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https://www.readbyqxmd.com/read/28420742/synergistic-internal-ribosome-entry-site-microrna-based-approach-for-flavivirus-attenuation-and-live-vaccine-development
#1
Konstantin A Tsetsarkin, Guangping Liu, Evgeniya Volkova, Alexander G Pletnev
The recent emergence of Zika virus underscores the need for new strategies for a rapid development of safe flavivirus vaccines. Using another flavivirus (Langat virus [LGTV]) that belongs to the group of tick-borne flaviviruses as a model, we describe a dual strategy for virus attenuation which synergistically accesses the specificity of microRNA (miRNA) genome targeting and the effectiveness of internal ribosome entry site (IRES) insertion. To increase the stability and immunogenicity of bicistronic LGTVs, we developed a novel approach in which the capsid (C) protein gene was relocated into the 3' noncoding region (NCR) and expressed under translational control from an IRES...
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28420741/new-mechanism-by-which-human-cytomegalovirus-micrornas-negate-the-proinflammatory-response-to-infection
#2
Andrew D Yurochko
Viruses have evolved many novel mechanisms to promote infection and to mitigate the host cell response to that infection. In the article by M. H. Hancock et al. (mBio 8:e00109-17, 2017, https://doi.org/10.1128/mBio.00109-17), the authors describe a new mechanism by which human cytomegalovirus (HCMV) microRNAs (miRNAs; miR-US5-1 and miR-UL112-3p) negate the proinflammatory response to infection. The authors document that these two viral miRNAs downregulate the NF-κB response through direct targeting of the IKKα and IKKβ mRNAs, which in turn, through diminished IκB kinases (IKKs), block production of proinflammatory cytokines (interleukin-6 [IL-6], CCL5, and tumor necrosis factor alpha [TNF-α])...
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28420740/erratum-for-roth-et-al-flavivirus-infection-uncouples-translation-suppression-from-cellular-stress-responses
#3
Hanna Roth, Vera Magg, Fabian Uch, Pascal Mutz, Philipp Klein, Katharina Haneke, Volker Lohmann, Ralf Bartenschlager, Oliver T Fackler, Nicolas Locker, Georg Stoecklin, Alessia Ruggieri
No abstract text is available yet for this article.
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28420739/the-dnak-chaperone-uses-different-mechanisms-to-promote-and-inhibit-replication-of-vibrio-cholerae-chromosome-2
#4
Jyoti K Jha, Mi Li, Rodolfo Ghirlando, Lisa M Miller Jenkins, Alexander Wlodawer, Dhruba Chattoraj
Replication of Vibrio cholerae chromosome 2 (Chr2) depends on molecular chaperone DnaK to facilitate binding of the initiator (RctB) to the replication origin. The binding occurs at two kinds of site, 12-mers and 39-mers, which promote and inhibit replication, respectively. Here we show that DnaK employs different mechanisms to enhance the two kinds of binding. We found that mutations in rctB that reduce DnaK binding also reduce 12-mer binding and initiation. The initiation defect is suppressed by second-site mutations that increase 12-mer binding only marginally...
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28420738/sar202-genomes-from-the-dark-ocean-predict-pathways-for-the-oxidation-of-recalcitrant-dissolved-organic-matter
#5
Zachary Landry, Brandon K Swan, Gerhard J Herndl, Ramunas Stepanauskas, Stephen J Giovannoni
Deep-ocean regions beyond the reach of sunlight contain an estimated 615 Pg of dissolved organic matter (DOM), much of which persists for thousands of years. It is thought that bacteria oxidize DOM until it is too dilute or refractory to support microbial activity. We analyzed five single-amplified genomes (SAGs) from the abundant SAR202 clade of dark-ocean bacterioplankton and found they encode multiple families of paralogous enzymes involved in carbon catabolism, including several families of oxidative enzymes that we hypothesize participate in the degradation of cyclic alkanes...
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28420737/tolerant-growing-cells-from-nutrient-shifts-are-not-persister-cells
#6
Jun-Seob Kim, Thomas K Wood
There is much controversy about the metabolic state of cells that are tolerant to antibiotics, known as persister cells. In this opinion piece, we offer an explanation for the discrepancy seen: some laboratories are studying metabolically active and growing cell populations (e.g., as a result of nutrient shifts) and attributing the phenotypes that they discern to persister cells while other labs are studying dormant cells. We argue here that the metabolically active cell population should more accurately be considered tolerant cells, while the dormant cells are the true persister population...
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28420736/deciphering-the-regulatory-network-between-the-srebp-pathway-and-protein-secretion-in-neurospora-crassa
#7
Lina Qin, Vincent W Wu, N Louise Glass
Sterol regulatory element binding proteins (SREBPs) are conserved from yeast to mammalian cells and function in the regulation of sterol homeostasis. In fungi, the SREBP pathway has been implicated in the adaptation to hypoxia and in virulence. In Neurospora crassa and Trichoderma reesei, the SREBP pathway also negatively regulates protein secretion under lignocellulolytic conditions. Here we utilized global transcriptional profiling combined with genetic and physiological analyses to address the regulatory link between the SREBP pathway and protein secretion in N...
April 18, 2017: MBio
https://www.readbyqxmd.com/read/28400530/phototaxis-of-cyanobacteria-under-complex-light-environments
#8
Minsu Kim
Photosynthetic bacteria are capable of producing their own food via photosynthesis. Unsurprisingly, they evolved the ability to move toward better light conditions (i.e., phototaxis). In a recent article in mBio, Chau et al. tuned the wavelength, flux, direction, and timing of light input and characterized the motility of the unicellular cyanobacterium Synechocystis sp. strain PCC6803 (R. M. W. Chau, D. Bhaya, and K. C. Huang, mBio 8:e02330-16, 2017, https://doi.org/10.1128/mBio.02330-16). The results revealed an intricate dependence of the motility on various light inputs, laying the fundamental groundwork toward understanding phototaxis under complex and dynamic light environments...
April 11, 2017: MBio
https://www.readbyqxmd.com/read/28400529/control-of-gdhr-expression-in-neisseria-gonorrhoeae-via-autoregulation-and-a-master-repressor-mtrr-of-a-drug-efflux-pump-operon
#9
Corinne E Rouquette-Loughlin, Yaramah M Zalucki, Vijaya L Dhulipala, Jacqueline T Balthazar, Raúl G Doyle, Robert A Nicholas, Afrin A Begum, Erica L Raterman, Ann E Jerse, William M Shafer
The MtrCDE efflux pump of Neisseria gonorrhoeae contributes to gonococcal resistance to a number of antibiotics used previously or currently in treatment of gonorrhea, as well as to host-derived antimicrobials that participate in innate defense. Overexpression of the MtrCDE efflux pump increases gonococcal survival and fitness during experimental lower genital tract infection of female mice. Transcription of mtrCDE can be repressed by the DNA-binding protein MtrR, which also acts as a global regulator of genes involved in important metabolic, physiologic, or regulatory processes...
April 11, 2017: MBio
https://www.readbyqxmd.com/read/28400528/within-host-evolution-of-burkholderia-pseudomallei-during-chronic-infection-of-seven-australasian-cystic-fibrosis-patients
#10
Linda T Viberg, Derek S Sarovich, Timothy J Kidd, James B Geake, Scott C Bell, Bart J Currie, Erin P Price
Cystic fibrosis (CF) is a genetic disorder characterized by progressive lung function decline. CF patients are at an increased risk of respiratory infections, including those by the environmental bacterium Burkholderia pseudomallei, the causative agent of melioidosis. Here, we compared the genomes of B. pseudomallei isolates collected between ~4 and 55 months apart from seven chronically infected CF patients. Overall, the B. pseudomallei strains showed evolutionary patterns similar to those of other chronic infections, including emergence of antibiotic resistance, genome reduction, and deleterious mutations in genes involved in virulence, metabolism, environmental survival, and cell wall components...
April 11, 2017: MBio
https://www.readbyqxmd.com/read/28400527/targeting-energy-metabolism-in-mycobacterium-tuberculosis-a-new-paradigm-in-antimycobacterial-drug-discovery
#11
REVIEW
Dirk Bald, Cristina Villellas, Ping Lu, Anil Koul
Drug-resistant mycobacterial infections are a serious global health challenge, leading to high mortality and socioeconomic burdens in developing countries worldwide. New innovative approaches, from identification of new targets to discovery of novel chemical scaffolds, are urgently needed. Recently, energy metabolism in mycobacteria, in particular the oxidative phosphorylation pathway, has emerged as an object of intense microbiological investigation and as a novel target pathway in drug discovery. New classes of antibacterials interfering with elements of the oxidative phosphorylation pathway are highly active in combating dormant or latent mycobacterial infections, with a promise of shortening tuberculosis chemotherapy...
April 11, 2017: MBio
https://www.readbyqxmd.com/read/28400526/plasmodium-falciparum-k13-mutations-differentially-impact-ozonide-susceptibility-and-parasite-fitness-in-vitro
#12
Judith Straimer, Nina F Gnädig, Barbara H Stokes, Michelle Ehrenberger, Audrey A Crane, David A Fidock
The emergence and spread in Southeast Asia of Plasmodium falciparum resistance to artemisinin (ART) derivatives, the cornerstone of first-line artemisinin-based combination therapies (ACTs), underscore the urgent need to identify suitable replacement drugs. Discovery and development efforts have identified a series of ozonides with attractive chemical and pharmacological properties that are being touted as suitable replacements. Partial resistance to ART, defined as delayed parasite clearance in malaria patients treated with an ART derivative or an ACT, has been associated with mutations in the P...
April 11, 2017: MBio
https://www.readbyqxmd.com/read/28400525/manipulation-of-the-host-cell-membrane-during-plasmodium-liver-stage-egress
#13
Paul-Christian Burda, Reto Caldelari, Volker T Heussler
A crucial step in the life cycle of Plasmodium parasites is the transition from the liver stage to the blood stage. Hepatocyte-derived merozoites reach the blood vessels of the liver inside host cell-derived vesicles called merosomes. The molecular basis of merosome formation is only partially understood. Here we show that Plasmodium berghei liver stage merozoites, upon rupture of the parasitophorous vacuole membrane, destabilize the host cell membrane (HCM) and induce separation of the host cell actin cytoskeleton from the HCM...
April 11, 2017: MBio
https://www.readbyqxmd.com/read/28377533/nonselective-bottlenecks-control-the-divergence-and-diversification-of-phase-variable-bacterial-populations
#14
Jack Aidley, Shweta Rajopadhye, Nwanekka M Akinyemi, Lea Lango-Scholey, Christopher D Bayliss
Phase variation occurs in many pathogenic and commensal bacteria and is a major generator of genetic variability. A putative advantage of phase variation is to counter reductions in variability imposed by nonselective bottlenecks during transmission. Genomes of Campylobacter jejuni, a widespread food-borne pathogen, contain multiple phase-variable loci whose rapid, stochastic variation is generated by hypermutable simple sequence repeat tracts. These loci can occupy a vast number of combinatorial expression states (phasotypes) enabling populations to rapidly access phenotypic diversity...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28377532/acknowledgment-of-invited-editors
#15
Arturo Casadevall
No abstract text is available yet for this article.
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28377531/further-evidence-for-bats-as-the-evolutionary-source-of-middle-east-respiratory-syndrome-coronavirus
#16
S J Anthony, K Gilardi, V D Menachery, T Goldstein, B Ssebide, R Mbabazi, I Navarrete-Macias, E Liang, H Wells, A Hicks, A Petrosov, D K Byarugaba, K Debbink, K H Dinnon, T Scobey, S H Randell, B L Yount, M Cranfield, C K Johnson, R S Baric, W I Lipkin, J A K Mazet
The evolutionary origins of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV) are unknown. Current evidence suggests that insectivorous bats are likely to be the original source, as several 2c CoVs have been described from various species in the family Vespertilionidae Here, we describe a MERS-like CoV identified from a Pipistrellus cf. hesperidus bat sampled in Uganda (strain PREDICT/PDF-2180), further supporting the hypothesis that bats are the evolutionary source of MERS-CoV. Phylogenetic analysis showed that PREDICT/PDF-2180 is closely related to MERS-CoV across much of its genome, consistent with a common ancestry; however, the spike protein was highly divergent (46% amino acid identity), suggesting that the two viruses may have different receptor binding properties...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28377530/topoisomerase-ii-inhibitors-induce-dna-damage-dependent-interferon-responses-circumventing-ebola-virus-immune-evasion
#17
Priya Luthra, Sebastian Aguirre, Benjamin C Yen, Colette A Pietzsch, Maria T Sanchez-Aparicio, Bersabeh Tigabu, Lorraine K Morlock, Adolfo García-Sastre, Daisy W Leung, Noelle S Williams, Ana Fernandez-Sesma, Alexander Bukreyev, Christopher F Basler
Ebola virus (EBOV) protein VP35 inhibits production of interferon alpha/beta (IFN) by blocking RIG-I-like receptor signaling pathways, thereby promoting virus replication and pathogenesis. A high-throughput screening assay, developed to identify compounds that either inhibit or bypass VP35 IFN-antagonist function, identified five DNA intercalators as reproducible hits from a library of bioactive compounds. Four, including doxorubicin and daunorubicin, are anthracycline antibiotics that inhibit topoisomerase II and are used clinically as chemotherapeutic drugs...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28377529/catabolism-of-the-last-two-steroid-rings-in-mycobacterium-tuberculosis-and-other-bacteria
#18
Adam M Crowe, Israël Casabon, Kirstin L Brown, Jie Liu, Jennifer Lian, Jason C Rogalski, Timothy E Hurst, Victor Snieckus, Leonard J Foster, Lindsay D Eltis
Most mycolic acid-containing actinobacteria and some proteobacteria use steroids as growth substrates, but the catabolism of the last two steroid rings has yet to be elucidated. In Mycobacterium tuberculosis, this pathway includes virulence determinants and has been proposed to be encoded by the KstR2-regulated genes, which include a predicted coenzyme A (CoA) transferase gene (ipdAB) and an acyl-CoA reductase gene (ipdC). In the presence of cholesterol, ΔipdC and ΔipdAB mutants of either M. tuberculosis or Rhodococcus jostii strain RHA1 accumulated previously undescribed metabolites: 3aα-H-4α(carboxyl-CoA)-5-hydroxy-7aβ-methylhexahydro-1-indanone (5-OH HIC-CoA) and (R)-2-(2-carboxyethyl)-3-methyl-6-oxocyclohex-1-ene-1-carboxyl-CoA (COCHEA-CoA), respectively...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28377528/listeriolysin-s-is-a-streptolysin-s-like-virulence-factor-that-targets-exclusively-prokaryotic-cells-in-vivo
#19
Juan J Quereda, Marie A Nahori, Jazmín Meza-Torres, Martin Sachse, Patricia Titos-Jiménez, Jaime Gomez-Laguna, Olivier Dussurget, Pascale Cossart, Javier Pizarro-Cerdá
Streptolysin S (SLS)-like virulence factors from clinically relevant Gram-positive pathogens have been proposed to behave as potent cytotoxins, playing key roles in tissue infection. Listeriolysin S (LLS) is an SLS-like hemolysin/bacteriocin present among Listeria monocytogenes strains responsible for human listeriosis outbreaks. As LLS cytotoxic activity has been associated with virulence, we investigated the LLS-specific contribution to host tissue infection. Surprisingly, we first show that LLS causes only weak red blood cell (RBC) hemolysis in vitro and neither confers resistance to phagocytic killing nor favors survival of L...
April 4, 2017: MBio
https://www.readbyqxmd.com/read/28377527/phage-inhibit-pathogen-dissemination-by-targeting-bacterial-migrants-in-a-chronic-infection-model
#20
Sophie E Darch, Kasper N Kragh, Evelyn A Abbott, Thomas Bjarnsholt, James J Bull, Marvin Whiteley
The microbial communities inhabiting chronic infections are often composed of spatially organized micrometer-sized, highly dense aggregates. It has recently been hypothesized that aggregates are responsible for the high tolerance of chronic infections to host immune functions and antimicrobial therapies. Little is currently known regarding the mechanisms controlling aggregate formation and antimicrobial tolerance primarily because of the lack of robust, biologically relevant experimental systems that promote natural aggregate formation...
April 4, 2017: MBio
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