scholarly journals Selection for phage resistance reduces virulence of Shigella flexneri .

2021 ◽  
Author(s):  
Kaitlyn E. Kortright ◽  
Rachel E. Done ◽  
Benjamin K. Chan ◽  
Valeria Souza ◽  
Paul E. Turner
Keyword(s):  
Genome Sequencing ◽  
Phage Therapy ◽  
Shigella Flexneri ◽  
Cell Membrane Permeability ◽  
Phage Resistance ◽  
Trade Off ◽  
Trade Offs ◽  
Resistant Mutants ◽  
Selection For ◽  
Intercellular Spread

There is increasing interest in phage therapy as an alternative to antibiotics for treating bacterial infections, especially using phages that select for evolutionary trade-offs between increased phage resistance and decreased fitness traits such as virulence in target bacteria. A vast repertoire of virulence factors allows the opportunistic bacterial pathogen, Shigella flexneri , to invade human gut epithelial cells, replicate intracellularly, and evade host immunity through intercellular spread. It is previously shown that OmpA is necessary for intercellular spread of S. flexneri . We hypothesized that a phage which uses OmpA as a receptor to infect S. flexneri , should select for phage-resistant mutants with attenuated intercellular spread. Here we show that phage A1-1, requires OmpA as a receptor and selects for reduced virulence in S. flexneri . We characterized five phage-resistant mutants by measuring phenotypic changes in various traits: cell-membrane permeability, total lipopolysaccharide (LPS), sensitivity to antibiotics, and susceptibility to other phages. Results separated the mutants into two groups: R1 and R2 phenotypically resembled ompA knockouts, whereas R3, R4 and R5 were similar to LPS-deficient strains. Whole genome sequencing confirmed that R1 and R2 had mutations in ompA , while R3, R4 and R5 showed mutations in LPS inner-core biosynthesis genes gmhA and gmhC . Bacterial plaque assays confirmed that all phage-resistant mutants were incapable of intercellular spread. We concluded that selection for S. flexneri resistance to phage A1-1 generally reduced virulence (i.e. intercellular spread), but this trade-off could be mediated either by mutations in ompA or in LPS-core genes that likely altered OmpA conformation. Author Summary Shigella flexneri is a facultative intracellular pathogen of humans, and a leading cause of bacillary dysentery. With few effective treatments and rising antibiotic resistance in these bacteria, there is increasing interest in alternatives to classical infection management of S. flexneri infections. Phage therapy poses an attractive alternative, particularly if a therapeutic phage can be found that results in an evolutionary trade-off between phage resistance and bacterial virulence. Here, we isolate a novel lytic phage from water collected in Cuatro Cienegas, Mexico that uses the OmpA porin of S. flexneri as a receptor. We use phenotypic assays and genome sequencing to show that phage A1-1 selects for phage-resistant mutants that can be grouped into two categories: OmpA-deficient mutants and LPS-deficient mutants. Despite these underlying mechanistic differences, we confirmed that naturally-occurring phage A1-1 selected for evolved phage resistance that coincided with impaired intercellular spread of S. flexneri in a eukaryotic infection model.

scholarly journals Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance

2020 ◽  
Vol 117 (21) ◽  
pp. 11207-11216 ◽  
Author(s):  
Alita R. Burmeister ◽  
Abigail Fortier ◽  
Carli Roush ◽  
Adam J. Lessing ◽  
Rose G. Bender ◽  
...  
Keyword(s):  
Antibiotic Resistance ◽  
Molecular Mechanisms ◽  
Efflux Pump ◽  
Resistance Mechanisms ◽  
Phage Resistance ◽  
Resistance Mutations ◽  
Trade Off ◽  
Trade Offs ◽  
Evolutionary Context ◽  
Structural Barrier

Bacteria frequently encounter selection by both antibiotics and lytic bacteriophages. However, the evolutionary interactions between antibiotics and phages remain unclear, in particular, whether and when phages can drive evolutionary trade-offs with antibiotic resistance. Here, we describeEscherichia coliphage U136B, showing it relies on two host factors involved in different antibiotic resistance mechanisms: 1) the efflux pump protein TolC and 2) the structural barrier molecule lipopolysaccharide (LPS). Since TolC and LPS contribute to antibiotic resistance, phage U136B should select for their loss or modification, thereby driving a trade-off between phage resistance and either of the antibiotic resistance mechanisms. To test this hypothesis, we used fluctuation experiments and experimental evolution to obtain phage-resistant mutants. Using these mutants, we compared the accessibility of specific mutations (revealed in the fluctuation experiments) to their actual success during ecological competition and coevolution (revealed in the evolution experiments). BothtolCand LPS-related mutants arise readily during fluctuation assays, withtolCmutations becoming more common during the evolution experiments. In support of the trade-off hypothesis, phage resistance viatolCmutations occurs with a corresponding reduction in antibiotic resistance in many cases. However, contrary to the hypothesis, some phage resistance mutations pleiotropically confer increased antibiotic resistance. We discuss the molecular mechanisms underlying this surprising pleiotropic result, consideration for applied phage biology, and the importance of ecology in evolution of phage resistance. We envision that phages may be useful for the reversal of antibiotic resistance, but such applications will need to account for unexpected pleiotropy and evolutionary context.

scholarly journals Phage Resistance in Multidrug-Resistant Klebsiella pneumoniae ST258 Evolves via Diverse Mutations That Culminate in Impaired Adsorption

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Shayla Hesse ◽  
Manoj Rajaure ◽  
Erin Wall ◽  
Joy Johnson ◽  
Valery Bliskovsky ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Cell Surface ◽  
Phage Therapy ◽  
Surface Structures ◽  
Phage Resistance ◽  
Cell Surface Structures ◽  
Phage Cocktail ◽  
Resistant Mutants

ABSTRACT The evolution of phage resistance poses an inevitable threat to the efficacy of phage therapy. The strategic selection of phage combinations that impose high genetic barriers to resistance and/or high compensatory fitness costs may mitigate this threat. However, for such a strategy to be effective, the evolution of phage resistance must be sufficiently constrained to be consistent. In this study, we isolated lytic phages capable of infecting a modified Klebsiella pneumoniae clinical isolate and characterized a total of 57 phage-resistant mutants that evolved from their prolonged coculture in vitro. Single- and double-phage-resistant mutants were isolated from independently evolved replicate cocultures grown in broth or on plates. Among resistant isolates evolved against the same phage under the same conditions, mutations conferring resistance occurred in different genes, yet in each case, the putative functions of these genes clustered around the synthesis or assembly of specific cell surface structures. All resistant mutants demonstrated impaired phage adsorption, providing a strong indication that these cell surface structures functioned as phage receptors. Combinations of phages targeting different host receptors reduced the incidence of resistance, while, conversely, one three-phage cocktail containing two phages targeting the same receptor increased the incidence of resistance (relative to its two-phage, nonredundant receptor-targeting counterpart). Together, these data suggest that laboratory characterization of phage-resistant mutants is a useful tool to help optimize therapeutic phage selection and cocktail design. IMPORTANCE The therapeutic use of bacteriophage (phage) is garnering renewed interest in the setting of difficult-to-treat infections. Phage resistance is one major limitation of phage therapy; therefore, developing effective strategies to avert or lessen its impact is critical. Characterization of in vitro phage resistance may be an important first step in evaluating the relative likelihood with which phage-resistant populations emerge, the most likely phenotypes of resistant mutants, and the effect of certain phage cocktail combinations in increasing or decreasing the genetic barrier to resistance. If this information confers predictive power in vivo, then routine studies of phage-resistant mutants and their in vitro evolution should be a valuable means for improving the safety and efficacy of phage therapy in humans.

scholarly journals Parallel evolution of phage resistance - virulence trade - offs during in vitro and nasal Pseudomonas aeruginosa phage treatment

2021 ◽  
Author(s):  
Meaghan Castledine ◽  
Daniel Padfield ◽  
Pawel Sierocinski ◽  
Jesica Soria Pascual ◽  
Adam Hughes ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Evolutionary Dynamics ◽  
Phage Therapy ◽  
De Novo ◽  
Resistant Bacteria ◽  
Phage Resistance ◽  
Lower Growth ◽  
Trade Offs

With rising antibiotic resistance, there has been increasing interest in the treatment of pathogenic bacteria with bacteriophages (phage therapy). One limitation of phage therapy is the ease at which bacteria can evolve resistance. The negative effects of resistance may be partially mitigated when resistance results in reduced bacterial growth and virulence, or when phage coevolve to overcome resistance. Resistance evolution and its consequences are highly contingent on the particular combination of bacteria and phage and the ecological context they interact in, making therapeutic outcomes hard to predict. One solution might be to conduct ″in vitro evolutionary simulations″ using the bacteria-phage combinations specific to the therapeutic context. Here, we investigate parallels between in vitro experiments and in vivo dynamics in a human participant. Evolutionary dynamics were similar in vivo and in vitro, with high levels of de novo resistance evolving quickly with limited evidence of phage evolution. Moreover, resistant bacteria – evolved both in vitro and in vivo – had lower virulence when measured in an insect model. In vivo, this was linked to lower growth rates of resistant isolates, whereas in vitro isolates evolved greater biofilm production with phage resistance. Population sequencing suggests resistance was typically the result of selection on de novo mutations rather than sorting of existing variants in the population. These results highlight the speed at which resistance to phages can evolve in vivo, and that in vitro evolution may give useful insights for evolutionary outcomes in vivo.

scholarly journals Selection for increased mass-independent maximal metabolic rate suppresses innate but not adaptive immune function

2013 ◽  
Vol 280 (1754) ◽  
pp. 20122636 ◽  
Author(s):  
Cynthia J. Downs ◽  
Jessi L. Brown ◽  
Bernard Wone ◽  
Edward R. Donovan ◽  
Kenneth Hunter ◽  
...  
Keyword(s):  
Metabolic Rate ◽  
Immune Function ◽  
Innate Immune ◽  
High Mass ◽  
Metabolic Rates ◽  
Trade Off ◽  
Adaptive Immune ◽  
Trade Offs ◽  
Maximal Metabolic Rate ◽  
Selection For

Both appropriate metabolic rates and sufficient immune function are essential for survival. Consequently, eco-immunologists have hypothesized that animals may experience trade-offs between metabolic rates and immune function. Previous work has focused on how basal metabolic rate (BMR) may trade-off with immune function, but maximal metabolic rate (MMR), the upper limit to aerobic activity, might also trade-off with immune function. We used mice artificially selected for high mass-independent MMR to test for trade-offs with immune function. We assessed (i) innate immune function by quantifying cytokine production in response to injection with lipopolysaccharide and (ii) adaptive immune function by measuring antibody production in response to injection with keyhole limpet haemocyanin. Selection for high mass-independent MMR suppressed innate immune function, but not adaptive immune function. However, analyses at the individual level also indicate a negative correlation between MMR and adaptive immune function. By contrast BMR did not affect immune function. Evolutionarily, natural selection may favour increasing MMR to enhance aerobic performance and endurance, but the benefits of high MMR may be offset by impaired immune function. This result could be important in understanding the selective factors acting on the evolution of metabolic rates.

scholarly journals Rapid and robust evolution of collateral sensitivity in Pseudomonas aeruginosa antibiotic-resistant mutants

2020 ◽  
Vol 6 (32) ◽  
pp. eaba5493
Author(s):  
Sara Hernando-Amado ◽  
Fernando Sanz-García ◽  
José Luis Martínez
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Antibiotic Resistance ◽  
Rational Design ◽  
Antibiotic Resistant ◽  
Trade Off ◽  
Collateral Sensitivity ◽  
Trade Offs ◽  
Resistant Mutants ◽  
Antibiotic Resistant Mutants

The analysis of trade-offs, as collateral sensitivity, associated with the acquisition of antibiotic resistance, is mainly based on the use of model strains. However, the possibility of exploiting these trade-offs for fighting already resistant isolates has not been addressed in depth, despite the fact that bacterial pathogens are frequently antibiotic-resistant, forming either homogeneous or heterogeneous populations. Using a set of Pseudomonas aeruginosa-resistant mutants, we found that ceftazidime selects pyomelanogenic tobramycin-hypersusceptible mutants presenting chromosomal deletions in the analyzed genetic backgrounds. Since pyomelanogenic resistant mutants frequently coexist with other morphotypes in patients with cystic fibrosis, we analyzed the exploitation of this trade-off to drive extinction of heterogeneous resistant populations by using tobramycin/ceftazidime alternation. Our work shows that this approach is feasible because phenotypic trade-offs associated with the use of ceftazidime are robust. The identification of conserved collateral sensitivity networks may guide the rational design of evolution-based antibiotic therapies in P. aeruginosa infections.

Dual Goals for Speed and Accuracy on the Same Performance Task

2012 ◽  
Vol 11 (3) ◽  
pp. 118-126 ◽  
Author(s):  
Olive Emil Wetter ◽  
Jürgen Wegge ◽  
Klaus Jonas ◽  
Klaus-Helmut Schmidt
Keyword(s):  
Memory Scanning ◽  
Performance Task ◽  
Performance Tasks ◽  
Trade Off ◽  
Test Experiment ◽  
Trade Offs ◽  
New Finding ◽  
Sternberg Paradigm ◽  
Speed Accuracy ◽  
Speed And Accuracy

In most work contexts, several performance goals coexist, and conflicts between them and trade-offs can occur. Our paper is the first to contrast a dual goal for speed and accuracy with a single goal for speed on the same task. The Sternberg paradigm (Experiment 1, n = 57) and the d2 test (Experiment 2, n = 19) were used as performance tasks. Speed measures and errors revealed in both experiments that dual as well as single goals increase performance by enhancing memory scanning. However, the single speed goal triggered a speed-accuracy trade-off, favoring speed over accuracy, whereas this was not the case with the dual goal. In difficult trials, dual goals slowed down scanning processes again so that errors could be prevented. This new finding is particularly relevant for security domains, where both aspects have to be managed simultaneously.

The Effects of Decision Time on Perceptions of Decisions and Decision Makers in (Moral) Trade-Off Scenarios

2019 ◽  
Author(s):  
Anna Katharina Spälti ◽  
Mark John Brandt ◽  
Marcel Zeelenberg
Keyword(s):  
Decision Process ◽  
Decision Time ◽  
Decision Makers ◽  
Process Information ◽  
Total N ◽  
Trade Off ◽  
Financial Gain ◽  
Trade Offs ◽  
Sacred Values ◽  
Moral Context

People often have to make trade-offs. We study three types of trade-offs: 1) "secular trade-offs" where no moral or sacred values are at stake, 2) "taboo trade-offs" where sacred values are pitted against financial gain, and 3) "tragic trade-offs" where sacred values are pitted against other sacred values. Previous research (Critcher et al., 2011; Tetlock et al., 2000) demonstrated that tragic and taboo trade-offs are not only evaluated by their outcomes, but are also evaluated based on the time it took to make the choice. We investigate two outstanding questions: 1) whether the effect of decision time differs for evaluations of decisions compared to decision makers and 2) whether moral contexts are unique in their ability to influence character evaluations through decision process information. In two experiments (total N = 1434) we find that decision time affects character evaluations, but not evaluations of the decision itself. There were no significant differences between tragic trade-offs and secular trade-offs, suggesting that the decisions structure may be more important in evaluations than moral context. Additionally, the magnitude of the effect of decision time shows us that decision time, may be of less practical use than expected. We thus urge, to take a closer examination of the processes underlying decision time and its perception.

Predicting Undesired Treatment Outcome in Mental Healthcare: Machine Learning Study (Preprint)

2019 ◽  
Author(s):  
Kasper Van Mens ◽  
Joran Lokkerbol ◽  
Richard Janssen ◽  
Robert de Lange ◽  
Bea Tiemens
Keyword(s):  
Machine Learning ◽  
Treatment Outcome ◽  
Mental Health Treatment ◽  
Mental Healthcare ◽  
Machine Learning Algorithms ◽  
Gradient Boosting ◽  
Trade Off ◽  
Trade Offs ◽  
Outcome Monitoring ◽  
Extreme Gradient Boosting

BACKGROUND It remains a challenge to predict which treatment will work for which patient in mental healthcare. OBJECTIVE In this study we compare machine algorithms to predict during treatment which patients will not benefit from brief mental health treatment and present trade-offs that must be considered before an algorithm can be used in clinical practice. METHODS Using an anonymized dataset containing routine outcome monitoring data from a mental healthcare organization in the Netherlands (n = 2,655), we applied three machine learning algorithms to predict treatment outcome. The algorithms were internally validated with cross-validation on a training sample (n = 1,860) and externally validated on an unseen test sample (n = 795). RESULTS The performance of the three algorithms did not significantly differ on the test set. With a default classification cut-off at 0.5 predicted probability, the extreme gradient boosting algorithm showed the highest positive predictive value (ppv) of 0.71(0.61 – 0.77) with a sensitivity of 0.35 (0.29 – 0.41) and area under the curve of 0.78. A trade-off can be made between ppv and sensitivity by choosing different cut-off probabilities. With a cut-off at 0.63, the ppv increased to 0.87 and the sensitivity dropped to 0.17. With a cut-off of at 0.38, the ppv decreased to 0.61 and the sensitivity increased to 0.57. CONCLUSIONS Machine learning can be used to predict treatment outcomes based on routine monitoring data.This allows practitioners to choose their own trade-off between being selective and more certain versus inclusive and less certain.

Challenges in the Empirical Study of Global Governance Legitimacy

2018 ◽  
Author(s):  
Steven Bernstein
Keyword(s):  
Empirical Study ◽  
Global Governance ◽  
Research Agenda ◽  
Cultural Factors ◽  
Theory Building ◽  
Trade Off ◽  
Trade Offs ◽  
Different Types ◽  
Political Communities

This commentary discusses three challenges for the promising and ambitious research agenda outlined in the volume. First, it interrogates the volume’s attempts to differentiate political communities of legitimation, which may vary widely in composition, power, and relevance across institutions and geographies, with important implications not only for who matters, but also for what gets legitimated, and with what consequences. Second, it examines avenues to overcome possible trade-offs from gains in empirical tractability achieved through the volume’s focus on actor beliefs and strategies. One such trade-off is less attention to evolving norms and cultural factors that may underpin actors’ expectations about what legitimacy requires. Third, it addresses the challenge of theory building that can link legitimacy sources, (de)legitimation practices, audiences, and consequences of legitimacy across different types of institutions.

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