#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#
preLekára.sk / Odborné časopisy / PLOS Pathogens / 2015 - 3

A Conserved NS3 Surface Patch Orchestrates NS2 Protease Stimulation, NS5A Hyperphosphorylation and HCV Genome Replication

English version České info

Hepatitis C virus (HCV) replicates its genome in close association to cellular membranes which serve as assembly site of multi-subunit replication complexes. The process of replication complex maturation must be properly controlled to prevent the non-functional maturation/assembly of these complexes. In this process, the temporal regulation of viral polyprotein processing often plays a pivotal role as exemplified by the strict requirement for NS2-NS3 cleavage for HCV genome replication. We demonstrate here that a conserved hydrophobic NS3 surface patch activates the NS2 protease to stimulate NS2-NS3 cleavage. By dissecting the role of these NS3 surface residues in viral RNA replication, we show that one of these NS3 residues is also a critical determinant for HCV genome replication by negatively regulating NS5A hyperphosphorylation. Surprisingly, further experiments revealed that the NS2-NS3 cleavage is a prerequisite for NS5A hyperphosphorylation. To fulfill the requirements for gradual assembly into functional replication complexes, an ordered cascade of molecular events takes place: in uncleaved NS2-NS3, the hydrophobic NS3 surface patch promotes NS2 protease stimulation; upon NS2-NS3 cleavage, this surface region becomes available for functional replicase assembly. As a consequence, the hydrophobic surface patch on free NS3 can promote NS5A hyperphosphorylation as an indication of functional replicase assembly.

Vyšlo v časopise: A Conserved NS3 Surface Patch Orchestrates NS2 Protease Stimulation, NS5A Hyperphosphorylation and HCV Genome Replication. PLoS Pathog 11(3): e32767. doi:10.1371/journal.ppat.1004736
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004736

Souhrn

Hepatitis C virus (HCV) replicates its genome in close association to cellular membranes which serve as assembly site of multi-subunit replication complexes. The process of replication complex maturation must be properly controlled to prevent the non-functional maturation/assembly of these complexes. In this process, the temporal regulation of viral polyprotein processing often plays a pivotal role as exemplified by the strict requirement for NS2-NS3 cleavage for HCV genome replication. We demonstrate here that a conserved hydrophobic NS3 surface patch activates the NS2 protease to stimulate NS2-NS3 cleavage. By dissecting the role of these NS3 surface residues in viral RNA replication, we show that one of these NS3 residues is also a critical determinant for HCV genome replication by negatively regulating NS5A hyperphosphorylation. Surprisingly, further experiments revealed that the NS2-NS3 cleavage is a prerequisite for NS5A hyperphosphorylation. To fulfill the requirements for gradual assembly into functional replication complexes, an ordered cascade of molecular events takes place: in uncleaved NS2-NS3, the hydrophobic NS3 surface patch promotes NS2 protease stimulation; upon NS2-NS3 cleavage, this surface region becomes available for functional replicase assembly. As a consequence, the hydrophobic surface patch on free NS3 can promote NS5A hyperphosphorylation as an indication of functional replicase assembly.

Zdroje

1. Thomas DL (2013) Global control of hepatitis C: where challenge meets opportunity. Nat Med 19 : 850–858. doi: 10.1038/nm.3184 23836235

2. McLauchlan J, Lemberg MK, Hope G, Martoglio B (2002) Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. EMBO J 21 : 3980–3988. 12145199

3. Hijikata M, Kato N, Ootusyama Y, Nakagawa M, Shimotohno K (1991) Gene mapping of the putative structural region of the hepatitis C virus genome by in vitro processing analysis. Proc Natl Acad Sci USA 88 : 5547–5551. 1648221

4. Lin C, Lindenbach BD, Prágal BM, McCourt DW, Rice CM (1994) Processing in the Hepatitis C Virus E2-NS2 region: identification of p7 and two distinct E2 -⁠ specific products with different C termini. J Virol 68 : 5063–5073. 7518529

5. Failla C, Tomei L, de Francesco R (1994) Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins. J Virol 68 : 3753–3760. 8189513

6. Kolykhalov AA, Agapov E V, Rice C (1994) Specificity of the Hepatitis C Virus NS3 serine protease: Effects of substitutions at the 3/4A, 4A/4B, and 5A/5B cleavage sites on polyprotein processing. J Virol 68 : 7525–7533. 7933136

7. Hijikata M, Mizushima H, Tanji Y, Komoda Y, Hirowatari Y, et al. (1993) Proteolytic processing and membrane association of putative nonstructural proteins of hepatitis C virus. Proc Natl Acad Sci U S A 90 : 10773–10777. 7504283

8. Bartenschlager R, Ahlborn-Laake L, Mous J, Jacobsen H (1994) Kinetic and structural analyses of hepatitis C virus polyprotein processing. J Virol 68 : 5045–5055. 8035505

9. Kim DW, Kim J, Gwack Y, Han JH, Choe J (1997) Mutational analysis of the hepatitis C virus RNA helicase. J Virol 71 : 9400–9409. 9371600

10. Santolini E, Pacini L, Fipaldini C, Migliaccio G, Monica N (1995) The NS2 protein of hepatitis C virus is a transmembrane polypeptide. J Virol 69 : 7461–7471. 7494252

11. Kim JE, Song WK, Chung KM, Back SH, Jang SK (1999) Subcellular localization of hepatitis C viral proteins in mammalian cells. Arch Virol 144 : 329–343. 10470257

12. Pallaoro M, Lahm A, Biasiol G, Brunetti M, Nardella C, et al. (2001) Characterization of the hepatitis C virus NS2/3 processing reaction by using a purified precursor protein. J Virol 75 : 9939–9946. 11559826

13. Grakoui A, Wychowsky C, Lin C, Feinstone S, Rice C (1993) Expression and identification of hepatitis C virus polyprotein cleavage products. J Virol 67 : 1385–1395. 7679746

14. Grakoui A, McCourt DW, Wychowski C, Feinstone SM, Rice C (1993) A second hepatitis C virus-encoded proteinase. Proc Natl Acad Sci USA 90 : 10583–10587. 8248148

15. Hijikata M, Mizushima H, Akagi T, Mori S, Kakiuchi N, et al. (1993) Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol 67 : 4665–4675. 8392606

16. Lorenz IC, Marcotrigiano J, Dentzer TG, Rice CM (2006) Structure of the catalytic domain of the hepatitis C virus NS2-3 protease. Nature 442 : 831–835. 16862121

17. Schregel V, Jacobi S, Penin F, Tautz N (2009) Hepatitis C virus NS2 is a protease stimulated by cofactor domains in NS3. Proc Natl Acad Sci U S A 106 : 5342–5347. doi: 10.1073/pnas.0810950106 19282477

18. Kolykhalov AA, Mihalik K, Feinstone SM, Rice CM (2000) Hepatitis C virus-encoded enzymatic activities and conserved RNA elements in the 3’ nontranslated region are essential for virus replication in vivo. J Virol 74 : 2046–2051. 10644379

19. Jones CT, Murray CL, Eastman DK, Tassello J, Rice CM (2007) Hepatitis C virus p7 and NS2 proteins are essential for production of infectious virus. J Virol 81 : 8374–8383. 17537845

20. Welbourn S, Pause A (2007) The hepatitis C virus NS2/3 protease. Curr Issues Mol Biol 9 : 63–69. 17263146

21. Dentzer TG, Lorenz IC, Evans MJ, Rice CM (2009) Determinants of the hepatitis C virus nonstructural protein 2 protease domain required for production of infectious virus. J Virol 83 : 12702–12713. doi: 10.1128/JVI.01184-09 19812162

22. Phan T, Beran RKF, Peters C, Lorenz I, Lindenbach BD (2009) Hepatitis C virus NS2 protein contributes to virus particle assembly via opposing epistatic interactions with the E1-E2 glycoprotein and NS3-4A enzyme complexes. J Virol 83 : 8379–8395. doi: 10.1128/JVI.00891-09 19515772

23. De la Fuente C, Goodman Z, Rice CM (n.d.) Genetic and functional characterization of the N-terminal region of the hepatitis C virus NS2 protein. J Virol 87 : 4130–4145. doi: 10.1128/JVI.03174-12 23408609

24. Stapleford KA, Lindenbach BD (2011) Hepatitis C virus NS2 coordinates virus particle assembly through physical interactions with the E1-E2 glycoprotein and NS3-NS4A enzyme complexes. J Virol 85 : 1706–1717. doi: 10.1128/JVI.02268-10 21147927

25. Jirasko V, Montserret R, Lee JY, Gouttenoire J, Moradpour D, et al. (2010) Structural and functional studies of nonstructural protein 2 of the hepatitis C virus reveal its key role as organizer of virion assembly. PLoS Pathog 6: e1001233. doi: 10.1371/journal.ppat.1001233 21187906

26. Jirasko V, Montserret R, Appel N, Janvier A, Eustachi L, et al. (2008) Structural and functional characterization of nonstructural protein 2 for its role in hepatitis C virus assembly. J Biol Chem 283 : 28546–28562. doi: 10.1074/jbc.M803981200 18644781

27. Ma Y, Anantpadma M, Timpe JM, Shanmugam S, Singh SM, et al. (2010) Hepatitis C Virus NS2 Protein Serves as a Scaffold for Virus Assembly by Interacting with both Structural and Nonstructural Proteins. J Virol 85 : 86–97. doi: 10.1128/JVI.01070-10 20962101

28. Popescu CI, Callens N, Trinel D, Roingeard P, Moradpour D, et al. (2011) NS2 Protein of Hepatitis C Virus Interacts with Structural and Non-Structural Proteins towards Virus Assembly. PLoS Pathog 7: e1001278. doi: 10.1371/journal.ppat.1001278 21347350

29. Yi M, Ma Y, Yates J, Lemon SM (2009) Trans-complementation of an NS2 defect in a late step in hepatitis C virus (HCV) particle assembly and maturation. PLoS Pathog 5: e1000403. doi: 10.1371/journal.ppat.1000403 19412343

30. Tedbury PR, Harris M (2007) Characterisation of the role of zinc in the hepatitis C virus NS2/3 auto-cleavage and NS3 protease activities. J Mol Biol 366 : 1652–1660. 17239391

31. Yao N, Reichert P, Taremi SS, Prosise WW, Weber PC (1999) Molecular views of viral polyprotein processing revealed by the crystal structure of the hepatitis C virus bifunctional protease-helicase. Structure 7 : 1353–1363. 10574797

32. Welbourn S, Green R, Gamache I, Dandache S, Lohmann V, et al. (2005) Hepatitis C virus NS2/3 processing is required for NS3 stability and viral RNA replication. J Biol Chem 280 : 29604–29611. 15980068

33. Fridell RA, Valera L, Qiu D, Kirk MJ, Wang C, et al. (2013) Intragenic complementation of hepatitis C virus NS5A RNA replication-defective alleles. J Virol 87 : 2320–2329. doi: 10.1128/JVI.02861-12 23236071

34. Ross-Thriepland D, Harris M (2014) Insights into the complexity and functionality of hepatitis C virus NS5A phosphorylation. J Virol 88 : 1421–1432. doi: 10.1128/JVI.03017-13 24257600

35. Appel N, Zayas M, Miller S, Krijnse-Locker J, Schaller T, et al. (2008) Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLoS Pathog 4: e1000035. doi: 10.1371/journal.ppat.1000035 18369481

36. Evans MJ, Rice CM, Goff SP (2004) Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. Proc Natl Acad Sci U S A 101 : 13038–13043. 15326295

37. Jirasko V, Montserret R, Appel N, Janvier A, Eustachi L, et al. (2008) Structural and functional characterization of nonstructural protein 2 for its role in hepatitis C virus assembly. J Biol Chem 283 : 28546–28562. doi: 10.1074/jbc.M803981200 18644781

38. Pietschmann T, Kaul A, Koutsoudakis G, Shavinskaya A, Kallis S, et al. (2006) Construction and characterization of infectious intragenotypic and intergenotypic hepatitis C virus chimeras. Proc Natl Acad Sci U S A 103 : 7408–7413. 16651538

39. Pacini L, Graziani R, Bartholomew L, De Francesco R, Paonessa G (2009) Naturally occurring hepatitis C virus subgenomic deletion mutants replicate efficiently in Huh-7 cells and are trans-packaged in vitro to generate infectious defective particles. J Virol 83 : 9079–9093. doi: 10.1128/JVI.00308-09 19587042

40. Dimitrova M, Imbert I, Kieny MP, Schuster C (2003) Protein-protein interactions between hepatitis C virus nonstructural proteins. J Virol 77 : 5401–5414. 12692242

41. Shin G, Yost SA, Miller MT, Elrod EJ, Grakoui A, et al. (2012) Structural and functional insights into alphavirus polyprotein processing and pathogenesis. Proc Natl Acad Sci U S A 109 : 16534–16539. doi: 10.1073/pnas.1210418109 23010928

42. Lulla A, Lulla V, Merits A (2012) Macromolecular assembly-driven processing of the 2/3 cleavage site in the alphavirus replicase polyprotein. J Virol 86 : 553–565. doi: 10.1128/JVI.05195-11 22031949

43. Marcotte LL, Wass AB, Gohara DW, Pathak HB, Arnold JJ, et al. (2007) Crystal structure of poliovirus 3CD protein: virally encoded protease and precursor to the RNA-dependent RNA polymerase. J Virol 81 : 3583–3596. 17251299

44. Koch JO, Bartenschlager R (1999) Modulation of hepatitis C virus NS5A hyperphosphorylation by nonstructural proteins NS3, NS4A, and NS4B. J Virol 73 : 7138–7146. 10438800

45. Asabe S-I, Tanji Y, Satho S, Kaneko T, Kimura K, et al. (1997) The N-terminal region of hepatitis C virus-encoded NS5A is important for NS4A-dependent phosphorylation. J Virol 71 : 790–796. 8985418

46. Kaneko T, Tanji Y, Satoh S, Hijikata M, Asabe S, et al. (1994) Production of two phosphoproteins from the NS5A region of the hepatitis C viral genome. Biochem Biophys Res Comm 205 : 320–326. 7999043

47. Lindenbach BD, Pragai BM, Montserret R, Beran RK, Pyle AM, et al. (2007) The C terminus of hepatitis C virus NS4A encodes an electrostatic switch that regulates NS5A hyperphosphorylation and viral replication. J Virol 81 : 8905–8918. 17581983

48. Huang Y, Staschke K, De Francesco R, Tan S-L (2007) Phosphorylation of hepatitis C virus NS5A nonstructural protein: a new paradigm for phosphorylation-dependent viral RNA replication? Virology 364 : 1–9. 17400273

49. Appel N, Pietschmann T, Bartenschlager R (2005) Mutational analysis of hepatitis C virus nonstructural protein 5A: potential role of differential phosphorylation in RNA replication and identification of a genetically flexible domain. J Virol 79 : 3187–3194. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=15709040. 15709040

50. Liu Q, Bhat RA, Prince AM, Zhang P (1999) The hepatitis C virus NS2 protein generated by NS2-3 autocleavage is required for NS5A phosphorylation. Biochem Biophys Res Comm 254 : 572–577. 9920780

51. Neddermann P, Clementi A, De Francesco R (1999) Hyperphosphorylation of the hepatitis C virus NS5A protein requires an active NS3 protease, NS4A, NS4B, and NS5A encoded on the same polyprotein. J Virol 73 : 9984–9991. 10559312

52. Madan V, Paul D, Lohmann V, Bartenschlager R (2014) Inhibition of HCV Replication by Cyclophilin Antagonists is Linked to Replication Fitness and Occurs by Inhibition of Membranous Web Formation. Gastroenterology 146 : 1361–1372. doi: 10.1053/j.gastro.2014.01.055 24486951

53. Beran RK, Pyle AM (2008) Hepatitis C viral NS3-4A protease activity is enhanced by the NS3 helicase. J Biol Chem 283 : 29929–29937. doi: 10.1074/jbc.M804065200 18723512

54. Schultz DE, Honda M, Whetter LE, McKnight KL, Lemon SM (1996) Mutations within the 5’ nontranslated RNA of cell culture-adapted hepatitis A virus which enhance cap-independent translation in cultured African green monkey kidney cells. J Virol 70 : 1041–1049. 8551562

55. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, et al. (1999) Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science (80-) 285 : 110–113. 10390360

56. Takamizawa A, Mori C, Fuke I, Manabe S, Murakami S, et al. (1991) Structure and organization of the hepatitis C virus genome isolated from human carriers. J Virol 65 : 1105–1113. 1847440

57. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, et al. (2005) Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med 11 : 791–796. 15951748

58. Isken O, Langerwisch U, Schonherr R, Lamp B, Schroder K, et al. (2014) Functional characterization of bovine viral diarrhea virus nonstructural protein 5A by reverse genetic analysis and live cell imaging. J Virol 88 : 82–98. doi: 10.1128/JVI.01957-13 24131714

59. Sutter G, Ohlmann M, Erfle V (1995) Non-replicating vaccinia vector efficiently expresses bacteriophage T7 RNA polymerase. FEBS Lett 371 : 9–12. 7664891

60. Lindenbach BD, Evans MJ, Syder AJ, Wölk B, Tellinghuisen TL, et al. (2005) Complete replication of hepatitis C virus in cell culture. Science 309 : 623–626. 15947137

61. Backes P, Quinkert D, Reiss S, Binder M, Zayas M, et al. (2010) Role of annexin A2 in the production of infectious hepatitis C virus particles. J Virol 84 : 5775–5789. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20335258. doi: 10.1128/JVI.02343-09 20335258

62. Paul D, Romero-Brey I, Gouttenoire J, Stoitsova S, Krijnse-Locker J, et al. (2011) NS4B self-interaction through conserved C-terminal elements is required for the establishment of functional hepatitis C virus replication complexes. J Virol 85 : 6963–6976. doi: 10.1128/JVI.00502-11 21543474

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium
Článek To Be or Not IIb: A Multi-Step Process for Epstein-Barr Virus Latency Establishment and Consequences for B Cell Tumorigenesis
Článek Is Antigenic Sin Always “Original?” Re-examining the Evidence Regarding Circulation of a Human H1 Influenza Virus Immediately Prior to the 1918 Spanish Flu
Článek The Great Escape: Pathogen Versus Host
Článek Coping with Stress and the Emergence of Multidrug Resistance in Fungi
Článek Catch Me If You Can: The Link between Autophagy and Viruses
Článek Bacterial Immune Evasion through Manipulation of Host Inhibitory Immune Signaling
Článek Evidence for Ubiquitin-Regulated Nuclear and Subnuclear Trafficking among Matrix Proteins
Článek BILBO1 Is a Scaffold Protein of the Flagellar Pocket Collar in the Pathogen
Článek Production of Anti-LPS IgM by B1a B Cells Depends on IL-1β and Is Protective against Lung Infection with LVS
Článek Virulence Regulation with Venus Flytrap Domains: Structure and Function of the Periplasmic Moiety of the Sensor-Kinase BvgS
Článek α-Hemolysin Counteracts the Anti-Virulence Innate Immune Response Triggered by the Rho GTPase Activating Toxin CNF1 during Bacteremia
Článek Induction of Interferon-Stimulated Genes by IRF3 Promotes Replication of
Článek Intracellular Growth Is Dependent on Tyrosine Catabolism in the Dimorphic Fungal Pathogen
Článek HCV Induces the Expression of Rubicon and UVRAG to Temporally Regulate the Maturation of Autophagosomes and Viral Replication
Článek Spatiotemporal Analysis of Hepatitis C Virus Infection
Článek Subgingival Microbial Communities in Leukocyte Adhesion Deficiency and Their Relationship with Local Immunopathology
Článek Interaction between the Type III Effector VopO and GEF-H1 Activates the RhoA-ROCK Pathway
Článek Attenuation of Tick-Borne Encephalitis Virus Using Large-Scale Random Codon Re-encoding
Článek Establishment of HSV1 Latency in Immunodeficient Mice Facilitates Efficient Reactivation
Článek XRN1 Stalling in the 5’ UTR of Hepatitis C Virus and Bovine Viral Diarrhea Virus Is Associated with Dysregulated Host mRNA Stability
Článek γδ T Cells Confer Protection against Murine Cytomegalovirus (MCMV)
Článek Rhadinovirus Host Entry by Co-operative Infection
Článek A Phospholipase Is Involved in Disruption of the Liver Stage Parasitophorous Vacuole Membrane
Článek Dermal Neutrophil, Macrophage and Dendritic Cell Responses to Transmitted by Fleas
Článek Elucidation of Sigma Factor-Associated Networks in Reveals a Modular Architecture with Limited and Function-Specific Crosstalk
Článek Host ESCRT Proteins Are Required for Bromovirus RNA Replication Compartment Assembly and Function
Článek Disruption of IL-21 Signaling Affects T Cell-B Cell Interactions and Abrogates Protective Humoral Immunity to Malaria
Článek Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection
Článek Diminished Reovirus Capsid Stability Alters Disease Pathogenesis and Littermate Transmission
Článek Characterization of CD8 T Cell Differentiation following SIVΔnef Vaccination by Transcription Factor Expression Profiling
Článek Visualization of HIV-1 Interactions with Penile and Foreskin Epithelia: Clues for Female-to-Male HIV Transmission
Článek Sensing Cytosolic RpsL by Macrophages Induces Lysosomal Cell Death and Termination of Bacterial Infection
Článek PKCη/Rdx-driven Phosphorylation of PDK1: A Novel Mechanism Promoting Cancer Cell Survival and Permissiveness for Parvovirus-induced Lysis
Článek Metalloprotease NleC Suppresses Host NF-κB/Inflammatory Responses by Cleaving p65 and Interfering with the p65/RPS3 Interaction
Článek Immune Antibodies and Helminth Products Drive CXCR2-Dependent Macrophage-Myofibroblast Crosstalk to Promote Intestinal Repair
Článek Adenovirus Entry From the Apical Surface of Polarized Epithelia Is Facilitated by the Host Innate Immune Response
Článek The RNA Template Channel of the RNA-Dependent RNA Polymerase as a Target for Development of Antiviral Therapy of Multiple Genera within a Virus Family
Článek Neutrophils: Between Host Defence, Immune Modulation, and Tissue Injury
Článek CD169-Mediated Trafficking of HIV to Plasma Membrane Invaginations in Dendritic Cells Attenuates Efficacy of Anti-gp120 Broadly Neutralizing Antibodies
Článek Japanese Encephalitis Virus Nonstructural Protein NS5 Interacts with Mitochondrial Trifunctional Protein and Impairs Fatty Acid β-Oxidation
Článek Yip1A, a Novel Host Factor for the Activation of the IRE1 Pathway of the Unfolded Protein Response during Infection
Článek TRIM26 Negatively Regulates Interferon-β Production and Antiviral Response through Polyubiquitination and Degradation of Nuclear IRF3
Článek Parallel Epigenomic and Transcriptomic Responses to Viral Infection in Honey Bees ()
Článek A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication
Článek Enhanced CD8 T Cell Responses through GITR-Mediated Costimulation Resolve Chronic Viral Infection
Článek Exome and Transcriptome Sequencing of Identifies a Locus That Confers Resistance to and Alters the Immune Response
Článek The Role of Misshapen NCK-related kinase (MINK), a Novel Ste20 Family Kinase, in the IRES-Mediated Protein Translation of Human Enterovirus 71
Článek Chitin Recognition via Chitotriosidase Promotes Pathologic Type-2 Helper T Cell Responses to Cryptococcal Infection
Článek Activates Both IL-1β and IL-1 Receptor Antagonist to Modulate Lung Inflammation during Pneumonic Plague
Článek Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds
Článek An 18 kDa Scaffold Protein Is Critical for Biofilm Formation
Článek Early Virological and Immunological Events in Asymptomatic Epstein-Barr Virus Infection in African Children
Článek Human CD8 T-cells Recognizing Peptides from () Presented by HLA-E Have an Unorthodox Th2-like, Multifunctional, Inhibitory Phenotype and Represent a Novel Human T-cell Subset
Článek Decreased HIV-Specific T-Regulatory Responses Are Associated with Effective DC-Vaccine Induced Immunity
Článek RSV Vaccine-Enhanced Disease Is Orchestrated by the Combined Actions of Distinct CD4 T Cell Subsets
Článek Concerted Activity of IgG1 Antibodies and IL-4/IL-25-Dependent Effector Cells Trap Helminth Larvae in the Tissues following Vaccination with Defined Secreted Antigens, Providing Sterile Immunity to Challenge Infection
Článek Structure of the Low pH Conformation of Chandipura Virus G Reveals Important Features in the Evolution of the Vesiculovirus Glycoprotein
Článek PPM1A Regulates Antiviral Signaling by Antagonizing TBK1-Mediated STING Phosphorylation and Aggregation
Článek Lipidomic Analysis Links Mycobactin Synthase K to Iron Uptake and Virulence in .
Článek Roles and Programming of Arabidopsis ARGONAUTE Proteins during Infection
Článek Impact of Infection on Host Macrophage Nuclear Physiology and Nucleopore Complex Integrity
Článek The Impact of Host Diet on Titer in
Článek Antimicrobial-Induced DNA Damage and Genomic Instability in Microbial Pathogens
Článek Herpesviral G Protein-Coupled Receptors Activate NFAT to Induce Tumor Formation via Inhibiting the SERCA Calcium ATPase
Článek The Causes and Consequences of Changes in Virulence following Pathogen Host Shifts
Článek Small GTPase Rab21 Mediates Fibronectin Induced Actin Reorganization in : Implications in Pathogen Invasion
Článek Positive Role of Promyelocytic Leukemia Protein in Type I Interferon Response and Its Regulation by Human Cytomegalovirus
Článek NEDDylation Is Essential for Kaposi’s Sarcoma-Associated Herpesvirus Latency and Lytic Reactivation and Represents a Novel Anti-KSHV Target
Článek β-HPV 5 and 8 E6 Disrupt Homology Dependent Double Strand Break Repair by Attenuating BRCA1 and BRCA2 Expression and Foci Formation
Článek An O Antigen Capsule Modulates Bacterial Pathogenesis in
Článek Variable Processing and Cross-presentation of HIV by Dendritic Cells and Macrophages Shapes CTL Immunodominance and Immune Escape
Článek Probing the Metabolic Network in Bloodstream-Form Using Untargeted Metabolomics with Stable Isotope Labelled Glucose
Článek Adhesive Fiber Stratification in Uropathogenic Biofilms Unveils Oxygen-Mediated Control of Type 1 Pili
Článek Vaccinia Virus Protein Complex F12/E2 Interacts with Kinesin Light Chain Isoform 2 to Engage the Kinesin-1 Motor Complex
Článek Modulates Host Macrophage Mitochondrial Metabolism by Hijacking the SIRT1-AMPK Axis
Článek Human T-Cell Leukemia Virus Type 1 (HTLV-1) Tax Requires CADM1/TSLC1 for Inactivation of the NF-κB Inhibitor A20 and Constitutive NF-κB Signaling
Článek Suppression of RNAi by dsRNA-Degrading RNaseIII Enzymes of Viruses in Animals and Plants
Článek Spatiotemporal Regulation of a T4SS Substrate by the Metaeffector SidJ
Článek Antigenic Properties of the Human Immunodeficiency Virus Envelope Glycoprotein Gp120 on Virions Bound to Target Cells
Článek Dependence of Intracellular and Exosomal microRNAs on Viral Oncogene Expression in HPV-positive Tumor Cells
Článek Identification of a Peptide-Pheromone that Enhances Escape from Host Cell Vacuoles
Článek Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Dihydrobiopterin in Adult Falciparum Malaria: Association with Disease Severity, Impaired Microvascular Function and Increased Endothelial Activation
Článek Transgenic Expression of the Dicotyledonous Pattern Recognition Receptor EFR in Rice Leads to Ligand-Dependent Activation of Defense Responses
Článek Comprehensive Antigenic Map of a Cleaved Soluble HIV-1 Envelope Trimer
Článek Low Doses of Imatinib Induce Myelopoiesis and Enhance Host Anti-microbial Immunity
Článek Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Oxidized Biopterins in Pediatric Falciparum Malaria: Association with Disease Severity
Článok vyšiel v časopise

PLOS Pathogens

2015 Číslo 3
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

nový kurz
Autori: doc. MUDr. David Zemánek, Ph.D., MUDr. Anna Chaloupka, Ph.D.
Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa

#ADS_BOTTOM_SCRIPTS#