Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden

Autoři: Nikhil J. Parekh aff001;  Tracy E. Krouse aff001;  Irene E. Reider aff001;  Ryan P. Hobbs aff001;  Brian M. Ward aff003;  Christopher C. Norbury aff001
Působiště autorů: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America aff001;  Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America aff002;  Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America aff003
Vyšlo v časopise: Type I interferon-dependent CCL4 is induced by a cGAS/STING pathway that bypasses viral inhibition and protects infected tissue, independent of viral burden. PLoS Pathog 15(10): e32767. doi:10.1371/journal.ppat.1007778
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.ppat.1007778


Type I interferons (T1-IFN) are critical in the innate immune response, acting upon infected and uninfected cells to initiate an antiviral state by expressing genes that inhibit multiple stages of the lifecycle of many viruses. T1-IFN triggers the production of Interferon-Stimulated Genes (ISGs), activating an antiviral program that reduces virus replication. The importance of the T1-IFN response is highlighted by the evolution of viral evasion strategies to inhibit the production or action of T1-IFN in virus-infected cells. T1-IFN is produced via activation of pathogen sensors within infected cells, a process that is targeted by virus-encoded immunomodulatory molecules. This is probably best exemplified by the prototypic poxvirus, Vaccinia virus (VACV), which uses at least 6 different mechanisms to completely block the production of T1-IFN within infected cells in vitro. Yet, mice lacking aspects of T1-IFN signaling are often more susceptible to infection with many viruses, including VACV, than wild-type mice. How can these opposing findings be rationalized? The cytosolic DNA sensor cGAS has been implicated in immunity to VACV, but has yet to be linked to the production of T1-IFN in response to VACV infection. Indeed, there are two VACV-encoded proteins that effectively prevent cGAS-mediated activation of T1-IFN. We find that the majority of VACV-infected cells in vivo do not produce T1-IFN, but that a small subset of VACV-infected cells in vivo utilize cGAS to sense VACV and produce T1-IFN to protect infected mice. The protective effect of T1-IFN is not mediated via ISG-mediated control of virus replication. Rather, T1-IFN drives increased expression of CCL4, which recruits inflammatory monocytes that constrain the VACV lesion in a virus replication-independent manner by limiting spread within the tissue. Our findings have broad implications in our understanding of pathogen detection and viral evasion in vivo, and highlight a novel immune strategy to protect infected tissue.

Klíčová slova:

Inflammation – Macrophages – Monocytes – Skin infections – Viral replication – Ear infections – Vaccinia virus


1. van den Broek MF, Muller U, Huang S, Zinkernagel RM, Aguet M. Immune defence in mice lacking type I and/or type II interferon receptors. Immunol Rev. 1995;148:5–18. doi: 10.1111/j.1600-065x.1995.tb00090.x 8825279.

2. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci. 1957;147(927):258–67. 13465720.

3. Nagano Y, Kojima Y, Sawai Y. [Immunity and interference in vaccinia; inhibition of skin infection by inactivated virus]. C R Seances Soc Biol Fil. 1954;148(7–8):750–2. 13190824.

4. Pestka S, Krause CD, Walter MR. Interferons, interferon-like cytokines, and their receptors. Immunol Rev. 2004;202:8–32. doi: 10.1111/j.0105-2896.2004.00204.x 15546383.

5. Yan N, Chen ZJ. Intrinsic antiviral immunity. Nat Immunol. 2012;13(3):214–22. doi: 10.1038/ni.2229 22344284; PubMed Central PMCID: PMC3549670.

6. Fu XY, Schindler C, Improta T, Aebersold R, Darnell JE Jr., The proteins of ISGF-3, the interferon alpha-induced transcriptional activator, define a gene family involved in signal transduction. Proc Natl Acad Sci U S A. 1992;89(16):7840–3. doi: 10.1073/pnas.89.16.7840 1502204; PubMed Central PMCID: PMC49807.

7. Schoggins JW, Rice CM. Interferon-stimulated genes and their antiviral effector functions. Curr Opin Virol. 2011;1(6):519–25. doi: 10.1016/j.coviro.2011.10.008 22328912; PubMed Central PMCID: PMC3274382.

8. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol. 2014;32:513–45. doi: 10.1146/annurev-immunol-032713-120231 24555472; PubMed Central PMCID: PMC4313732.

9. Sen GC. Viruses and interferons. Annu Rev Microbiol. 2001;55:255–81. doi: 10.1146/annurev.micro.55.1.255 11544356.

10. Hoffmann HH, Schneider WM, Rice CM. Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol. 2015;36(3):124–38. doi: 10.1016/j.it.2015.01.004 25704559; PubMed Central PMCID: PMC4384471.

11. Garcia-Sastre A. Ten Strategies of Interferon Evasion by Viruses. Cell Host Microbe. 2017;22(2):176–84. doi: 10.1016/j.chom.2017.07.012 PubMed Central PMCID: PMC5576560. 28799903

12. Alcami A, Koszinowski UH. Viral mechanisms of immune evasion. 2000;8(9):410–8. doi: 10.1016/s0966-842x(00)01830-8 10989308

13. Cao H, Dai P, Wang W, Li H, Yuan J, Wang F, et al. Innate immune response of human plasmacytoid dendritic cells to poxvirus infection is subverted by vaccinia E3 via its Z-DNA/RNA binding domain. PLoS One. 2012;7(5):e36823. doi: 10.1371/journal.pone.0036823 22606294; PubMed Central PMCID: PMC3351467.

14. Dai P, Wang W, Cao H, Avogadri F, Dai L, Drexler I, et al. Modified vaccinia virus Ankara triggers type I IFN production in murine conventional dendritic cells via a cGAS/STING-mediated cytosolic DNA-sensing pathway. PLoS Pathog. 2014;10(4):e1003989. doi: 10.1371/journal.ppat.1003989 24743339; PubMed Central PMCID: PMC3990710.

15. Meade N, Furey C, Li H, Verma R, Chai Q, Rollins MG, et al. Poxviruses Evade Cytosolic Sensing through Disruption of an mTORC1-mTORC2 Regulatory Circuit. Cell. 2018;174(5):1143–57 e17. doi: 10.1016/j.cell.2018.06.053 30078703; PubMed Central PMCID: PMC6172959.

16. Georgana I, Sumner RP, Towers GJ, Maluquer de Motes C. Virulent poxviruses inhibit DNA sensing by preventing STING activation. J Virol. 2018. doi: 10.1128/JVI.02145-17 29491158; PubMed Central PMCID: PMC5923072.

17. Scutts SR, Ember SW, Ren H, Ye C, Lovejoy CA, Mazzon M, et al. DNA-PK Is Targeted by Multiple Vaccinia Virus Proteins to Inhibit DNA Sensing. Cell Rep. 2018;25(7):1953–65 e4. doi: 10.1016/j.celrep.2018.10.034 30428360.

18. Eaglesham JB, Pan Y, Kupper TS, Kranzusch PJ. Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling. Nature. 2019;566(7743):259–63. doi: 10.1038/s41586-019-0928-6 30728498.

19. Hickman HD, Reynoso GV, Ngudiankama BF, Rubin EJ, Magadan JG, Cush SS, et al. Anatomically restricted synergistic antiviral activities of innate and adaptive immune cells in the skin. Cell host & microbe. 2013;13(2):155–68. Epub 2013/02/19. doi: 10.1016/j.chom.2013.01.004 23414756; PubMed Central PMCID: PMC3591514.

20. Deng L, Dai P, Parikh T, Cao H, Bhoj V, Sun Q, et al. Vaccinia virus subverts a mitochondrial antiviral signaling protein-dependent innate immune response in keratinocytes through its double-stranded RNA binding protein, E3. J Virol. 2008;82(21):10735–46. doi: 10.1128/JVI.01305-08 18715932; PubMed Central PMCID: PMC2573174.

21. Tscharke DC, Smith GL. A model for vaccinia virus pathogenesis and immunity based on intradermal injection of mouse ear pinnae. J Gen Virol. 1999;80 (Pt 10):2751–5. doi: 10.1099/0022-1317-80-10-2751 10573171.

22. Tscharke DC, Reading PC, Smith GL. Dermal infection with vaccinia virus reveals roles for virus proteins not seen using other inoculation routes. J Gen Virol. 2002;83(Pt 8):1977–86. doi: 10.1099/0022-1317-83-8-1977 12124461.

23. Jaks E, Gavutis M, Uze G, Martal J, Piehler J. Differential receptor subunit affinities of type I interferons govern differential signal activation. J Mol Biol. 2007;366(2):525–39. Epub 2006/12/19. doi: 10.1016/j.jmb.2006.11.053 17174979.

24. Li L, Sherry B. IFN-alpha expression and antiviral effects are subtype and cell type specific in the cardiac response to viral infection. Virology. 2010;396(1):59–68. Epub 2009/11/10. doi: 10.1016/j.virol.2009.10.013 19896686; PubMed Central PMCID: PMC2787694.

25. Marie I, Durbin JE, Levy DE. Differential viral induction of distinct interferon-alpha genes by positive feedback through interferon regulatory factor-7. EMBO J. 1998;17(22):6660–9. doi: 10.1093/emboj/17.22.6660 9822609; PubMed Central PMCID: PMC1171011.

26. Sato M, Hata N, Asagiri M, Nakaya T, Taniguchi T, Tanaka N. Positive feedback regulation of type I IFN genes by the IFN-inducible transcription factor IRF-7. FEBS Lett. 1998;441(1):106–10. doi: 10.1016/s0014-5793(98)01514-2 9877175.

27. Horvath CM, Darnell JE. The state of the STATs: recent developments in the study of signal transduction to the nucleus. Curr Opin Cell Biol. 1997;9(2):233–9. doi: 10.1016/s0955-0674(97)80067-1 9069254.

28. Levy DE, Marie IJ, Durbin JE. Induction and function of type I and III interferon in response to viral infection. Curr Opin Virol. 2011;1(6):476–86. doi: 10.1016/j.coviro.2011.11.001 22323926; PubMed Central PMCID: PMC3272644.

29. Bowie A, Kiss-Toth E, Symons JA, Smith GL, Dower SK, O'Neill LA. A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. Proc Natl Acad Sci U S A. 2000;97(18):10162–7. doi: 10.1073/pnas.160027697 10920188.

30. Stack J, Haga IR, Schroder M, Bartlett NW, Maloney G, Reading PC, et al. Vaccinia virus protein A46R targets multiple Toll-like-interleukin-1 receptor adaptors and contributes to virulence. J Exp Med. 2005;201(6):1007–18. doi: 10.1084/jem.20041442 15767367.

31. Zhang P, Langland JO, Jacobs BL, Samuel CE. Protein kinase PKR-dependent activation of mitogen-activated protein kinases occurs through mitochondrial adapter IPS-1 and is antagonized by vaccinia virus E3L. J Virol. 2009;83(11):5718–25. doi: 10.1128/JVI.00224-09 19321614; PubMed Central PMCID: PMC2681938.

32. Davies ML, Sei JJ, Siciliano NA, Xu RH, Roscoe F, Sigal LJ, et al. MyD88-dependent immunity to a natural model of vaccinia virus infection does not involve Toll-like receptor 2. J Virol. 2014;88(6):3557–67. doi: 10.1128/JVI.02776-13 24403581; PubMed Central PMCID: PMC3957935.

33. Martinez J, Huang X, Yang Y. Direct TLR2 signaling is critical for NK cell activation and function in response to vaccinia viral infection. PLoS pathogens. 2010;6(3):e1000811. Epub 2010/03/20. doi: 10.1371/journal.ppat.1000811 20300608; PubMed Central PMCID: PMC2837413.

34. Quigley M, Martinez J, Huang X, Yang Y. A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection. Blood. 2009;113(10):2256–64. Epub 2008/10/25. doi: 10.1182/blood-2008-03-148809 18948575; PubMed Central PMCID: PMC2652371.

35. Zhao Y, De Trez C, Flynn R, Ware CF, Croft M, Salek-Ardakani S. The adaptor molecule MyD88 directly promotes CD8 T cell responses to vaccinia virus. Journal of immunology. 2009;182(10):6278–86. Epub 2009/05/06. doi: 10.4049/jimmunol.0803682 19414781; PubMed Central PMCID: PMC2712123.

36. Martinez J, Huang X, Yang Y. Toll-like receptor 8-mediated activation of murine plasmacytoid dendritic cells by vaccinia viral DNA. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(14):6442–7. Epub 2010/03/24. doi: 10.1073/pnas.0913291107 20308556; PubMed Central PMCID: PMC2851984.

37. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, et al. Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature. 2003;424(6950):743–8. doi: 10.1038/nature01889 12872135.

38. Meade N, King M, Munger J, Walsh D. mTOR Dysregulation by Vaccinia Virus F17 Controls Multiple Processes with Varying Roles in Infection. J Virol. 2019;93(15). doi: 10.1128/JVI.00784-19 31118254.

39. 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(7485):691–5. doi: 10.1038/nature12862 24284630; PubMed Central PMCID: PMC4077721.

40. Lian H, Wei J, Zang R, Ye W, Yang Q, Zhang XN, et al. ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response. Nat Commun. 2018;9(1):3349. doi: 10.1038/s41467-018-05559-w 30135424; PubMed Central PMCID: PMC6105683.

41. Abe T, Barber GN. Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kappaB activation through TBK1. J Virol. 2014;88(10):5328–41. doi: 10.1128/JVI.00037-14 24600004; PubMed Central PMCID: PMC4019140.

42. Fang R, Wang C, Jiang Q, Lv M, Gao P, Yu X, et al. NEMO-IKKbeta Are Essential for IRF3 and NF-kappaB Activation in the cGAS-STING Pathway. J Immunol. 2017;199(9):3222–33. doi: 10.4049/jimmunol.1700699 28939760.

43. Cai X, Chiu YH, Chen ZJ. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol Cell. 2014;54(2):289–96. doi: 10.1016/j.molcel.2014.03.040 24766893.

44. Chen H, Sun H, You F, Sun W, Zhou X, Chen L, et al. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell. 2011;147(2):436–46. Epub 2011/10/18. doi: 10.1016/j.cell.2011.09.022 22000020.

45. Bhat N, Fitzgerald KA. Recognition of cytosolic DNA by cGAS and other STING-dependent sensors. Eur J Immunol. 2014;44(3):634–40. doi: 10.1002/eji.201344127 24356864; PubMed Central PMCID: PMC4621431.

46. Rubio D, Xu RH, Remakus S, Krouse TE, Truckenmiller ME, Thapa RJ, et al. Cross-talk between the Type I interferon and Nuclear Factor Kappa B pathways rescues resistance to a viral disease. Cell Host Microbe. 2013;In press.

47. Howell MD, Gao P, Kim BE, Lesley LJ, Streib JE, Taylor PA, et al. The signal transducer and activator of transcription 6 gene (STAT6) increases the propensity of patients with atopic dermatitis toward disseminated viral skin infections. J Allergy Clin Immunol. 2011;128(5):1006–14. doi: 10.1016/j.jaci.2011.06.003 21762972; PubMed Central PMCID: PMC3205328.

48. Di Pilato M, Mejias-Perez E, Sorzano COS, Esteban M. Distinct Roles of Vaccinia Virus NF-kappaB Inhibitor Proteins A52, B15, and K7 in the Immune Response. J Virol. 2017;91(13). doi: 10.1128/JVI.00575-17 28424281; PubMed Central PMCID: PMC5469261.

49. Howell MD, Gallo RL, Boguniewicz M, Jones JF, Wong C, Streib JE, et al. Cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus. Immunity. 2006;24(3):341–8. Epub 2006/03/21. doi: 10.1016/j.immuni.2006.02.006 16546102.

50. Mahalingam S, Karupiah G, Takeda K, Akira S, Matthaei KI, Foster PS. Enhanced resistance in STAT6-deficient mice to infection with ectromelia virus. Proc Natl Acad Sci U S A. 2001;98(12):6812–7. doi: 10.1073/pnas.111151098 11371617.

51. Ember SW, Ren H, Ferguson BJ, Smith GL. Vaccinia virus protein C4 inhibits NF-kappaB activation and promotes virus virulence. The Journal of general virology. 2012;93(Pt 10):2098–108. Epub 2012/07/14. doi: 10.1099/vir.0.045070-0 22791606; PubMed Central PMCID: PMC3541790.

52. Fischer MA, Davies ML, Reider IE, Heipertz EL, Epler MR, Sei JJ, et al. CD11b(+), Ly6G(+) cells produce type I interferon and exhibit tissue protective properties following peripheral virus infection. PLoS Pathog. 2011;7(11):e1002374. doi: 10.1371/journal.ppat.1002374 22102816; PubMed Central PMCID: PMC3213107.

53. Gale M Jr., Understanding the Expanding Roles of Interferon and Cytokines in Health and Disease. J Interferon Cytokine Res. 2018;38(5):195–6. doi: 10.1089/jir.2018.29007-mgj 29791283.

54. Gale M Jr., Looking Forward in Interferon and Cytokine Research: Defining Effector Genes of Interferon and Cytokine Actions. J Interferon Cytokine Res. 2018;38(6):235. doi: 10.1089/jir.2018.29008.mgj 29920132.

55. Davies ML, Parekh NJ, Kaminsky LW, Soni C, Reider IE, Krouse TE, et al. A systemic macrophage response is required to contain a peripheral poxvirus infection. PLoS Pathog. 2017;13(6):e1006435. doi: 10.1371/journal.ppat.1006435 28614386; PubMed Central PMCID: PMC5484545.

56. Iannacone M, Moseman EA, Tonti E, Bosurgi L, Junt T, Henrickson SE, et al. Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus. Nature. 2010;465(7301):1079–83. Epub 2010/06/26. doi: 10.1038/nature09118 20577213; PubMed Central PMCID: PMC2892812.

57. Junt T, Moseman EA, Iannacone M, Massberg S, Lang PA, Boes M, et al. Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature. 2007;450(7166):110–4. Epub 2007/10/16. doi: 10.1038/nature06287 17934446.

58. Moseman EA, Iannacone M, Bosurgi L, Tonti E, Chevrier N, Tumanov A, et al. B cell maintenance of subcapsular sinus macrophages protects against a fatal viral infection independent of adaptive immunity. Immunity. 2012;36(3):415–26. doi: 10.1016/j.immuni.2012.01.013 22386268; PubMed Central PMCID: PMC3359130.

59. Frederico B, Chao B, Lawler C, May JS, Stevenson PG. Subcapsular sinus macrophages limit acute gammaherpesvirus dissemination. J Gen Virol. 2015;96(8):2314–27. doi: 10.1099/vir.0.000140 25872742.

60. Farrell HE, Davis-Poynter N, Bruce K, Lawler C, Dolken L, Mach M, et al. Lymph Node Macrophages Restrict Murine Cytomegalovirus Dissemination. J Virol. 2015;89(14):7147–58. doi: 10.1128/JVI.00480-15 25926638; PubMed Central PMCID: PMC4473555.

61. Broder CC, Kennedy PE, Michaels F, Berger EA. Expression of foreign genes in cultured human primary macrophages using recombinant vaccinia virus vectors. Gene. 1994;142(2):167–74. doi: 10.1016/0378-1119(94)90257-7 8194748.

62. Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T, Latz E, et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature. 2013;503(7477):530–4. Epub 2013/10/01. doi: 10.1038/nature12640 24077100.

63. Xu S, Ducroux A, Ponnurangam A, Vieyres G, Franz S, Musken M, et al. cGAS-Mediated Innate Immunity Spreads Intercellularly through HIV-1 Env-Induced Membrane Fusion Sites. Cell Host Microbe. 2016;20(4):443–57. doi: 10.1016/j.chom.2016.09.003 27736643.

64. Rice AD, Turner PC, Embury JE, Moldawer LL, Baker HV, Moyer RW. Roles of vaccinia virus genes E3L and K3L and host genes PKR and RNase L during intratracheal infection of C57BL/6 mice. J Virol. 2011;85(1):550–67. doi: 10.1128/JVI.00254-10 20943971; PubMed Central PMCID: PMC3014211.

65. Rivas C, Gil J, Melkova Z, Esteban M, Diaz-Guerra M. Vaccinia virus E3L protein is an inhibitor of the interferon (i.f.n.)-induced 2-5A synthetase enzyme. Virology. 1998;243(2):406–14. doi: 10.1006/viro.1998.9072 9568039.

66. Chang HW, Watson JC, Jacobs BL. The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase. Proc Natl Acad Sci U S A. 1992;89(11):4825–9. doi: 10.1073/pnas.89.11.4825 1350676; PubMed Central PMCID: PMC49180.

67. Odendall C, Dixit E, Stavru F, Bierne H, Franz KM, Durbin AF, et al. Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nat Immunol. 2014;15(8):717–26. doi: 10.1038/ni.2915 24952503; PubMed Central PMCID: PMC4106986.

68. Alcami A, Symons JA, Smith GL. The vaccinia virus soluble alpha/beta interferon (IFN) receptor binds to the cell surface and protects cells from the antiviral effects of IFN. J Virol. 2000;74(23):11230–9. doi: 10.1128/jvi.74.23.11230-11239.2000 11070021.

69. Najarro P, Traktman P, Lewis JA. Vaccinia virus blocks gamma interferon signal transduction: viral VH1 phosphatase reverses Stat1 activation. J Virol. 2001;75(7):3185–96. doi: 10.1128/JVI.75.7.3185-3196.2001 11238845; PubMed Central PMCID: PMC114112.

70. Baldanta S, Fernandez-Escobar M, Acin-Perez R, Albert M, Camafeita E, Jorge I, et al. ISG15 governs mitochondrial function in macrophages following vaccinia virus infection. PLoS Pathog. 2017;13(10):e1006651. doi: 10.1371/journal.ppat.1006651 29077752; PubMed Central PMCID: PMC5659798.

71. Guerra S, Caceres A, Knobeloch KP, Horak I, Esteban M. Vaccinia virus E3 protein prevents the antiviral action of ISG15. PLoS Pathog. 2008;4(7):e1000096. doi: 10.1371/journal.ppat.1000096 18604270; PubMed Central PMCID: PMC2434199.

72. Haga IR, Bowie AG. Evasion of innate immunity by vaccinia virus. Parasitology. 2005;130 Suppl:S11–25. doi: 10.1017/S0031182005008127 16281988.

73. Harte MT, Haga IR, Maloney G, Gray P, Reading PC, Bartlett NW, et al. The poxvirus protein A52R targets Toll-like receptor signaling complexes to suppress host defense. J Exp Med. 2003;197(3):343–51. doi: 10.1084/jem.20021652 12566418.

74. Norbury CC, Malide D, Gibbs JS, Bennink JR, Yewdell JW. Visualizing priming of virus-specific CD8+ T cells by infected dendritic cells in vivo. Nat Immunol. 2002;3(3):265–71. doi: 10.1038/ni762 11828323.

75. Lehmann MH, Kastenmuller W, Kandemir JD, Brandt F, Suezer Y, Sutter G. Modified vaccinia virus ankara triggers chemotaxis of monocytes and early respiratory immigration of leukocytes by induction of CCL2 expression. J Virol. 2009;83(6):2540–52. doi: 10.1128/JVI.01884-08 19129447; PubMed Central PMCID: PMC2648269.

76. Lehmann MH, Torres-Dominguez LE, Price PJ, Brandmuller C, Kirschning CJ, Sutter G. CCL2 expression is mediated by type I IFN receptor and recruits NK and T cells to the lung during MVA infection. J Leukoc Biol. 2016;99(6):1057–64. doi: 10.1189/jlb.4MA0815-376RR 26992431.

77. Bonduelle O, Duffy D, Verrier B, Combadiere C, Combadiere B. Cutting edge: Protective effect of CX3CR1+ dendritic cells in a vaccinia virus pulmonary infection model. Journal of immunology. 2012;188(3):952–6. Epub 2012/01/06. doi: 10.4049/jimmunol.1004164 22219332.

78. Restifo NP, Bacik I, Irvine KR, Yewdell JW, McCabe BJ, Anderson RW, et al. Antigen processing in vivo and the elicitation of primary CTL responses. J Immunol. 1995;154(9):4414–22. 7722298.

79. Lev A, Dimberu P, Das SR, Maynard JC, Nicchitta CV, Bennink JR, et al. Efficient cross-priming of antiviral CD8+ T cells by antigen donor cells is GRP94 independent. J Immunol. 2009;183(7):4205–10. doi: 10.4049/jimmunol.0901828 19752220; PubMed Central PMCID: PMC2749969.

80. Strickland JE, Greenhalgh DA, Koceva-Chyla A, Hennings H, Restrepo C, Balaschak M, et al. Development of murine epidermal cell lines which contain an activated rasHa oncogene and form papillomas in skin grafts on athymic nude mouse hosts. Cancer Res. 1988;48(1):165–9. 3121168.

81. Kim J, Huh J, Hwang M, Kwon EH, Jung DJ, Brinkmann MM, et al. Acidic amino acid residues in the juxtamembrane region of the nucleotide-sensing TLRs are important for UNC93B1 binding and signaling. J Immunol. 2013;190(10):5287–95. doi: 10.4049/jimmunol.1202767 23585677.

82. Tian T, Jin MQ, Dubin K, King SL, Hoetzenecker W, Murphy GF, et al. IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection. J Immunol. 2017;198(11):4341–51. doi: 10.4049/jimmunol.1500106 28468973; PubMed Central PMCID: PMC5506850.

83. Ochoa-Callejero L, Perez-Martinez L, Rubio-Mediavilla S, Oteo JA, Martinez A, Blanco JR. Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model. PLoS One. 2013;8(1):e53992. Epub 2013/01/18. doi: 10.1371/journal.pone.0053992 23326556; PubMed Central PMCID: PMC3541191.

Hygiena a epidemiologie Infekční lékařství Laboratoř

Článek vyšel v časopise

PLOS Pathogens

2019 Číslo 10
Nejčtenější tento týden
Nejčtenější v tomto čísle

Zvyšte si kvalifikaci online z pohodlí domova

Hypertenze a hypercholesterolémie – synergický efekt léčby
nový kurz
Autoři: prof. MUDr. Hana Rosolová, DrSc.

Multidisciplinární zkušenosti u pacientů s diabetem
Autoři: Prof. MUDr. Martin Haluzík, DrSc., prof. MUDr. Vojtěch Melenovský, CSc., prof. MUDr. Vladimír Tesař, DrSc.

Úloha kombinovaných preparátů v léčbě arteriální hypertenze
Autoři: prof. MUDr. Martin Haluzík, DrSc.

Autoři: MUDr. Ladislav Korábek, CSc., MBA

Terapie roztroušené sklerózy v kostce
Autoři: MUDr. Dominika Šťastná, Ph.D.

Všechny kurzy
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