The ETS transcription factor ELF1 regulates a broadly antiviral program distinct from the type I interferon response

Autoři: Leon Louis Seifert aff001;  Clara Si aff002;  Debjani Saha aff003;  Mohammad Sadic aff002;  Maren de Vries aff002;  Sarah Ballentine aff002;  Aaron Briley aff002;  Guojun Wang aff003;  Ana M. Valero-Jimenez aff002;  Adil Mohamed aff002;  Uwe Schaefer aff005;  Hong M. Moulton aff006;  Adolfo García-Sastre aff003;  Shashank Tripathi aff003;  Brad R. Rosenberg aff003;  Meike Dittmann aff002
Působiště autorů: Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, United States of America aff001;  Department of Microbiology, New York University School of Medicine, New York, New York, United States of America aff002;  Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff003;  Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff004;  Laboratory of Immune Cell Epigenetics and Signaling, The Rockefeller University, New York, New York, United States of America aff005;  Carlson College of Veterinary Medicine, Oregon State University, Corvallis, Oregon, United States of America aff006;  Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff007;  The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America aff008;  Microbiology and Cell Biology Department, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India aff009
Vyšlo v časopise: The ETS transcription factor ELF1 regulates a broadly antiviral program distinct from the type I interferon response. PLoS Pathog 15(11): e32767. doi:10.1371/journal.ppat.1007634
Kategorie: Research Article
doi: 10.1371/journal.ppat.1007634


Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1’s antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNA-seq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons.

Klíčová slova:

DNA transcription – Gene expression – Influenza A virus – Influenza viruses – Interferons – Transcription factors – Viral replication – Antiviral immune response


1. Schoggins JW. Interferon-Stimulated Genes: What Do They All Do? Annu Rev Virol. 2019; doi: 10.1146/annurev-virology-092818-015756 31283436

2. Dittmann M, Hoffmann H-H, Scull MA, Gilmore RH, Bell KL, Ciancanelli M, et al. A serpin shapes the extracellular environment to prevent influenza a virus maturation. Cell. 2015;160. doi: 10.1016/j.cell.2015.01.040 25679759

3. Schoggins JW, MacDuff DA, Imanaka N, Gainey MD, Shrestha B, Eitson JL, et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature. 2014;505: 691–695. doi: 10.1038/nature12862 24284630

4. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT, Bieniasz P, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011/04/12. 2011;472: 481–485. doi: 10.1038/nature09907 [pii] 21478870

5. Perelman SS, Abrams ME, Eitson JL, Chen D, Jimenez A, Mettlen M, et al. Cell-Based Screen Identifies Human Interferon-Stimulated Regulators of Listeria monocytogenes Infection. PLoS Pathog. 2016/12/22. 2016;12: e1006102. doi: 10.1371/journal.ppat.1006102 28002492

6. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol. 2014;32: 513–545. doi: 10.1146/annurev-immunol-032713-120231 24555472

7. Fu XY, Kessler DS, Veals SA, Levy DE, Darnell JE Jr. ISGF3, the transcriptional activator induced by interferon alpha, consists of multiple interacting polypeptide chains. Proc Natl Acad Sci U S A. 1990/11/01. 1990;87: 8555–8559. Available: doi: 10.1073/pnas.87.21.8555 2236065

8. Levy DE, Kessler DS, Pine R, Darnell JE Jr. Cytoplasmic activation of ISGF3, the positive regulator of interferon-alpha-stimulated transcription, reconstituted in vitro. Genes Dev. 1989/09/01. 1989;3: 1362–1371. Available: doi: 10.1101/gad.3.9.1362 2606351

9. Meraz MA, White JM, Sheehan KCF, Bach EA, Rodig SJ, Dighe AS, et al. Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell. 1996; doi: 10.1016/S0092-8674(00)81288-X

10. Park C, Li S, Cha E, Schindler C. Immune response in Stat2 knockout mice. Immunity. 2000; doi: 10.1016/S1074-7613(00)00077–7

11. Hatesuer B, Hoang HTT, Riese P, Trittel S, Gerhauser I, Elbahesh H, et al. Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection. J Innate Immun. 2017; doi: 10.1159/000450705 27811478

12. Nair S, Poddar S, Shimak RM, Diamond MS. Interferon regulatory factor-1 (IRF-1) protects against chikungunya virus induced immunopathology by restricting infection in muscle cells. J Virol. 2017; doi: 10.1128/JVI.01419-17 28835505

13. Ciancanelli MJ, Huang SX, Luthra P, Garner H, Itan Y, Volpi S, et al. Infectious disease. Life-threatening influenza and impaired interferon amplification in human IRF7 deficiency. Science (80-). 2015;348: 448–453. doi: 10.1126/science.aaa1578 25814066

14. Kar A, Gutierrez-Hartmann A. Molecular mechanisms of ETS transcription factor-mediated tumorigenesis. Critical Reviews in Biochemistry and Molecular Biology. 2013. doi: 10.3109/10409238.2013.838202 24066765

15. Randi AM, Sperone A, Dryden NH, Birdsey GM. Regulation of angiogenesis by ETS transcription factors. Biochemical Society Transactions. 2009. doi: 10.1042/BST0371248 19909256

16. Hollenhorst PC, Shah AA, Hopkins C, Graves BJ. Genome-wide analyses reveal properties of redundant and specific promoter occupancy within the ETS gene family. Genes Dev. 2007;21: 1882–1894. doi: 10.1101/gad.1561707 17652178

17. Choi HJ, Geng Y, Cho H, Li S, Giri PK, Felio K, et al. Differential requirements for the Ets transcription factor Elf-1 in the development of NKT cells and NK cells. Blood. 2011;117: 1880–1887. doi: 10.1182/blood-2010-09-309468 21148815

18. You F, Wang P, Yang L, Yang G, Zhao YO, Qian F, et al. ELF4 is critical for induction of type I interferon and the host antiviral response. Nat Immunol. 2013;14: 1237–1246. doi: 10.1038/ni.2756 24185615

19. Sarasin-Filipowicz M, Oakeley EJ, Duong FHT, Christen V, Terracciano L, Filipowicz W, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci. 2008/05/10. 2008;105: 7034–7039. doi: 10.1073/pnas.0707882105 18467494

20. Pine R, Canova A, Schindler C. Tyrosine phosphorylated p91 binds to a single element in the ISGF2/IRF-1 promoter to mediate induction by IFN alpha and IFN gamma, and is likely to autoregulate the p91 gene. EMBO J. 1994;13: 158–167. Available: 8306959

21. Gruenert DC, Finkbeiner WE, Widdicombe JH. Culture and transformation of human airway epithelial cells. Am J Physiol. 1995;268: L347–60. doi: 10.1152/ajplung.1995.268.3.L347 7900815

22. Cheon H, Holvey-Bates EG, Schoggins JW, Forster S, Hertzog P, Imanaka N, et al. IFNbeta-dependent increases in STAT1, STAT2, and IRF9 mediate resistance to viruses and DNA damage. EMBO J. 2013/09/26. 2013;32: 2751–2763. doi: 10.1038/emboj.2013.203 24065129

23. Dittmann M, Hoffmann HH, Scull MA, Gilmore RH, Bell KL, Ciancanelli M, et al. A serpin shapes the extracellular environment to prevent influenza a virus maturation. Cell. 2015;160: 631–643. doi: 10.1016/j.cell.2015.01.040 25679759

24. Elf1tm1Jml [Internet]. Available:

25. Rajsbaum R, Versteeg GA, Schmid S, Maestre AM, Belicha-Villanueva A, Martinez-Romero C, et al. Unanchored K48-linked polyubiquitin synthesized by the E3-ubiquitin ligase TRIM6 stimulates the interferon-IKKepsilon kinase-mediated antiviral response. Immunity. 2014;40: 880–895. doi: 10.1016/j.immuni.2014.04.018 24882218

26. Verger A, Buisine E, Carrère S, Wintjens R, Flourens A, Coll J, et al. Identification of Amino Acid Residues in the ETS Transcription Factor Erg That Mediate Erg-Jun/Fos-DNA Ternary Complex Formation. J Biol Chem. 2001;276: 17181–17189. doi: 10.1074/jbc.M010208200 11278640

27. Bredemeier-Ernst I, Nordheim A, Janknecht R. Transcriptional activity and constitutive nuclear localization of the ETS protein Elf-1. FEBS Lett. 1997;408: 47–51. Available: doi: 10.1016/s0014-5793(97)00387-6 9180266

28. Stirnweiss A, Ksienzyk A, Klages K, Rand U, Grashoff M, Hauser H, et al. No Title. 2010/03/24. 2010;184: 5179–5185. doi: 10.4049/jimmunol.0902264

29. Levy DE, Kessler DS, Pine R, Reich N, Darnell JE Jr. Interferon-induced nuclear factors that bind a shared promoter element correlate with positive and negative transcriptional control. Genes Dev. 1988/04/01. 1988;2: 383–393. Available: doi: 10.1101/gad.2.4.383 3371658

30. van Boxel-Dezaire AH, Rani MR, Stark GR. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity. 2006/09/19. 2006;25: 361–372. doi: 10.1016/j.immuni.2006.08.014 16979568

31. De La Cruz-Rivera PC, Kanchwala M, Liang H, Kumar A, Wang L-FF, Xing C, et al. The IFN Response in Bats Displays Distinctive IFN-Stimulated Gene Expression Kinetics with Atypical RNASEL Induction. J Immunol. 2017/11/29. 2018;200: 209–217. doi: 10.4049/jimmunol.1701214 29180486

32. Larsen S, Kawamoto S, Tanuma S, Uchiumi F. The hematopoietic regulator, ELF-1, enhances the transcriptional response to Interferon-beta of the OAS1 anti-viral gene. Sci Rep. 2015;5: 17497. doi: 10.1038/srep17497 26643049

33. Lecine P, Algarte M, Rameil P, Beadling C, Bucher P, Nabholz M, et al. Elf-1 and Stat5 bind to a critical element in a new enhancer of the human interleukin-2 receptor alpha gene. Mol Cell Biol. Available:

34. Rellahan BL, Jensen JP, Howcroft TK, Singer DS, Bonvini E, Weissman AM. Elf-1 regulates basal expression from the T cell antigen receptor zeta-chain gene promoter. J Immunol. 1998;160: 2794–2801. Available: 9510181

35. Matsuyama T, Kimura T, Kitagawa M, Pfeffer K, Kawakami T, Watanabe N, et al. Targeted disruption of IRF-1 or IRF-2 results in abnormal type I IFN gene induction and aberrant lymphocyte development. Cell. 1993;75: 83–97. Available: 8402903

36. Ogasawara K, Hida S, Azimi N, Tagaya Y, Sato T, Yokochi-Fukuda T, et al. Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature. 1998;391: 700–703. doi: 10.1038/35636 9490414

37. Kimura T, Nakayama K, Penninger J, Kitagawa M, Harada H, Matsuyama T, et al. Involvement of the IRF-1 transcription factor in antiviral responses to interferons. Science (80-). 1994;264: 1921–1924. Available:

38. Pine R, Decker T, Kessler DS, Levy DE, Darnell Jr. JE. Purification and cloning of interferon-stimulated gene factor 2 (ISGF2): ISGF2 (IRF-1) can bind to the promoters of both beta interferon- and interferon-stimulated genes but is not a primary transcriptional activator of either. Mol Cell Biol. 1990;10: 2448–2457. Available: doi: 10.1128/mcb.10.6.2448 2342456

39. Ochiai K, Maienschein-Cline M, Simonetti G, Chen J, Rosenthal R, Brink R, et al. Transcriptional Regulation of Germinal Center B and Plasma Cell Fates by Dynamical Control of IRF4. Immunity. 2013;38: 918–929. doi: 10.1016/j.immuni.2013.04.009 23684984

40. Derler I, Jardin I, Romanin C. The molecular mechanisms of STIM/Orai communications. A Review in the Theme: STIM and Orai Proteins in Calcium Signaling. Am J Physiol—Cell Physiol. 2016; doi: 10.1152/ajpcell.00007.2016

41. Srikanth S, Woo JS, Wu B, El-Sherbiny YM, Leung J, Chupradit K, et al. The Ca 2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat Immunol. 2019; doi: 10.1038/s41590-018-0287-8 30643259

42. Soni D, Regmi SC, Wang D-M, DebRoy A, Zhao Y-Y, Vogel SM, et al. Pyk2 phosphorylation of VE-PTP downstream of STIM1-induced Ca 2+ entry regulates disassembly of adherens junctions. Am J Physiol Cell Mol Physiol. 2017; doi: 10.1152/ajplung.00008.2017 28385807

43. Nish S, Medzhitov R. Host defense pathways: role of redundancy and compensation in infectious disease phenotypes. Immunity. 2011/05/28. 2011;34: 629–636. doi: 10.1016/j.immuni.2011.05.009 21616433

44. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J Exp Med. 2016/11/09. 2016;213: 2527–2538. doi: 10.1084/jem.20161596 27821552

45. Yamazaki K, Umeno J, Takahashi A, Hirano A, Johnson TA, Kumasaka N, et al. A genome-wide association study identifies 2 susceptibility Loci for Crohn’s disease in a Japanese population. Gastroenterology. 2013;144: 781–788. doi: 10.1053/j.gastro.2012.12.021 23266558

46. Fuyuno Y, Yamazaki K, Takahashi A, Esaki M, Kawaguchi T, Takazoe M, et al. Genetic characteristics of inflammatory bowel disease in a Japanese population. J Gastroenterol. 2016;51: 672–681. doi: 10.1007/s00535-015-1135-3 26511940

47. Aiba Y, Yamazaki K, Nishida N, Kawashima M, Hitomi Y, Nakamura H, et al. Disease susceptibility genes shared by primary biliary cirrhosis and Crohn’s disease in the Japanese population. J Hum Genet. 2015;60: 525–531. doi: 10.1038/jhg.2015.59 26084578

48. Peloquin JM, Goel G, Kong L, Huang H, Haritunians T, Sartor RB, et al. Characterization of candidate genes in inflammatory bowel disease-associated risk loci. JCI Insight. 2016;1: e87899. doi: 10.1172/jci.insight.87899 27668286

49. Liu TC, Stappenbeck TS. Genetics and Pathogenesis of Inflammatory Bowel Disease. Annu Rev Pathol. 2016;11: 127–148. doi: 10.1146/annurev-pathol-012615-044152 26907531

50. Yang J, Yang W, Hirankarn N, Ye DQ, Zhang Y, Pan HF, et al. ELF1 is associated with systemic lupus erythematosus in Asian populations. Hum Mol Genet. 2011;20: 601–607. doi: 10.1093/hmg/ddq474 21044949

51. Juang YT, Tenbrock K, Nambiar MP, Gourley MF, Tsokos GC. Defective production of functional 98-kDa form of Elf-1 is responsible for the decreased expression of TCR zeta-chain in patients with systemic lupus erythematosus. J Immunol. 2002;169: 6048–6055. Available: doi: 10.4049/jimmunol.169.10.6048 12421992

52. Atreya I, Atreya R, Neurath MF. NF-kappaB in inflammatory bowel disease. J Intern Med. 2008;263: 591–596. doi: 10.1111/j.1365-2796.2008.01953.x 18479258

53. Maeda S, Hsu LC, Liu H, Bankston LA, Iimura M, Kagnoff MF, et al. Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing. Science (80-). 2005;307: 734–738. doi: 10.1126/science.1103685 15692052

54. Zubair A, Frieri M. NF-kappaB and systemic lupus erythematosus: examining the link. J Nephrol. 2013;26: 953–959. doi: 10.5301/jn.5000272 23807646

55. Crow MK. Type I interferon in the pathogenesis of lupus. J Immunol. 2014;192: 5459–5468. doi: 10.4049/jimmunol.1002795 24907379

56. Ghosh S, Chaudhary R, Carpani M, Playford R. Interfering with interferons in inflammatory bowel disease. Gut. 2006;55: 1071–1073. doi: 10.1136/gut.2005.090134 16849343

57. Fais S, Capobianchi MR, Silvestri M, Mercuri F, Pallone F, Dianzani F. Interferon expression in Crohn’s disease patients: increased interferon-gamma and -alpha mRNA in the intestinal lamina propria mononuclear cells. J Interf Res. 1994;14: 235–238. Available:

58. Bolen CR, Ding S, Robek MD, Kleinstein SH. No Title. Hepatology. 2013/08/10. 59: 1262–1272. doi: 10.1002/hep.26657

59. Shalek AK, Satija R, Shuga J, Trombetta JJ, Gennert D, Lu D, et al. Single-cell RNA-seq reveals dynamic paracrine control of cellular variation. Nature. 2014/06/12. 2014;510: 363–369. doi: 10.1038/nature13437 24919153

60. Yan C, Higgins PJ. Drugging the undruggable: transcription therapy for cancer. Biochim Biophys Acta. 2013;1835: 76–85. doi: 10.1016/j.bbcan.2012.11.002 23147197

61. Mansilla S, Portugal J. Sp1 transcription factor as a target for anthracyclines: effects on gene transcription. Biochimie. 2008/01/30. 2008;90: 976–987. doi: 10.1016/j.biochi.2007.12.008 18226599

62. Buchwald P. Small-molecule protein-protein interaction inhibitors: therapeutic potential in light of molecular size, chemical space, and ligand binding efficiency considerations. IUBMB Life. 2010/10/28. 2010;62: 724–731. doi: 10.1002/iub.383 20979208

63. Scheuermann TH, Tomchick DR, Machius M, Guo Y, Bruick RK, Gardner KH. Artificial ligand binding within the HIF2alpha PAS-B domain of the HIF2 transcription factor. Proc Natl Acad Sci U S A. 2009/01/09. 2009;106: 450–455. doi: 10.1073/pnas.0808092106 19129502

64. Baud D, Gubler DJ, Schaub B, Lanteri MC, Musso D. An update on Zika virus infection. Lancet. 2017/06/26. 2017;390: 2099–2109. doi: 10.1016/S0140-6736(17)31450-2 28647173

65. Nkengasong JN, Onyebujoh P. Response to the Ebola virus disease outbreak in the Democratic Republic of the Congo. Lancet. 2018/06/20. 2018;391: 2395–2398. doi: 10.1016/S0140-6736(18)31326-6 29916371

66. Alonzo 3rd F, Kozhaya L, Rawlings SA, Reyes-Robles T, DuMont AL, Myszka DG, et al. CCR5 is a receptor for Staphylococcus aureus leukotoxin ED. Nature. 2013;493: 51–55. doi: 10.1038/nature11724 23235831

67. Zhang L, Bukreyev A, Thompson CI, Watson B, Peeples ME, Collins PL, et al. Infection of ciliated cells by human parainfluenza virus type 3 in an in vitro model of human airway epithelium. J Virol. 2005;79: 1113–1124. doi: 10.1128/JVI.79.2.1113-1124.2005 15613339

68. Feuer R, Mena I, Pagarigan R, Slifka MK, Whitton JL. Cell cycle status affects coxsackievirus replication, persistence, and reactivation in vitro. J Virol. 2002;76: 4430–4440. Available: doi: 10.1128/JVI.76.9.4430-4440.2002 11932410

69. Jones CT, Catanese MT, Law LM, Khetani SR, Syder AJ, Ploss A, et al. Real-time imaging of hepatitis C virus infection using a fluorescent cell-based reporter system. Nat Biotechnol. 2010;28: 167–171. doi: 10.1038/nbt.1604 20118917

70. Benboudjema L, Mulvey M, Gao Y, Pimplikar SW, Mohr I. Association of the herpes simplex virus type 1 Us11 gene product with the cellular kinesin light-chain-related protein PAT1 results in the redistribution of both polypeptides. J Virol. 2003;77: 9192–9203. Available: doi: 10.1128/JVI.77.17.9192-9203.2003 12915535

71. Chartier C, Degryse E, Gantzer M, Dieterle A, Pavirani A, Mehtali M. Efficient generation of recombinant adenovirus vectors by homologous recombination in Escherichia coli. J Virol. 1996;70: 4805–4810. Available: 8676512

72. Evans JD, Hearing P. Distinct roles of the Adenovirus E4 ORF3 protein in viral DNA replication and inhibition of genome concatenation. J Virol. 2003;77: 5295–5304. Available: doi: 10.1128/JVI.77.9.5295-5304.2003 12692231

73. Stapleford KA, Coffey LL, Lay S, Borderia A V, Duong V, Isakov O, et al. Emergence and transmission of arbovirus evolutionary intermediates with epidemic potential. Cell Host Microbe. 2014;15: 706–716. doi: 10.1016/j.chom.2014.05.008 24922573

74. Kim D, Langmead B, Salzberg SL. HISAT: a fast spliced aligner with low memory requirements. Nat Methods. 2015;12: 357–360. doi: 10.1038/nmeth.3317 25751142

75. Liao Y, Smyth GK, Shi W. FeatureCounts: An efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014; doi: 10.1093/bioinformatics/btt656 24227677

76. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15: 550. doi: 10.1186/s13059-014-0550-8 25516281

77. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43: e47. doi: 10.1093/nar/gkv007 25605792

78. Law CW, Chen Y, Shi W, Smyth GK. voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol. 2014;15: R29. doi: 10.1186/gb-2014-15-2-r29 24485249

79. Benjamini Y, Hochberg Y. Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. J R Stat Soc Ser B. 1995; doi: 10.1111/j.2517-6161.1995.tb02031.x

80. Young MD, Wakefield MJ, Smyth GK, Oshlack A. Gene ontology analysis for RNA-seq: accounting for selection bias. Genome Biol. 2010;11: R14. doi: 10.1186/gb-2010-11-2-r14 20132535

81. Walter W, Sanchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics. 2015;31: 2912–2914. doi: 10.1093/bioinformatics/btv300 25964631

Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens

2019 Číslo 11

Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Deprese u dětí a adolescentů
nový kurz
Autoři: MUDr. Vlastimil Nesnídal

Konsenzuální postupy v léčbě močových infekcí

COVID-19 up to date
Autoři: doc. MUDr. Vladimír Koblížek, Ph.D., MUDr. Mikuláš Skála, prof. MUDr. František Kopřiva, Ph.D., prof. MUDr. Roman Prymula, CSc., Ph.D.

Betablokátory a Ca antagonisté z jiného úhlu
Autoři: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Chronické žilní onemocnění a možnosti konzervativní léčby

Všechny kurzy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu, se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se