunity. Although the benefits of resisting phage infection are evident, this can come at a cost of inhibiting the acquisition of other beneficial genes through HGT. Despite the ability of CRISPR-Cas to limit HGT through conjugation and transformation, its role in transduction is largely overlooked. Transduction is the phage-mediated transfer of bacterial DNA between cells and arguably has the greatest impact on HGT. We demonstrate that in Pectobacterium atrosepticum, CRISPR-Cas can inhibit the transduction of plasmids and chromosomal loci. In addition, we detected phage-mediated transfer of a large plant pathogenicity genomic island and show that CRISPR-Cas can inhibit its transduction. Despite these inhibitory effects of CRISPR-Cas on transduction, its more common role in phage resistance promotes rather than diminishes HGT via transduction by protecting bacteria from phage infection. This protective effect can also increase transduction of phage-sensitive members of mixed populations. CRISPR-Cas systems themselves display evidence of HGT, but little is known about their lateral dissemination between bacteria and whether transduction can contribute. We show that, through transduction, bacteria can acquire an entire chromosomal CRISPR-Cas system, including cas genes and phage-targeting spacers. We propose that the positive effect of CRISPR-Cas phage immunity on enhancing transduction surpasses the rarer cases where gene flow by transduction is restricted.IMPORTANCE The generation of genetic diversity through acquisition of DNA is a powerful contributor to microbial evolution and occurs through transformation, conjugation, and transduction. Of these, transduction, the phage-mediated transfer of bacterial DNA, is arguably the major route for genetic exchange. CRISPR-Cas adaptive immune systems control gene transfer by conjugation and transformation, but transduction has been mostly overlooked. Our results indicate that CRISPR-Cas can impede, but typically enhances the transduction of plasmids, chromosomal genes, and pathogenicity islands. By limiting wild-type phage replication, CRISPR-Cas immunity increases transduction in both phage-resistant and -sensitive members of mixed populations. Furthermore, we demonstrate mobilization of a chromosomal CRISPR-Cas system containing phage-targeting spacers by generalized transduction, which might partly account for the uneven distribution of these systems in nature. Overall, the ability of CRISPR-Cas to promote transduction reveals an unexpected impact of adaptive immunity on horizontal gene transfer, with broader implications for microbial evolution. | 2018 | 29440578 |
| 8265 | 3 | 0.9968 | Mathematical modelling of CRISPR-Cas system effects on biofilm formation. Clustered regularly interspaced short palindromic repeats (CRISPR), linked with CRISPR associated (Cas) genes, can confer adaptive immunity to bacteria, against bacteriophage infections. Thus from a therapeutic standpoint, CRISPR immunity increases biofilm resistance to phage therapy. Recently, however, CRISPR-Cas genes have been implicated in reducing biofilm formation in lysogenized cells. Thus CRISPR immunity can have complex effects on phage-host-lysogen interactions, particularly in a biofilm. In this contribution, we develop and analyse a series of dynamical systems to elucidate and disentangle these interactions. Two competition models are used to study the effects of lysogens (first model) and CRISPR-immune bacteria (second model) in the biofilm. In the third model, the effect of delivering lysogens to a CRISPR-immune biofilm is investigated. Using standard analyses of equilibria, stability and bifurcations, our models predict that lysogens may be able to displace CRISPR-immune bacteria in a biofilm, and thus suggest strategies to eliminate phage-resistant biofilms. | 2017 | 28426329 |
| 9176 | 4 | 0.9968 | Evolutionary Dynamics between Phages and Bacteria as a Possible Approach for Designing Effective Phage Therapies against Antibiotic-Resistant Bacteria. With the increasing global threat of antibiotic resistance, there is an urgent need to develop new effective therapies to tackle antibiotic-resistant bacterial infections. Bacteriophage therapy is considered as a possible alternative over antibiotics to treat antibiotic-resistant bacteria. However, bacteria can evolve resistance towards bacteriophages through antiphage defense mechanisms, which is a major limitation of phage therapy. The antiphage mechanisms target the phage life cycle, including adsorption, the injection of DNA, synthesis, the assembly of phage particles, and the release of progeny virions. The non-specific bacterial defense mechanisms include adsorption inhibition, superinfection exclusion, restriction-modification, and abortive infection systems. The antiphage defense mechanism includes a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system. At the same time, phages can execute a counterstrategy against antiphage defense mechanisms. However, the antibiotic susceptibility and antibiotic resistance in bacteriophage-resistant bacteria still remain unclear in terms of evolutionary trade-offs and trade-ups between phages and bacteria. Since phage resistance has been a major barrier in phage therapy, the trade-offs can be a possible approach to design effective bacteriophage-mediated intervention strategies. Specifically, the trade-offs between phage resistance and antibiotic resistance can be used as therapeutic models for promoting antibiotic susceptibility and reducing virulence traits, known as bacteriophage steering or evolutionary medicine. Therefore, this review highlights the synergistic application of bacteriophages and antibiotics in association with the pleiotropic trade-offs of bacteriophage resistance. | 2022 | 35884169 |
| 8264 | 5 | 0.9967 | Anti-CRISPR Phages Cooperate to Overcome CRISPR-Cas Immunity. Some phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here, we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As a consequence, Acr-phages often need to cooperate in order to overcome CRISPR resistance, with a first phage blocking the host CRISPR-Cas immune system to allow a second Acr-phage to successfully replicate. This cooperation leads to epidemiological tipping points in which the initial density of Acr-phage tips the balance from phage extinction to a phage epidemic. Furthermore, both higher levels of CRISPR-Cas immunity and weaker Acr activities shift the tipping points toward higher initial phage densities. Collectively, these data help elucidate how interactions between phage-encoded immune suppressors and the CRISPR systems they target shape bacteria-phage population dynamics. | 2018 | 30033365 |
| 9192 | 6 | 0.9967 | Antimicrobial peptides: Sustainable application informed by evolutionary constraints. The proliferation and global expansion of multidrug-resistant (MDR) bacteria have deepened the need to develop novel antimicrobials. Antimicrobial peptides (AMPs) are regarded as promising antibacterial agents because of their broad-spectrum antibacterial activity and multifaceted mechanisms of action with non-specific targets. However, if AMPs are to be applied sustainably, knowledge of how they induce resistance in pathogenic bacteria must be mastered to avoid repeating the traditional antibiotic resistance mistakes currently faced. Furthermore, the evolutionary constraints on the acquisition of AMP resistance by microorganisms in the natural environment, such as functional compatibility and fitness trade-offs, inform the translational application of AMPs. Consequently, the shortcut to achieve sustainable utilization of AMPs is to uncover the evolutionary constraints of bacteria on AMP resistance in nature and find the tricks to exploit these constraints, such as applying AMP cocktails to minimize the efficacy of selection for resistance or combining nanomaterials to maximize the costs of AMP resistance. Altogether, this review dissects the benefits, challenges, and opportunities of utilizing AMPs against disease-causing bacteria, and highlights the use of AMP cocktails or nanomaterials to proactively address potential AMP resistance crises in the future. | 2022 | 35752270 |
| 9388 | 7 | 0.9967 | Suboptimal environmental conditions prolong phage epidemics in bacterial populations. Infections by filamentous phages, which are usually nonlethal to the bacterial cells, influence bacterial fitness in various ways. While phage-encoded accessory genes, for example virulence genes, can be highly beneficial, the production of viral particles is energetically costly and often reduces bacterial growth. Consequently, if costs outweigh benefits, bacteria evolve resistance, which can shorten phage epidemics. Abiotic conditions are known to influence the net-fitness effect for infected bacteria. Their impact on the dynamics and trajectories of host resistance evolution, however, remains yet unknown. To address this, we experimentally evolved the bacterium Vibrio alginolyticus in the presence of a filamentous phage at three different salinity levels, that is (1) ambient, (2) 50% reduction and (3) fluctuations between reduced and ambient. In all three salinities, bacteria rapidly acquired resistance through super infection exclusion (SIE), whereby phage-infected cells acquired immunity at the cost of reduced growth. Over time, SIE was gradually replaced by evolutionary fitter surface receptor mutants (SRM). This replacement was significantly faster at ambient and fluctuating conditions compared with the low saline environment. Our experimentally parameterized mathematical model explains that suboptimal environmental conditions, in which bacterial growth is slower, slow down phage resistance evolution ultimately prolonging phage epidemics. Our results may explain the high prevalence of filamentous phages in natural environments where bacteria are frequently exposed to suboptimal conditions and constantly shifting selections regimes. Thus, our future ocean may favour the emergence of phage-born pathogenic bacteria and impose a greater risk for disease outbreaks, impacting not only marine animals but also humans. | 2024 | 37337348 |
| 8282 | 8 | 0.9967 | Gut microbiota: a new player in regulating immune- and chemo-therapy efficacy. Development of drug resistance represents the major cause of cancer therapy failure, determines disease progression and results in poor prognosis for cancer patients. Different mechanisms are responsible for drug resistance. Intrinsic genetic modifications of cancer cells induce the alteration of expression of gene controlling specific pathways that regulate drug resistance: drug transport and metabolism; alteration of drug targets; DNA damage repair; and deregulation of apoptosis, autophagy, and pro-survival signaling. On the other hand, a complex signaling network among the entire cell component characterizes tumor microenvironment and regulates the pathways involved in the development of drug resistance. Gut microbiota represents a new player in the regulation of a patient's response to cancer therapies, including chemotherapy and immunotherapy. In particular, commensal bacteria can regulate the efficacy of immune checkpoint inhibitor therapy by modulating the activation of immune responses to cancer. Commensal bacteria can also regulate the efficacy of chemotherapeutic drugs, such as oxaliplatin, gemcitabine, and cyclophosphamide. Recently, it has been shown that such bacteria can produce extracellular vesicles (EVs) that can mediate intercellular communication with human host cells. Indeed, bacterial EVs carry RNA molecules with gene expression regulatory ability that can be delivered to recipient cells of the host and potentially regulate the expression of genes involved in controlling the resistance to cancer therapy. On the other hand, host cells can also deliver human EVs to commensal bacteria and similarly, regulate gene expression. EV-mediated intercellular communication between commensal bacteria and host cells may thus represent a novel research area into potential mechanisms regulating the efficacy of cancer therapy. | 2020 | 33062956 |
| 9173 | 9 | 0.9967 | Bacterial defences: mechanisms, evolution and antimicrobial resistance. Throughout their evolutionary history, bacteria have faced diverse threats from other microorganisms, including competing bacteria, bacteriophages and predators. In response to these threats, they have evolved sophisticated defence mechanisms that today also protect bacteria against antibiotics and other therapies. In this Review, we explore the protective strategies of bacteria, including the mechanisms, evolution and clinical implications of these ancient defences. We also review the countermeasures that attackers have evolved to overcome bacterial defences. We argue that understanding how bacteria defend themselves in nature is important for the development of new therapies and for minimizing resistance evolution. | 2023 | 37095190 |
| 8286 | 10 | 0.9967 | RNA Modifications in Pathogenic Bacteria: Impact on Host Adaptation and Virulence. RNA modifications are involved in numerous biological processes and are present in all RNA classes. These modifications can be constitutive or modulated in response to adaptive processes. RNA modifications play multiple functions since they can impact RNA base-pairings, recognition by proteins, decoding, as well as RNA structure and stability. However, their roles in stress, environmental adaptation and during infections caused by pathogenic bacteria have just started to be appreciated. With the development of modern technologies in mass spectrometry and deep sequencing, recent examples of modifications regulating host-pathogen interactions have been demonstrated. They show how RNA modifications can regulate immune responses, antibiotic resistance, expression of virulence genes, and bacterial persistence. Here, we illustrate some of these findings, and highlight the strategies used to characterize RNA modifications, and their potential for new therapeutic applications. | 2021 | 34440299 |
| 9175 | 11 | 0.9967 | Fitness Trade-Offs Resulting from Bacteriophage Resistance Potentiate Synergistic Antibacterial Strategies. Bacteria that cause life-threatening infections in humans are becoming increasingly difficult to treat. In some instances, this is due to intrinsic and acquired antibiotic resistance, indicating that new therapeutic approaches are needed to combat bacterial pathogens. There is renewed interest in utilizing viruses of bacteria known as bacteriophages (phages) as potential antibacterial therapeutics. However, critics suggest that similar to antibiotics, the development of phage-resistant bacteria will halt clinical phage therapy. Although the emergence of phage-resistant bacteria is likely inevitable, there is a growing body of literature showing that phage selective pressure promotes mutations in bacteria that allow them to subvert phage infection, but with a cost to their fitness. Such fitness trade-offs include reduced virulence, resensitization to antibiotics, and colonization defects. Resistance to phage nucleic acid entry, primarily via cell surface modifications, compromises bacterial fitness during antibiotic and host immune system pressure. In this minireview, we explore the mechanisms behind phage resistance in bacterial pathogens and the physiological consequences of acquiring phage resistance phenotypes. With this knowledge, it may be possible to use phages to alter bacterial populations, making them more tractable to current therapeutic strategies. | 2020 | 32094257 |
| 8285 | 12 | 0.9967 | Bacterial stress response: understanding the molecular mechanics to identify possible therapeutic targets. INTRODUCTION: Bacteria are ubiquitous and many of them are pathogenic in nature. Entry of bacteria in host and its recognition by host defense system induce stress in host cells. With time, bacteria have also developed strategies including drug resistance to escape from antibacterial therapy as well as host defense mechanism. AREAS COVERED: Bacterial stress initiates and promotes adaptive immune response through several integrated mechanisms. The mechanisms of bacteria to up and down regulate different pathways involved in these responses have been discussed. The genetic expression of these pathways can be manipulated by the pharmacological interventions. Present review discusses in these contexts and explores the possibilities to overcome stress induced by bacterial pathogens and to suggest new possible therapeutic targets. EXPERT OPINION: In our opinion, there are two important fronts to regulate the bacterial stress. One is to target caspase involved in the process of transformation and translation at gene level and protein expression. Second is the identification of bacterial genes that lead to synthesis of abnormal end products supporting bacterial survival in host environment and also to surpass the host defense mechanism. Identification of such genes and their expression products could be an effective option to encounter bacterial resistance. | 2021 | 32811215 |
| 9604 | 13 | 0.9966 | Extreme Antibiotic Persistence via Heterogeneity-Generating Mutations Targeting Translation. Antibiotic persistence, the noninherited tolerance of a subpopulation of bacteria to high levels of antibiotics, is a bet-hedging phenomenon with broad clinical implications. Indeed, the isolation of bacteria with substantially increased persistence rates from chronic infections suggests that evolution of hyperpersistence is a significant factor in clinical therapy resistance. However, the pathways that lead to hyperpersistence and the underlying cellular states have yet to be systematically studied. Here, we show that laboratory evolution can lead to increase in persistence rates by orders of magnitude for multiple independently evolved populations of Escherichia coli and that the driving mutations are highly enriched in translation-related genes. Furthermore, two distinct adaptive mutations converge on concordant transcriptional changes, including increased population heterogeneity in the expression of several genes. Cells with extreme expression of these genes showed dramatic differences in persistence rates, enabling isolation of subpopulations in which a substantial fraction of cells are persisters. Expression analysis reveals coherent regulation of specific pathways that may be critical to establishing the hyperpersistence state. Hyperpersister mutants can thus enable the systematic molecular characterization of this unique physiological state, a critical prerequisite for developing antipersistence strategies.IMPORTANCE Bacterial persistence is a fascinating phenomenon in which a small subpopulation of bacteria becomes phenotypically tolerant to lethal antibiotic exposure. There is growing evidence that populations of bacteria in chronic clinical infections develop a hyperpersistent phenotype, enabling a substantially larger subpopulation to survive repeated antibiotic treatment. The mechanisms of persistence and modes of increasing persistence rates remain largely unknown. Here, we utilized experimental evolution to select for Escherichia coli mutants that have more than a thousandfold increase in persistence rates. We discovered that a variety of individual mutations to translation-related processes are causally involved. Furthermore, we found that these mutations lead to population heterogeneity in the expression of specific genes. We show that this can be used to isolate populations in which the majority of bacteria are persisters, thereby enabling systems-level characterization of this fascinating and clinically significant microbial phenomenon. | 2020 | 31964772 |
| 9172 | 14 | 0.9966 | These Are the Genes You're Looking For: Finding Host Resistance Genes. Humanity's ongoing struggle with new, re-emerging and endemic infectious diseases serves as a frequent reminder of the need to understand host-pathogen interactions. Recent advances in genomics have dramatically advanced our understanding of how genetics contributes to host resistance or susceptibility to bacterial infection. Here we discuss current trends in defining host-bacterial interactions at the genome-wide level, including screens that harness CRISPR/Cas9 genome editing, natural genetic variation, proteomics, and transcriptomics. We report on the merits, limitations, and findings of these innovative screens and discuss their complementary nature. Finally, we speculate on future innovation as we continue to progress through the postgenomic era and towards deeper mechanistic insight and clinical applications. | 2021 | 33004258 |
| 8266 | 15 | 0.9966 | Remarkable Mechanisms in Microbes to Resist Phage Infections. Bacteriophages (phages) specifically infect bacteria and are the most abundant biological entities on Earth. The constant exposure to phage infection imposes a strong selective pressure on bacteria to develop viral resistance strategies that promote prokaryotic survival. Thus, this parasite-host relationship results in an evolutionary arms race of adaptation and counteradaptation between the interacting partners. The evolutionary outcome is a spectrum of remarkable strategies used by the bacteria and phages as they attempt to coexist. These approaches include adsorption inhibition, injection blocking, abortive infection, toxin-antitoxin, and CRISPR-Cas systems. In this review, we highlight the diverse and complementary antiphage systems in bacteria, as well as the evasion mechanisms used by phages to escape these resistance strategies. | 2014 | 26958724 |
| 9182 | 16 | 0.9966 | Harnessing CRISPR/Cas9 in engineering biotic stress immunity in crops. There is significant potential for CRISPR/Cas9 to be used in developing crops that can adapt to biotic stresses such as fungal, bacterial, viral, and pest infections and weeds. The increasing global population and climate change present significant threats to food security by putting stress on plants, making them more vulnerable to diseases and productivity losses caused by pathogens, pests, and weeds. Traditional breeding methods are inadequate for the rapid development of new plant traits needed to counteract this decline in productivity. However, modern advances in genome-editing technologies, particularly CRISPR/Cas9, have transformed crop protection through precise and targeted modifications of plant genomes. This enables the creation of resilient crops with improved resistance to pathogens, pests, and weeds. This review examines various methods by which CRISPR/Cas9 can be utilized for crop protection. These methods include knocking out susceptibility genes, introducing resistance genes, and modulating defense genes. Potential applications of CRISPR/Cas9 in crop protection involve introducing genes that confer resistance to pathogens, disrupting insect genes responsible for survival and reproduction, and engineering crops that are resistant to herbicides. In conclusion, CRISPR/Cas9 holds great promise for advancing crop protection and ensuring food security in the face of environmental challenges and increasing population pressures. The most recent advancements in CRISPR technology for creating resistance to bacteria, fungi, viruses, and pests are covered here. We wrap up by outlining the most pressing issues and technological shortcomings, as well as unanswered questions for further study. | 2025 | 40663257 |
| 8337 | 17 | 0.9966 | Dynamic Boolean modelling reveals the influence of energy supply on bacterial efflux pump expression. Antimicrobial resistance (AMR) is a global health issue. One key factor contributing to AMR is the ability of bacteria to export drugs through efflux pumps, which relies on the ATP-dependent expression and interaction of several controlling genes. Recent studies have shown that significant cell-to-cell ATP variability exists within clonal bacterial populations, but the contribution of intrinsic cell-to-cell ATP heterogeneity is generally overlooked in understanding efflux pumps. Here, we consider how ATP variability influences gene regulatory networks controlling expression of efflux pump genes in two bacterial species. We develop and apply a generalizable Boolean modelling framework, developed to incorporate the dependence of gene expression dynamics on available cellular energy supply. Theoretical results show that differences in energy availability can cause pronounced downstream heterogeneity in efflux gene expression. Cells with higher energy availability have a superior response to stressors. Furthermore, in the absence of stress, model bacteria develop heterogeneous pulses of efflux pump gene expression which contribute to a sustained sub-population of cells with increased efflux expression activity, potentially conferring a continuous pool of intrinsically resistant bacteria. This modelling approach thus reveals an important source of heterogeneity in cell responses to antimicrobials and sheds light on potentially targetable aspects of efflux pump-related antimicrobial resistance. | 2022 | 35078338 |
| 8331 | 18 | 0.9966 | An activator regulates the DNA damage response and anti-phage defense networks in Moraxellaceae. DNA-damage chemicals, including many antibiotics, often induce prophage induction and phage outbreaks within microbial communities, posing a significant threat to bacterial survival. Moraxellaceae strains are clinically relevant due to their remarkable resistance to antibiotics and radiation. However, the cellular-level regulation mechanisms that underlie their DNA damage response and anti-phage defense remain extensively unexplored. Here, we report a WYL family protein, DdaA, that has replaced the ubiquitous SOS system during the evolution of Moraxellaceae. DdaA functions as an activator and directly regulates the transcriptional networks of both DNA damage response and anti-phage defense genes under conditions of DNA damage stress. Our findings elucidate a pathway that shows how these bacteria enhance their immunity under DNA damage and shed light on controlling the resistance of Moraxellaceae strains in clinical practice. | 2025 | 40874593 |
| 589 | 19 | 0.9966 | Insulin Signaling and Insulin Resistance Facilitate Trained Immunity in Macrophages Through Metabolic and Epigenetic Changes. Adaptation of the innate immune system has been recently acknowledged, explaining sustained changes of innate immune responses. Such adaptation is termed trained immunity. Trained immunity is initiated by extracellular signals that trigger a cascade of events affecting cell metabolism and mediating chromatin changes on genes that control innate immune responses. Factors demonstrated to facilitate trained immunity are pathogenic signals (fungi, bacteria, viruses) as well non-pathogenic signals such as insulin, cytokines, adipokines or hormones. These signals initiate intracellular signaling cascades that include AKT kinases and mTOR as well as histone methylases and demethylases, resulting in metabolic changes and histone modifications. In the context of insulin resistance, AKT signaling is affected resulting in sustained activation of mTORC1 and enhanced glycolysis. In macrophages elevated glycolysis readily impacts responses to pathogens (bacteria, fungi) or danger signals (TLR-driven signals of tissue damage), partly explaining insulin resistance-related pathologies. Thus, macrophages lacking insulin signaling exhibit reduced responses to pathogens and altered metabolism, suggesting that insulin resistance is a state of trained immunity. Evidence from Insulin Receptor as well as IGF1Receptor deficient macrophages support the contribution of insulin signaling in macrophage responses. In addition, clinical evidence highlights altered macrophage responses to pathogens or metabolic products in patients with systemic insulin resistance, being in concert with cell culture and animal model studies. Herein, we review the current knowledge that supports the impact of insulin signaling and other insulin resistance related signals as modulators of trained immunity. | 2019 | 31244863 |