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1. Changes in hepatitis C burden and treatment trends in Europe during the era of direct-acting antivirals: a modelling study

   https://doi.org/10.1136/bmjopen-2018-026726  

   Chen, Qiushi; Ayer, Turgay; Bethea, Emily; Kanwal, Fasiha; Wang, Xiaojie; Roberts, Mark; Zhuo, Yueran; Fagiuoli, Stefano; Petersen, Jorg; Chhatwal, Jagpreet (June 2019, BMJ Open)

   Objectives Oral direct-acting antivirals (DAAs) for hepatitis C virus (HCV) have dramatically changed the treatment paradigm. Our aim was to project temporal trends in HCV diagnosis, treatment and disease burden in France, Germany, Italy, Spain and the UK. Design A mathematical simulation model of natural history of HCV infection. Participants HCV-infected patients defined based on country-specific age, fibrosis and genotype distributions. Interventions HCV screening practice and availability of different waves of DAA treatment in each country. Outcome measures Temporal trends in the number of patients who achieve sustained virological response (SVR), fail treatment (by drug regimen) and develop advanced sequelae from 2014 to 2030 in each country. Results We projected that 1 324 000 individuals would receive treatment from 2014 to 2030 in the five European countries and 12 000–37 000 of them would fail to achieve SVR. By 2021, the number of individuals cured of HCV would supersede the number of actively infected individuals in France, Germany, Spain and the UK. Under status quo, the diagnosis rate would reach between 65% and 75% and treatment coverage between 65% and 74% by 2030 in these countries. The number of patients who fail treatment would decrease over time, with the majority of those who fail treatment having been exposed to non-structural protein 5A inhibitors. Conclusions In the era of DAAs, the number of people with HCV who achieved a cure will exceed the number of viraemic patients, but many patients will remain undiagnosed, untreated, fail multiple treatments and develop advanced sequelae. Scaling-up screening and treatment capacity, and timely and effective retreatment are needed to avail the full benefits of DAAs and to meet HCV elimination targets set by WHO. 

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2. The Landscape of Phenotypic and Transcriptional Responses to Ciprofloxacin in Acinetobacter baumannii: Acquired Resistance Alleles Modulate Drug-Induced SOS Response and Prophage Replication

   https://doi.org/10.1128/mBio.01127-19  

   Geisinger, Edward; Vargas-Cuebas, Germán; Mortman, Nadav J.; Syal, Sapna; Dai, Yunfei; Wainwright, Elizabeth L.; Lazinski, David; Wood, Stephen; Zhu, Zeyu; Anthony, Jon; et al (June 2019, mBio)

   Miller, Samuel I. (Ed.)

   ABSTRACT The emergence of fluoroquinolone resistance in nosocomial pathogens has restricted the clinical efficacy of this antibiotic class. In Acinetobacter baumannii , the majority of clinical isolates now show high-level resistance due to mutations in gyrA (DNA gyrase) and parC (topoisomerase IV [topo IV]). To investigate the molecular basis for fluoroquinolone resistance, an exhaustive mutation analysis was performed in both drug-sensitive and -resistant strains to identify loci that alter ciprofloxacin sensitivity. To this end, parallel fitness tests of over 60,000 unique insertion mutations were performed in strains with various alleles in genes encoding the drug targets. The spectra of mutations that altered drug sensitivity were found to be similar in the drug-sensitive and gyrA parC double-mutant backgrounds, having resistance alleles in both genes. In contrast, the introduction of a single gyrA resistance allele, resulting in preferential poisoning of topo IV by ciprofloxacin, led to extreme alterations in the insertion mutation fitness landscape. The distinguishing feature of preferential topo IV poisoning was enhanced induction of DNA synthesis in the region of two endogenous prophages, with DNA synthesis associated with excision and circularization of the phages. Induction of the selective DNA synthesis in the gyrA background was also linked to heightened prophage gene transcription and enhanced activation of the mutagenic SOS response relative to that observed in either the wild-type (WT) or gyrA parC double mutant. Therefore, the accumulation of mutations that result in the stepwise evolution of high ciprofloxacin resistance is tightly connected to modulation of the SOS response and endogenous prophage DNA synthesis. IMPORTANCE Fluoroquinolones have been extremely successful antibiotics due to their ability to target multiple bacterial enzymes critical to DNA replication, the topoisomerases DNA gyrase and topo IV. Unfortunately, mutations lowering drug affinity for both enzymes are now widespread, rendering these drugs ineffective for many pathogens. To undermine this form of resistance, we examined how bacteria with target alterations differentially cope with fluoroquinolone exposures. We studied this problem in the nosocomial pathogen A. baumannii , which causes drug-resistant life-threatening infections. Employing genome-wide approaches, we uncovered numerous pathways that could be exploited to raise fluoroquinolone sensitivity independently of target alteration. Remarkably, fluoroquinolone targeting of topo IV in specific mutants caused dramatic hyperinduction of prophage replication and enhanced the mutagenic DNA damage response, but these responses were muted in strains with DNA gyrase as the primary target. This work demonstrates that resistance evolution via target modification can profoundly modulate the antibiotic stress response, revealing potential resistance-associated liabilities. 

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3. Mathematical Modeling of RNA Virus Sensing Pathways Reveals Paracrine Signaling as the Primary Factor Regulating Excessive Cytokine Production

   https://doi.org/10.3390/pr8060719  

   Weaver, Jordan J.; Shoemaker, Jason E. (June 2020, Processes)

   null (Ed.)

   RNA viruses, such as influenza and Severe Acute Respiratory Syndrome (SARS), invoke excessive immune responses; however, the kinetics that regulate inflammatory responses within infected cells remain unresolved. Here, we develop a mathematical model of the RNA virus sensing pathways, to determine the intracellular events that primarily regulate interferon, an important protein for the activation and management of inflammation. Within the ordinary differential equation (ODE) model, we incorporate viral replication, cell death, interferon stimulated genes’ antagonistic effects on viral replication, and virus sensor protein (TLR and RIG-I) kinetics. The model is parameterized to influenza infection data using Markov chain Monte Carlo and then validated against infection data from an NS1 knockout strain of influenza, demonstrating that RIG-I antagonism significantly alters cytokine signaling trajectory. Global sensitivity analysis suggests that paracrine signaling is responsible for the majority of cytokine production, suggesting that rapid cytokine production may be best managed by influencing extracellular cytokine levels. As most of the model kinetics are host cell specific and not virus specific, the model presented provides an important step to modeling the intracellular immune dynamics of many RNA viruses, including the viruses responsible for SARS, Middle East Respiratory Syndrome (MERS), and Coronavirus Disease (COVID-19). 

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4. Idiosyncratic Fitness Costs of Ampicillin-Resistant Mutants Derived from a Long-Term Experiment with Escherichia coli

   https://doi.org/10.3390/antibiotics11030347  

   Jordan, Jalin A.; Lenski, Richard E.; Card, Kyle J. (March 2022, Antibiotics)

   Antibiotic resistance is a growing concern that has prompted a renewed focus on drug discovery, stewardship, and evolutionary studies of the patterns and processes that underlie this phenomenon. A resistant strain’s competitive fitness relative to its sensitive counterparts in the absence of drug can impact its spread and persistence in both clinical and community settings. In a prior study, we examined the fitness of tetracycline-resistant clones that evolved from five different Escherichia coli genotypes, which had diverged during a long-term evolution experiment. In this study, we build on that work to examine whether ampicillin-resistant mutants are also less fit in the absence of the drug than their sensitive parents, and whether the cost of resistance is constant or variable among independently derived lines. Like the tetracycline-resistant lines, the ampicillin-resistant mutants were often less fit than their sensitive parents, with significant variation in the fitness costs among the mutants. This variation was not associated with the level of resistance conferred by the mutations, nor did it vary across the different parental backgrounds. In our earlier study, some of the variation in fitness costs associated with tetracycline resistance was explained by the effects of different mutations affecting the same cellular pathway and even the same gene. In contrast, the variance among the ampicillin-resistant mutants was associated with different sets of target genes. About half of the resistant clones suffered large fitness deficits, and their mutations impacted major outer-membrane proteins or subunits of RNA polymerases. The other mutants experienced little or no fitness costs and with, one exception, they had mutations affecting other genes and functions. Our findings underscore the importance of comparative studies on the evolution of antibiotic resistance, and they highlight the nuanced processes that shape these phenotypes. 

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5. Assessing in vivo mutation frequencies and creating a high-resolution genome-wide map of fitness costs of Hepatitis C virus

   https://doi.org/10.1371/journal.pgen.1010179  

   Tisthammer, Kaho H.; Solis, Caroline; Orcales, Faye; Nzerem, Madu; Winstead, Ryan; Dong, Weiyan; Joy, Jeffrey B.; Pennings, Pleuni S. (May 2022, PLOS Genetics)

   Wahl, Lindi (Ed.)

   Like many viruses, Hepatitis C Virus (HCV) has a high mutation rate, which helps the virus adapt quickly, but mutations come with fitness costs. Fitness costs can be studied by different approaches, such as experimental or frequency-based approaches. The frequency-based approach is particularly useful to estimate in vivo fitness costs, but this approach works best with deep sequencing data from many hosts are. In this study, we applied the frequency-based approach to a large dataset of 195 patients and estimated the fitness costs of mutations at 7957 sites along the HCV genome. We used beta regression and random forest models to better understand how different factors influenced fitness costs. Our results revealed that costs of nonsynonymous mutations were three times higher than those of synonymous mutations, and mutations at nucleotides A or T had higher costs than those at C or G. Genome location had a modest effect, with lower costs for mutations in HVR1 and higher costs for mutations in Core and NS5B. Resistance mutations were, on average, costlier than other mutations. Our results show that in vivo fitness costs of mutations can be site and virus specific, reinforcing the utility of constructing in vivo fitness cost maps of viral genomes. 

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