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Bacterial Hypoxic Responses Revealed as Critical Determinants of the Host-Pathogen Outcome by TnSeq Analysis of Staphylococcus aureus Invasive Infection.
Wilde AD, Snyder DJ, Putnam NE, Valentino MD, Hammer ND, Lonergan ZR, Hinger SA, Aysanoa EE, Blanchard C, Dunman PM, Wasserman GA, Chen J, Shopsin B, Gilmore MS, Skaar EP, Cassat JE
(2015) PLoS Pathog 11: e1005341
MeSH Terms: Animals, Cell Hypoxia, Cell Line, DNA Transposable Elements, Disease Models, Animal, Female, Gene Expression Regulation, Bacterial, Genes, Viral, Host-Pathogen Interactions, Humans, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Osteomyelitis, Quorum Sensing, Reverse Transcriptase Polymerase Chain Reaction, Staphylococcal Infections, Staphylococcus aureus, Virulence, Virulence Factors
Show Abstract · Added February 8, 2016
Staphylococcus aureus is capable of infecting nearly every organ in the human body. In order to infiltrate and thrive in such diverse host tissues, staphylococci must possess remarkable flexibility in both metabolic and virulence programs. To investigate the genetic requirements for bacterial survival during invasive infection, we performed a transposon sequencing (TnSeq) analysis of S. aureus during experimental osteomyelitis. TnSeq identified 65 genes essential for staphylococcal survival in infected bone and an additional 148 mutants with compromised fitness in vivo. Among the loci essential for in vivo survival was SrrAB, a staphylococcal two-component system previously reported to coordinate hypoxic and nitrosative stress responses in vitro. Healthy bone is intrinsically hypoxic, and intravital oxygen monitoring revealed further decreases in skeletal oxygen concentrations upon S. aureus infection. The fitness of an srrAB mutant during osteomyelitis was significantly increased by depletion of neutrophils, suggesting that neutrophils impose hypoxic and/or nitrosative stresses on invading bacteria. To more globally evaluate staphylococcal responses to changing oxygenation, we examined quorum sensing and virulence factor production in staphylococci grown under aerobic or hypoxic conditions. Hypoxic growth resulted in a profound increase in quorum sensing-dependent toxin production, and a concomitant increase in cytotoxicity toward mammalian cells. Moreover, aerobic growth limited quorum sensing and cytotoxicity in an SrrAB-dependent manner, suggesting a mechanism by which S. aureus modulates quorum sensing and toxin production in response to environmental oxygenation. Collectively, our results demonstrate that bacterial hypoxic responses are key determinants of the staphylococcal-host interaction.
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20 MeSH Terms
Serotype-specific differences in inhibition of reovirus infectivity by human-milk glycans are determined by viral attachment protein σ1.
Iskarpatyoti JA, Morse EA, McClung RP, Ikizler M, Wetzel JD, Contractor N, Dermody TS
(2012) Virology 433: 489-97
MeSH Terms: Animals, Capsid Proteins, Cattle, Female, G(M3) Ganglioside, Gangliosides, Genes, Viral, HeLa Cells, Hemagglutination Inhibition Tests, Host-Pathogen Interactions, Humans, L Cells (Cell Line), Mammalian orthoreovirus 3, Mice, Milk, Human, Oligosaccharides, Orthoreovirus, Mammalian, Polysaccharides, Reoviridae Infections, Serotyping, Species Specificity, Virus Attachment
Show Abstract · Added December 10, 2013
Human milk contains many bioactive components, including secretory IgA, oligosaccharides, and milk-associated proteins. We assessed the antiviral effects of several components of milk against mammalian reoviruses. We found that glucocerebroside (GCB) inhibited the infectivity of reovirus strain type 1 Lang (T1L), whereas gangliosides GD3 and GM3 and 3'-sialyllactose (3SL) inhibited the infectivity of reovirus strain type 3 Dearing (T3D). Agglutination of erythrocytes mediated by T1L and T3D was inhibited by GD3, GM3, and bovine lactoferrin. Additionally, α-sialic acid, 3SL, 6'-sialyllactose, sialic acid, human lactoferrin, osteopontin, and α-lactalbumin inhibited hemagglutination mediated by T3D. Using single-gene reassortant viruses, we found that serotype-specific differences segregate with the gene encoding the viral attachment protein. Furthermore, GD3, GM3, and 3SL inhibit T3D infectivity by blocking binding to host cells, whereas GCB inhibits T1L infectivity post-attachment. These results enhance an understanding of reovirus cell attachment and define a mechanism for the antimicrobial activity of human milk.
Copyright © 2012 Elsevier Inc. All rights reserved.
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22 MeSH Terms
Human papillomavirus and cervical cancer: biomarkers for improved prevention efforts.
Sahasrabuddhe VV, Luhn P, Wentzensen N
(2011) Future Microbiol 6: 1083-98
MeSH Terms: Alphapapillomavirus, Biomarkers, Tumor, Early Detection of Cancer, Female, Genes, Viral, Humans, Mass Screening, Molecular Diagnostic Techniques, Papillomavirus Infections, Uterine Cervical Neoplasms
Show Abstract · Added March 5, 2014
While organized screening programs in industrialized countries have significantly reduced cervical cancer incidence, cytology-based screening has several limitations. Equivocal or mildly abnormal Pap tests require costly retesting or diagnostic work-up by colposcopy and biopsy. In low-resource countries, it has been difficult to establish and sustain cytology-based programs. Advances in understanding human papillomavirus biology and the natural history of human papillomavirus-related precancers and cancers have led to the discovery of a range of novel biomarkers in the past decade. In this article, we will discuss the potential role of new biomarkers for primary screening, triage and diagnosis in high-resource countries and their promise for prevention efforts in resource constrained settings.
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Reverse genetics for mammalian reovirus.
Boehme KW, Ikizler M, Kobayashi T, Dermody TS
(2011) Methods 55: 109-13
MeSH Terms: Animals, Cell Culture Techniques, Cells, Cultured, Cloning, Molecular, Cricetinae, Genes, Viral, Genetic Vectors, Mutagenesis, Site-Directed, Orthoreovirus, Mammalian, Plasmids, Reverse Genetics, Transfection, Virus Replication
Show Abstract · Added December 10, 2013
Mammalian orthoreoviruses (reoviruses) are highly tractable models for studies of viral replication and pathogenesis. The versatility of reovirus as an experimental model has been enhanced by development of a plasmid-based reverse genetics system. Infectious reovirus can be recovered from cells transfected with plasmids encoding cDNAs of each reovirus gene segment using a strategy that does not require helper virus and is independent of selection. In this system, transcription of each gene segment is driven by bacteriophage T7 RNA polymerase, which can be supplied transiently by recombinant vaccinia virus (rDIs-T7pol) or by cells that constitutively express the enzyme. Reverse genetics systems have been developed for two prototype reovirus strains, type 1 Lang (T1L) and type 3 Dearing (T3D). Each reovirus cDNA was encoded on an independent plasmid for the first-generation rescue system. The efficiency of virus recovery was enhanced in a second-generation system by combining the cDNAs for multiple reovirus gene segments onto single plasmids to reduce the number of plasmids from 10 to 4. The reduction in plasmid number and the use of baby hamster kidney cells that express T7 RNA polymerase increased the efficiency of viral rescue, reduced the incubation time required to recover infectious virus, and eliminated potential biosafety concerns associated with the use of recombinant vaccinia virus. Reovirus reverse genetics has been used to introduce mutations into viral capsid and nonstructural components to study viral protein-structure activity relationships and can be exploited to engineer recombinant reoviruses for vaccine and oncolytic applications.
Copyright © 2011 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Dual selection mechanisms drive efficient single-gene reverse genetics for rotavirus.
Trask SD, Taraporewala ZF, Boehme KW, Dermody TS, Patton JT
(2010) Proc Natl Acad Sci U S A 107: 18652-7
MeSH Terms: Amino Acid Sequence, Base Sequence, Cell Line, DNA, Viral, Genes, Viral, Genetic Engineering, Humans, Molecular Sequence Data, Mutation, RNA Interference, RNA-Binding Proteins, Recombinant Proteins, Recombination, Genetic, Rotavirus, Selection, Genetic, Sequence Homology, Amino Acid, Sequence Homology, Nucleic Acid, Temperature, Viral Nonstructural Proteins
Show Abstract · Added December 10, 2013
Current methods for engineering the segmented double-stranded RNA genome of rotavirus (RV) are limited by inefficient recovery of the recombinant virus. In an effort to expand the utility of RV reverse genetics, we developed a method to recover recombinant viruses in which independent selection strategies are used to engineer single-gene replacements. We coupled a mutant SA11 RV encoding a temperature-sensitive (ts) defect in the NSP2 protein with RNAi-mediated degradation of NSP2 mRNAs to isolate a virus containing a single recombinant gene that evades both selection mechanisms. Recovery is rapid and simple; after two rounds of selective passage the recombinant virus reaches titers of ≥10(4) pfu/mL. We used this reverse genetics method to generate a panel of viruses with chimeric NSP2 genes. For one of the chimeric viruses, the introduced NSP2 sequence was obtained from a pathogenic, noncultivated human RV isolate, demonstrating that this reverse genetics system can be used to study the molecular biology of circulating RVs. Combining characterized RV ts mutants and validated siRNA targets should permit the extension of this "two-hit" reverse genetics methodology to other RV genes. Furthermore, application of a dual selection strategy to previously reported reverse genetics methods for RV may enhance the efficiency of recombinant virus recovery.
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19 MeSH Terms
JAM-A-independent, antibody-mediated uptake of reovirus into cells leads to apoptosis.
Danthi P, Hansberger MW, Campbell JA, Forrest JC, Dermody TS
(2006) J Virol 80: 1261-70
MeSH Terms: Animals, Antibodies, Viral, Apoptosis, CHO Cells, Cell Adhesion Molecules, Cricetinae, Cytopathogenic Effect, Viral, Genes, Viral, HeLa Cells, Humans, Junctional Adhesion Molecules, Mammalian orthoreovirus 3, Mice, Orthoreovirus, Mammalian, Receptors, Fc, Recombinant Proteins, Sequence Deletion, Transfection
Show Abstract · Added December 10, 2013
Apoptosis plays a major role in the cytopathic effect induced by reovirus following infection of cultured cells and newborn mice. Strain-specific differences in the capacity of reovirus to induce apoptosis segregate with the S1 and M2 gene segments, which encode attachment protein sigma1 and membrane penetration protein mu1, respectively. Virus strains that bind to both junctional adhesion molecule-A (JAM-A) and sialic acid are the most potent inducers of apoptosis. In addition to receptor binding, events in reovirus replication that occur during or after viral disassembly but prior to initiation of viral RNA synthesis also are required for reovirus-induced apoptosis. To determine whether reovirus infection initiated in the absence of JAM-A and sialic acid results in apoptosis, Chinese hamster ovary (CHO) cells engineered to express Fc receptors were infected with reovirus using antibodies directed against viral outer-capsid proteins. Fc-mediated infection of CHO cells induced apoptosis in a sigma1-independent manner. Apoptosis following this uptake mechanism requires acid-dependent proteolytic disassembly, since treatment of cells with the weak base ammonium chloride diminished the apoptotic response. Analysis of T1L x T3D reassortant viruses revealed that the mu1-encoding M2 gene segment is the only viral determinant of the apoptosis-inducing capacity of reovirus when infection is initiated via Fc receptors. Additionally, a temperature-sensitive, membrane penetration-defective M2 mutant, tsA279.64, is an inefficient inducer of apoptosis. These data suggest that signaling pathways activated by binding of sigma1 to JAM-A and sialic acid are dispensable for reovirus-mediated apoptosis and that the mu1 protein plays an essential role in stimulating proapoptotic signaling.
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18 MeSH Terms
Junctional adhesion molecule a serves as a receptor for prototype and field-isolate strains of mammalian reovirus.
Campbell JA, Schelling P, Wetzel JD, Johnson EM, Forrest JC, Wilson GA, Aurrand-Lions M, Imhof BA, Stehle T, Dermody TS
(2005) J Virol 79: 7967-78
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, CHO Cells, Cell Adhesion Molecules, Cricetinae, DNA Primers, Genes, Viral, HeLa Cells, Humans, Junctional Adhesion Molecules, L Cells (Cell Line), Mammals, Mice, Molecular Sequence Data, Receptors, Virus, Reoviridae, Sequence Alignment, Sequence Homology, Amino Acid, Tight Junctions
Show Abstract · Added December 10, 2013
Reovirus infections are initiated by the binding of viral attachment protein sigma1 to receptors on the surface of host cells. The sigma1 protein is an elongated fiber comprised of an N-terminal tail that inserts into the virion and a C-terminal head that extends from the virion surface. The prototype reovirus strains type 1 Lang/53 (T1L/53) and type 3 Dearing/55 (T3D/55) use junctional adhesion molecule A (JAM-A) as a receptor. The C-terminal half of the T3D/55 sigma1 protein interacts directly with JAM-A, but the determinants of receptor-binding specificity have not been identified. In this study, we investigated whether JAM-A also mediates the attachment of the prototype reovirus strain type 2 Jones/55 (T2J/55) and a panel of field-isolate strains representing each of the three serotypes. Antibodies specific for JAM-A were capable of inhibiting infections of HeLa cells by T1L/53, T2J/55, and T3D/55, demonstrating that strains of all three serotypes use JAM-A as a receptor. To corroborate these findings, we introduced JAM-A or the structurally related JAM family members JAM-B and JAM-C into Chinese hamster ovary cells, which are poorly permissive for reovirus infection. Both prototype and field-isolate reovirus strains were capable of infecting cells transfected with JAM-A but not those transfected with JAM-B or JAM-C. A sequence analysis of the sigma1-encoding S1 gene segment of the strains chosen for study revealed little conservation in the deduced sigma1 amino acid sequences among the three serotypes. This contrasts markedly with the observed sequence variability within each serotype, which is confined to a small number of amino acids. Mapping of these residues onto the crystal structure of sigma1 identified regions of conservation and variability, suggesting a likely mode of JAM-A binding via a conserved surface at the base of the sigma1 head domain.
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Moderate mutation rate in the SARS coronavirus genome and its implications.
Zhao Z, Li H, Wu X, Zhong Y, Zhang K, Zhang YP, Boerwinkle E, Fu YX
(2004) BMC Evol Biol 4: 21
MeSH Terms: Coronavirus, Evolution, Molecular, Genes, Viral, Genome, Viral, Mutagenesis, Phylogeny, SARS Virus, Viral Structural Proteins
Show Abstract · Added March 5, 2014
BACKGROUND - The outbreak of severe acute respiratory syndrome (SARS) caused a severe global epidemic in 2003 which led to hundreds of deaths and many thousands of hospitalizations. The virus causing SARS was identified as a novel coronavirus (SARS-CoV) and multiple genomic sequences have been revealed since mid-April, 2003. After a quiet summer and fall in 2003, the newly emerged SARS cases in Asia, particularly the latest cases in China, are reinforcing a wide-spread belief that the SARS epidemic would strike back. With the understanding that SARS-CoV might be with humans for years to come, knowledge of the evolutionary mechanism of the SARS-CoV, including its mutation rate and emergence time, is fundamental to battle this deadly pathogen. To date, the speed at which the deadly virus evolved in nature and the elapsed time before it was transmitted to humans remains poorly understood.
RESULTS - Sixteen complete genomic sequences with available clinical histories during the SARS outbreak were analyzed. After careful examination of multiple-sequence alignment, 114 single nucleotide variations were identified. To minimize the effects of sequencing errors and additional mutations during the cell culture, three strategies were applied to estimate the mutation rate by 1) using the closely related sequences as background controls; 2) adjusting the divergence time for cell culture; or 3) using the common variants only. The mutation rate in the SARS-CoV genome was estimated to be 0.80 - 2.38 x 10-3 nucleotide substitution per site per year which is in the same order of magnitude as other RNA viruses. The non-synonymous and synonymous substitution rates were estimated to be 1.16 - 3.30 x 10-3 and 1.67 - 4.67 x 10-3 per site per year, respectively. The most recent common ancestor of the 16 sequences was inferred to be present as early as the spring of 2002.
CONCLUSIONS - The estimated mutation rates in the SARS-CoV using multiple strategies were not unusual among coronaviruses and moderate compared to those in other RNA viruses. All estimates of mutation rates led to the inference that the SARS-CoV could have been with humans in the spring of 2002 without causing a severe epidemic.
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8 MeSH Terms
Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells.
Cahir-McFarland ED, Carter K, Rosenwald A, Giltnane JM, Henrickson SE, Staudt LM, Kieff E
(2004) J Virol 78: 4108-19
MeSH Terms: Apoptosis, B-Lymphocytes, Cell Line, Cell Survival, Gene Expression Profiling, Genes, Viral, Herpesvirus 4, Human, Humans, Mitogen-Activated Protein Kinase 8, Mitogen-Activated Protein Kinases, NF-kappa B, Nitriles, Organic Chemicals, Sulfones, Transcription, Genetic, Viral Matrix Proteins, Virus Latency, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added March 5, 2014
Epstein-Barr virus (EBV) latency III infection converts B lymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins, EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumor necrosis factor receptor pathways. The role of NF-kappa B in LMP1 and overall EBV latency III transcriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly and irreversibly inhibited NF-kappa B, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-kappa B inhibitor, Delta N-I kappa B alpha, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with Delta N-I kappa B alpha expression decreased with BAY11 treatment. Newly identified NF-kappa B-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and I kappa B epsilon. Of 776 significantly changed array elements, 134 were fourfold upregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereas only 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated gene products mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1 alpha, MIP1 beta, CXCR5, and RGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activated protein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-gamma R alpha, IRF-4, and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated B cells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs with IgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells. Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways further distinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.
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Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-beta receptor exhibit impaired mammary development and enhanced mammary tumor formation.
Gorska AE, Jensen RA, Shyr Y, Aakre ME, Bhowmick NA, Moses HL
(2003) Am J Pathol 163: 1539-49
MeSH Terms: Animals, Carcinoma, Female, Gene Expression, Genes, Dominant, Genes, Viral, Lactation, Mammary Glands, Animal, Mammary Neoplasms, Animal, Mammary Tumor Virus, Mouse, Mice, Mice, Transgenic, Mutation, Neoplasm Invasiveness, Pregnancy, Promoter Regions, Genetic, Receptors, Transforming Growth Factor beta, Transforming Growth Factor alpha, Transforming Growth Factor beta, Transforming Growth Factor beta2
Show Abstract · Added February 17, 2014
We have previously shown that expression of a dominant-negative type II transforming growth factor-beta receptor (DNIIR) in mammary epithelium under control of the MMTV promoter/enhancer causes alveolar hyperplasia and differentiation in virgin mice. Here we show that MMTV-DNIIR female mice have accelerated mammary gland differentiation during early pregnancy with impaired development during late pregnancy and lactation followed by delayed postlactational involution. Mammary tumors, mostly carcinoma in situ, developed spontaneously in the MMTV-DNIIR mice with a long median latency (27.5 months). Crossbreeding to MMTV-transforming growth factor (TGF)-alpha mice to obtain mice expressing both transgenes resulted in mammary tumor formation with a much shorter latency more similar to those expressing only the MMTV-TGF-alpha transgene (<10 months median latency). The major difference in mammary tumors arising in MMTV-TGF-alpha compared to bigenic MMTV-DNIIR/MMTV-TGF-alpha was the marked suppression of tumor invasion by DNIIR transgene expression. Invading carcinoma cells in both MMTV-DNIIR and bigenic animals showed loss of DNIIR transgene expression as determined by in situ hybridization. The data indicate that signaling from endogenous TGF-betas not only plays an important role in normal mammary gland physiology but also can also suppress the early stage of tumor formation and contribute to tumor invasion once carcinomas have developed.
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20 MeSH Terms