-
Články
- Časopisy
- Kurzy
- Témy
- Kongresy
- Videa
- Podcasty
An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation
Vaccines suffice for protecting public health against seasonal influenza viruses, but when unexpected strains appear against which the vaccine does not confer protection, alternative treatments are necessary. In this work, we used gene expression and virus growth data from influenza-infected mice to determine how moderate and deadly influenza viruses may invoke unique inflammatory responses and the role these responses play in disease pathology. We found that the relationship between virus growth and the inflammatory response for all viruses tested can be characterized by ultrasensitive response in which the inflammatory response is gated until a threshold concentration of virus is exceeded in the lung after which strong inflammatory gene expression and cytokine production occurs. This finding challenges the notion that deadly influenza viruses invoke unique cytokine and inflammatory responses and provides additional evidence that pathology is regulated by virus load, albeit in a highly nonlinear fashion. These findings suggests immunomodulatory treatments could focus on altering inflammatory response dynamics to improve disease pathology.
Vyšlo v časopise: An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation. PLoS Pathog 11(6): e32767. doi:10.1371/journal.ppat.1004856
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004856Souhrn
Vaccines suffice for protecting public health against seasonal influenza viruses, but when unexpected strains appear against which the vaccine does not confer protection, alternative treatments are necessary. In this work, we used gene expression and virus growth data from influenza-infected mice to determine how moderate and deadly influenza viruses may invoke unique inflammatory responses and the role these responses play in disease pathology. We found that the relationship between virus growth and the inflammatory response for all viruses tested can be characterized by ultrasensitive response in which the inflammatory response is gated until a threshold concentration of virus is exceeded in the lung after which strong inflammatory gene expression and cytokine production occurs. This finding challenges the notion that deadly influenza viruses invoke unique cytokine and inflammatory responses and provides additional evidence that pathology is regulated by virus load, albeit in a highly nonlinear fashion. These findings suggests immunomodulatory treatments could focus on altering inflammatory response dynamics to improve disease pathology.
Zdroje
1. Qian C, Cao X. Regulation of Toll-like receptor signaling pathways in innate immune responses. Ann N Y Acad Sci. 2013;1283 : 67–74. doi: 10.1111/j.1749-6632.2012.06786.x 23163321
2. Loo Y-M, Gale M. Immune signaling by RIG-I-like receptors. Immunity. Elsevier Inc.; 2011;34 : 680–92. doi: 10.1016/j.immuni.2011.05.003 21616437
3. Le Goffic R, Pothlichet J, Vitour D, Fujita T, Meurs E, Chignard M, et al. Cutting Edge: Influenza A Virus Activates TLR3-Dependent Inflammatory and RIG-I-Dependent Antiviral Responses in Human Lung Epithelial Cells. J Immunol. 2007;178 : 3368–3372. http://www.jimmunol.org/cgi/content/abstract/178/6/3368 17339430
4. Lund JM, Alexopoulou L, Sato A, Karow M, Adams NC, Gale NW, et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc Natl Acad Sci U S A. 2004;101 : 5598–5603. 15034168
5. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441 : 101–105. http://www.ncbi.nlm.nih.gov/pubmed/16625202 16625202
6. Pichlmair A, Schulz O, Tan CP, Näslund TI, Liljeström P, Weber F, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5’-phosphates. Science. 2006;314 : 997–1001. 17038589
7. Hornung V, Ellegast J, Kim S, Brzózka K, Jung A, Kato H, et al. 5’-Triphosphate RNA is the ligand for RIG-I. Science. 2006;314 : 994–7. 17038590
8. Kobasa D, Jones SM, Shinya K, Kash JC, Copps J, Ebihara H, et al. Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus. Nature. 2007;445 : 319–23. 17230189
9. Kash JC, Tumpey TM, Proll SC, Carter V, Perwitasari O, Thomas MJ, et al. Genomic analysis of increased host immune and cell death responses induced by 1918 influenza virus. Nature. 2006;443 : 578–81. 17006449
10. Cilloniz C, Pantin-Jackwood MJ, Ni C, Goodman AG, Peng X, Proll SC, et al. Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection. J Virol. 2010;84 : 7613–24. doi: 10.1128/JVI.00553-10 20504916
11. Neumann G, Chen H, Gao GF, Shu Y, Kawaoka Y. H5N1 influenza viruses: outbreaks and biological properties. Cell Res. Nature Publishing Group; 2010;20 : 51–61. doi: 10.1038/cr.2009.124 19884910
12. De Jong MD, Simmons CP, Thanh TT, Hien VM, Smith GJD, Chau TNB, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006;12 : 1203–7. 16964257
13. Itoh Y, Shinya K, Kiso M, Watanabe T, Sakoda Y, Hatta M, et al. In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature. Macmillan Publishers Limited. All rights reserved; 2009;460 : 1021–5. doi: 10.1038/nature08260 19672242
14. Shoemaker JE, Fukuyama S, Eisfeld AJ, Muramoto Y, Watanabe S, Watanabe T, et al. Integrated network analysis reveals a novel role for the cell cycle in 2009 pandemic influenza virus-induced inflammation in macaque lungs. BMC Syst Biol. BMC Systems Biology; 2012;6 : 117. doi: 10.1186/1752-0509-6-117 22937776
15. Boon ACM, Finkelstein D, Zheng M, Liao G, Allard J, Klumpp K, et al. H5N1 influenza virus pathogenesis in genetically diverse mice is mediated at the level of viral load. MBio. American Society for Microbiology; 2011;2.
16. Hatta Y, Hershberger K, Shinya K, Proll SC, Dubielzig RR, Hatta M, et al. Viral replication rate regulates clinical outcome and CD8 T cell responses during highly pathogenic H5N1 influenza virus infection in mice. PLoS Pathog. 2010;6: e1001139. doi: 10.1371/journal.ppat.1001139 20949022
17. Tchitchek N, Eisfeld AJ, Tisoncik-Go J, Josset L, Gralinski LE, Bécavin C, et al. Specific mutations in H5N1 mainly impact the magnitude and velocity of the host response in mice. BMC Syst Biol. 2013;7 : 69. doi: 10.1186/1752-0509-7-69 23895213
18. Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008;9 : 559. doi: 10.1186/1471-2105-9-559 19114008
19. Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, et al. DAVID Bioinformatics Resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res. 2007;35: W169–75. 17576678
20. Kaimal V, Bardes EE, Tabar SC, Jegga AG, Aronow BJ. ToppCluster: a multiple gene list feature analyzer for comparative enrichment clustering and network-based dissection of biological systems. Nucleic Acids Res. 2010;38: W96–102. doi: 10.1093/nar/gkq418 20484371
21. Sun L, Liu S, Chen ZJ. SnapShot: pathways of antiviral innate immunity. Cell. 2010;140 : 436–436.e2. doi: 10.1016/j.cell.2010.01.041 20144765
22. Menachery VD, Eisfeld AJ, Schäfer A, Josset L, Sims AC, Proll S, et al. Pathogenic Influenza Viruses and Coronaviruses Utilize Similar and Contrasting Approaches To Control Interferon-Stimulated Gene Responses. MBio. 2014;5 : 1–11.
23. Shoemaker JE, Lopes TJS, Ghosh S, Matsuoka Y, Kawaoka Y, Kitano H. CTen: a web-based platform for identifying enriched cell types from heterogeneous microarray data. BMC Genomics. BMC Genomics; 2012;13 : 460. doi: 10.1186/1471-2164-13-460 22953731
24. Cillóniz C, Shinya K, Peng X, Korth MJ, Proll SC, Aicher LD, et al. Lethal influenza virus infection in macaques is associated with early dysregulation of inflammatory related genes. PLoS Pathog. 2009;5: e1000604. doi: 10.1371/journal.ppat.1000604 19798428
25. Shinya K, Gao Y, Cilloniz C, Suzuki Y, Fujie M, Deng G, et al. Integrated clinical, pathologic, virologic, and transcriptomic analysis of H5N1 influenza virus-induced viral pneumonia in the rhesus macaque. J Virol. 2012;86 : 6055–66. doi: 10.1128/JVI.00365-12 22491448
26. Lin KL, Suzuki Y, Nakano H, Ramsburg E, Gunn MD. CCR2+ monocyte-derived dendritic cells and exudate macrophages produce influenza-induced pulmonary immune pathology and mortality. J Immunol. 2008;180 : 2562–72. http://www.ncbi.nlm.nih.gov/pubmed/18250467 18250467
27. Brandes M, Klauschen F, Kuchen S, Germain RN. A systems analysis identifies a feedforward inflammatory circuit leading to lethal influenza infection. Cell. 2013;154 : 197–212. doi: 10.1016/j.cell.2013.06.013 23827683
28. Voineagu I, Wang X, Johnston P, Lowe JK, Tian Y, Horvath S, et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature. Nature Publishing Group; 2011;474 : 380–4. doi: 10.1038/nature10110 21614001
29. Kristiansen H, Scherer C a, McVean M, Iadonato SP, Vends S, Thavachelvam K, et al. Extracellular 2’-5' oligoadenylate synthetase stimulates RNase L-independent antiviral activity: a novel mechanism of virus-induced innate immunity. J Virol. 2010;84 : 11898–904. doi: 10.1128/JVI.01003-10 20844035
30. Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, et al. Systematic and quantitative assessment of the ubiquitin-modified proteome. Mol Cell. Elsevier Inc.; 2011;44 : 325–40. doi: 10.1016/j.molcel.2011.08.025 21906983
31. Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, et al. The transcriptional landscape of the mammalian genome. Science. 2005;309 : 1559–63. 16141072
32. Trunnell NB, Poon AC, Kim SY, Ferrell JE. Ultrasensitivity in the Regulation of Cdc25C by Cdk1. Mol Cell. Elsevier Inc.; 2011;41 : 263–74. doi: 10.1016/j.molcel.2011.01.012 21292159
33. Bagci EZ, Vodovotz Y, Billiar TR, Ermentrout GB, Bahar I. Bistability in apoptosis: roles of bax, bcl-2, and mitochondrial permeability transition pores. Biophys J. 2006;90 : 1546–59. 16339882
34. Goulev Y, Charvin G. Ultrasensitivity and positive feedback to promote sharp mitotic entry. Mol Cell. 2011;41 : 243–4. doi: 10.1016/j.molcel.2011.01.016 21292155
35. Huang CY, Ferrell JE. Ultrasensitivity in the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1996;93 : 10078–83. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=38339&tool=pmcentrez&rendertype=abstract 8816754
36. Shoemaker JE, Doyle FJ. Identifying fragilities in biochemical networks: robust performance analysis of Fas signaling-induced apoptosis. Biophys J. Elsevier; 2008;95 : 2610–23. doi: 10.1529/biophysj.107.123398 18539637
37. Qi L, Kash JC, Dugan VG, Jagger BW, Lau Y, Crouch EC, et al. The Ability of Pandemic Influenza Virus Hemagglutinins to Induce Lower Respiratory Pathology is Associated with Decreased Surfactant Protein D Binding. J Virol. 2012;412 : 426–434.
38. García-Sastre a, Egorov a, Matassov D, Brandt S, Levy DE, Durbin JE, et al. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems. Virology. 1998;252 : 324–30. http://www.ncbi.nlm.nih.gov/pubmed/9878611 9878611
39. Pal S, Rosas JM, Rosas-Acosta G. Identification of the non-structural influenza A viral protein NS1A as a bona fide target of the Small Ubiquitin-like MOdifier by the use of dicistronic expression constructs. J Virol Methods. 2010;163 : 498–504. doi: 10.1016/j.jviromet.2009.11.010 19917317
40. Xu K, Klenk C, Liu B, Keiner B, Cheng J, Zheng B-J, et al. Modification of nonstructural protein 1 of influenza A virus by SUMO1. J Virol. 2011;85 : 1086–1098. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3020006&tool=pmcentrez&rendertype=abstract doi: 10.1128/JVI.00877-10 21047957
41. Santos A, Pal S, Chacón J, Meraz K, Gonzalez J, Prieto K, et al. SUMOylation affects the interferon blocking activity of the influenza A nonstructural protein NS1 without affecting its stability or cellular localization. J Virol. 2013;87 : 5602–20. doi: 10.1128/JVI.02063-12 23468495
42. Seo S-U, Kwon H-J, Song J-H, Byun Y-H, Seong BL, Kawai T, et al. MyD88 signaling is indispensable for primary influenza A virus infection but dispensable for secondary infection. J Virol. 2010;84 : 12713–22. doi: 10.1128/JVI.01675-10 20943980
43. Shinya K, Okamura T, Sueta S, Kasai N, Tanaka M, Ginting TE, et al. Toll-like receptor pre-stimulation protects mice against lethal infection with highly pathogenic influenza viruses. Virol J. BioMed Central Ltd; 2011;8 : 97. doi: 10.1186/1743-422X-8-97 21375734
44. Smyth GK. Linear models and empirical Bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3.
45. Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009;37: W305–11. doi: 10.1093/nar/gkp427 19465376
46. Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-toh K, et al. Systematic discovery of regulatory motifs in human promoters and 3 UTRs by comparison of several mammals. Nature. 2005;434 : 338–345. 15735639
47. Liberzon A, Subramanian A, Pinchback R, Thorvaldsdóttir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27 : 1739–40. doi: 10.1093/bioinformatics/btr260 21546393
48. De Veer MJ, Holko M, Frevel M, Walker E, Der S, Paranjape JM, et al. Functional classification of interferon-stimulated genes identified using microarrays. J Leukoc Biol. 2001;69 : 912–920. 11404376
49. Muggeo VMR. segmented: an R package to fit regression models with broken-line relationships. 2007;2.
50. Hothorn T, Bretz F, Westfall P. Simultaneous inference in general parametric models. Biometrical J. 2008;50 : 346–63. doi: 10.1002/bimj.200810425 18481363
Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium
Článek Clearance of Pneumococcal Colonization in Infants Is Delayed through Altered Macrophage TraffickingČlánek An Model of Latency and Reactivation of Varicella Zoster Virus in Human Stem Cell-Derived NeuronsČlánek Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPsČlánek Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African TrypanosomiasisČlánek Peptidoglycan Branched Stem Peptides Contribute to Virulence by Inhibiting Pneumolysin ReleaseČlánek HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T CellsČlánek Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes
Článok vyšiel v časopisePLOS Pathogens
Najčítanejšie tento týždeň
2015 Číslo 6- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
-
Všetky články tohto čísla
- Introducing “Research Matters”
- Exploring Host–Pathogen Interactions through Biological Control
- Analysis of Bottlenecks in Experimental Models of Infection
- Expected and Unexpected Features of the Newly Discovered Bat Influenza A-like Viruses
- Clearance of Pneumococcal Colonization in Infants Is Delayed through Altered Macrophage Trafficking
- Recombinant Murine Gamma Herpesvirus 68 Carrying KSHV G Protein-Coupled Receptor Induces Angiogenic Lesions in Mice
- TRIM30α Is a Negative-Feedback Regulator of the Intracellular DNA and DNA Virus-Triggered Response by Targeting STING
- Targeting Human Transmission Biology for Malaria Elimination
- Two Cdc2 Kinase Genes with Distinct Functions in Vegetative and Infectious Hyphae in
- An Model of Latency and Reactivation of Varicella Zoster Virus in Human Stem Cell-Derived Neurons
- Protective mAbs and Cross-Reactive mAbs Raised by Immunization with Engineered Marburg Virus GPs
- Virulence Factors of Induce Both the Unfolded Protein and Integrated Stress Responses in Airway Epithelial Cells
- Peptide-MHC-I from Endogenous Antigen Outnumber Those from Exogenous Antigen, Irrespective of APC Phenotype or Activation
- Specific Cell Targeting Therapy Bypasses Drug Resistance Mechanisms in African Trypanosomiasis
- An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation
- The Role of Human Transportation Networks in Mediating the Genetic Structure of Seasonal Influenza in the United States
- Host Delivery of Favorite Meals for Intracellular Pathogens
- Complement-Opsonized HIV-1 Overcomes Restriction in Dendritic Cells
- Inter-Seasonal Influenza is Characterized by Extended Virus Transmission and Persistence
- A Critical Role for CLSP2 in the Modulation of Antifungal Immune Response in Mosquitoes
- Twilight, a Novel Circadian-Regulated Gene, Integrates Phototropism with Nutrient and Redox Homeostasis during Fungal Development
- Surface-Associated Lipoproteins Link Virulence to Colitogenic Activity in IL-10-Deficient Mice Independent of Their Expression Levels
- Latent Membrane Protein LMP2A Impairs Recognition of EBV-Infected Cells by CD8+ T Cells
- Bank Vole Prion Protein As an Apparently Universal Substrate for RT-QuIC-Based Detection and Discrimination of Prion Strains
- Neuronal Subtype and Satellite Cell Tropism Are Determinants of Varicella-Zoster Virus Virulence in Human Dorsal Root Ganglia Xenografts
- Molecular Basis for the Selective Inhibition of Respiratory Syncytial Virus RNA Polymerase by 2'-Fluoro-4'-Chloromethyl-Cytidine Triphosphate
- Structure of the Virulence Factor, SidC Reveals a Unique PI(4)P-Specific Binding Domain Essential for Its Targeting to the Bacterial Phagosome
- Activated Brain Endothelial Cells Cross-Present Malaria Antigen
- Fungal Morphology, Iron Homeostasis, and Lipid Metabolism Regulated by a GATA Transcription Factor in
- Peptidoglycan Branched Stem Peptides Contribute to Virulence by Inhibiting Pneumolysin Release
- A Macrophage Subversion Factor Is Shared by Intracellular and Extracellular Pathogens
- A Novel AT-Rich DNA Recognition Mechanism for Bacterial Xenogeneic Silencer MvaT
- Reovirus FAST Proteins Drive Pore Formation and Syncytiogenesis Using a Novel Helix-Loop-Helix Fusion-Inducing Lipid Packing Sensor
- The Role of ExoS in Dissemination of during Pneumonia
- IRF-5-Mediated Inflammation Limits CD8 T Cell Expansion by Inducing HIF-1α and Impairing Dendritic Cell Functions during Infection
- Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection
- Crystal Structure of USP7 Ubiquitin-like Domains with an ICP0 Peptide Reveals a Novel Mechanism Used by Viral and Cellular Proteins to Target USP7
- HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T Cells
- HPV16 Down-Regulates the Insulin-Like Growth Factor Binding Protein 2 to Promote Epithelial Invasion in Organotypic Cultures
- The νSaα Specific Lipoprotein Like Cluster () of . USA300 Contributes to Immune Stimulation and Invasion in Human Cells
- RSV-Induced H3K4 Demethylase KDM5B Leads to Regulation of Dendritic Cell-Derived Innate Cytokines and Exacerbates Pathogenesis
- Leukocidin A/B (LukAB) Kills Human Monocytes via Host NLRP3 and ASC when Extracellular, but Not Intracellular
- Border Patrol Gone Awry: Lung NKT Cell Activation by Exacerbates Tularemia-Like Disease
- The Curious Road from Basic Pathogen Research to Clinical Translation
- From Cell and Organismal Biology to Drugs
- Adenovirus Tales: From the Cell Surface to the Nuclear Pore Complex
- A 21st Century Perspective of Poliovirus Replication
- Is Development of a Vaccine against Feasible?
- Waterborne Viruses: A Barrier to Safe Drinking Water
- Battling Phages: How Bacteria Defend against Viral Attack
- Archaea in and on the Human Body: Health Implications and Future Directions
- Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche
- Natural Variants of the KPC-2 Carbapenemase have Evolved Increased Catalytic Efficiency for Ceftazidime Hydrolysis at the Cost of Enzyme Stability
- Potent Cell-Intrinsic Immune Responses in Dendritic Cells Facilitate HIV-1-Specific T Cell Immunity in HIV-1 Elite Controllers
- The Mammalian Cell Cycle Regulates Parvovirus Nuclear Capsid Assembly
- Host Reticulocytes Provide Metabolic Reservoirs That Can Be Exploited by Malaria Parasites
- The Proteome of the Isolated Containing Vacuole Reveals a Complex Trafficking Platform Enriched for Retromer Components
- NK-, NKT- and CD8-Derived IFNγ Drives Myeloid Cell Activation and Erythrophagocytosis, Resulting in Trypanosomosis-Associated Acute Anemia
- Successes and Challenges on the Road to Cure Hepatitis C
- BRCA1 Regulates IFI16 Mediated Nuclear Innate Sensing of Herpes Viral DNA and Subsequent Induction of the Innate Inflammasome and Interferon-β Responses
- A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers
- Phosphorylation of the Peptidoglycan Synthase PonA1 Governs the Rate of Polar Elongation in Mycobacteria
- Human Immunodeficiency Virus Type 1 Nef Inhibits Autophagy through Transcription Factor EB Sequestration
- Sequence-Specific Fidelity Alterations Associated with West Nile Virus Attenuation in Mosquitoes
- EBV BART MicroRNAs Target Multiple Pro-apoptotic Cellular Genes to Promote Epithelial Cell Survival
- Single-Cell and Single-Cycle Analysis of HIV-1 Replication
- TRIM32 Senses and Restricts Influenza A Virus by Ubiquitination of PB1 Polymerase
- The Herpes Simplex Virus Protein pUL31 Escorts Nucleocapsids to Sites of Nuclear Egress, a Process Coordinated by Its N-Terminal Domain
- Host Transcriptional Response to Influenza and Other Acute Respiratory Viral Infections – A Prospective Cohort Study
- PLOS Pathogens
- Archív čísel
- Aktuálne číslo
- Informácie o časopise
Najčítanejšie v tomto čísle- HIV Latency Is Established Directly and Early in Both Resting and Activated Primary CD4 T Cells
- Battling Phages: How Bacteria Defend against Viral Attack
- A 21st Century Perspective of Poliovirus Replication
- Adenovirus Tales: From the Cell Surface to the Nuclear Pore Complex
Prihlásenie#ADS_BOTTOM_SCRIPTS#Zabudnuté hesloZadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
- Časopisy