A Systems Immunology Approach to Plasmacytoid Dendritic Cell Function in Cytopathic Virus Infections

English version České info

Plasmacytoid dendritic cell (pDC)-mediated protection against cytopathic virus infection involves various molecular, cellular, tissue-scale, and organism-scale events. In order to better understand such multiscale interactions, we have implemented a systems immunology approach focusing on the analysis of the structure, dynamics and operating principles of virus-host interactions which constrain the initial spread of the pathogen. Using high-resolution experimental data sets coming from the well-described mouse hepatitis virus (MHV) model, we first calibrated basic modules including MHV infection of its primary target cells, i.e. pDCs and macrophages (Mφs). These basic building blocks were used to generate and validate an integrative mathematical model for in vivo infection dynamics. Parameter estimation for the system indicated that on a per capita basis, one infected pDC secretes sufficient type I IFN to protect 10³ to 10⁴ Mφs from cytopathic viral infection. This extremely high protective capacity of pDCs secures the spleen's capability to function as a ‘sink’ for the virus produced in peripheral organs such as the liver. Furthermore, our results suggest that the pDC population in spleen ensures a robust protection against virus variants which substantially down-modulate IFN secretion. However, the ability of pDCs to protect against severe disease caused by virus variants exhibiting an enhanced liver tropism and higher replication rates appears to be rather limited. Taken together, this systems immunology analysis suggests that antiviral therapy against cytopathic viruses should primarily limit viral replication within peripheral target organs.

Vyšlo v časopise: A Systems Immunology Approach to Plasmacytoid Dendritic Cell Function in Cytopathic Virus Infections. PLoS Pathog 6(7): e32767. doi:10.1371/journal.ppat.1001017
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001017

Souhrn

Zdroje

1. YoungD

StarkJ

KirschnerD

2008 Systems biology of persistent infection: tuberculosis as a case study. Nat Rev Microbiol 6 520 528

2. JuntT

ScandellaE

LudewigB

2008 Form follows function: lymphoid tissue microarchitecture in antimicrobial immune defence. Nat Rev Immunol 8 764 775

3. ColonnaM

TrinchieriG

LiuYJ

2004 Plasmacytoid dendritic cells in immunity. Nat Immunol 5 1219 1226

4. VilladangosJA

YoungL

2008 Antigen-presentation properties of plasmacytoid dendritic cells. Immunity 29 352 361

5. BarchetW

CellaM

ColonnaM

2005 Plasmacytoid dendritic cells–virus experts of innate immunity. Semin Immunol 17 253 261

6. BergmannCC

LaneTE

StohlmanSA

2006 Coronavirus infection of the central nervous system: host-virus stand-off. Nat Rev Microbiol 4 121 132

7. PerlmanS

NetlandJ

2009 Coronaviruses post-SARS: update on replication and pathogenesis. Nat Rev Microbiol 7 439 450

8. Cervantes-BarraganL

ZustR

WeberF

SpiegelM

LangKS

2007 Control of coronavirus infection through plasmacytoid dendritic-cell-derived type I interferon. Blood 109 1131 1137

9. LangPA

Cervantes-BarraganL

VerschoorA

NavariniAA

RecherM

2009 Hematopoietic cell-derived interferon controls viral replication and virus-induced disease. Blood 113 1045 1052

10. Cervantes-BarraganL

KalinkeU

ZustR

KonigM

ReizisB

2009 Type I IFN-mediated protection of macrophages and dendritic cells secures control of murine coronavirus infection. J Immunol 182 1099 1106

11. BocharovG

FordNJ

LudewigB

2005 A mathematical approach for optimizing dendritic cell-based immunotherapy. Methods Mol Med 109 19 34

12. LudewigB

BocharovG

2006 A systems biologist's view on dendritic cell-cytotoxic T lymphocyte interaction.

LutzM

RomaniN

SteinkassererA

Handbook of Dendritic Cells. Biology, Diseases and Therapy. Weinheim Wiley-VCH 455 479

13. ZüstR

Cervantes-BarraganL

KuriT

BlakqoriG

WeberF

2007 Identification of Coronavirus Non-Structural Protein 1 as a Major Pathogenicity Factor - Implications for the Rational Design of Live Attenuated Coronavirus Vaccines. PLoS Pathog 3 e109

14. ThielV

WeberF

2008 Interferon and cytokine responses to SARS-coronavirus infection. Cytokine Growth Factor Rev 19 121 132

15. TumpeyTM

BaslerCF

AguilarPV

ZengH

SolorzanoA

2005 Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310 77 80

16. RollingT

KoernerI

ZimmermannP

HolzK

HallerO

2009 Adaptive mutations resulting in enhanced polymerase activity contribute to high virulence of influenza A virus in mice. J Virol 83 6673 6680

17. PerlmanS

DandekarAA

2005 Immunopathogenesis of coronavirus infections: implications for SARS. Nat Rev Immunol 5 917 927

18. JuntT

MosemanEA

IannaconeM

MassbergS

LangPA

2007 Subcapsular sinus macrophages in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450 110 114

19. OchsenbeinAF

PinschewerDD

OdermattB

CarrollMC

HengartnerH

1999 Protective T cell-independent antiviral antibody responses are dependent on complement. J Exp Med 190 1165 1174

20. de LangA

BaasT

SmitsSL

KatzeMG

OsterhausAD

2009 Unraveling the complexities of the interferon response during SARS-CoV infection. Future Virol 4 71 78

21. Phipps-YonasH

SetoJ

SealfonSC

MoranTM

Fernandez-SesmaA

2008 Interferon-beta pretreatment of conventional and plasmacytoid human dendritic cells enhances their activation by influenza virus. PLoS Pathog 4 e1000193

22. ShortmanK

NaikSH

2007 Steady-state and inflammatory dendritic-cell development. Nat Rev Immunol 7 19 30

23. WollenbergA

WagnerM

GuntherS

TowarowskiA

TumaE

2002 Plasmacytoid dendritic cells: a new cutaneous dendritic cell subset with distinct role in inflammatory skin diseases. J Invest Dermatol 119 1096 1102

24. de HeerHJ

HammadH

SoullieT

HijdraD

VosN

2004 Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen. J Exp Med 200 89 98

25. WendlandM

CzelothN

MachN

MalissenB

KremmerE

2007 CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc Natl Acad Sci U S A 104 6347 6352

26. CellaM

JarrossayD

FacchettiF

AlebardiO

NakajimaH

1999 Plasmacytoid monocytes migrate to inflamed lymph nodes and produce large amounts of type I interferon. Nat Med 5 919 923

27. YoneyamaH

MatsunoK

ZhangY

NishiwakiT

KitabatakeM

2004 Evidence for recruitment of plasmacytoid dendritic cell precursors to inflamed lymph nodes through high endothelial venules. Int Immunol 16 915 928

28. CisseB

CatonML

LehnerM

MaedaT

ScheuS

2008 Transcription factor E2-2 is an essential and specific regulator of plasmacytoid dendritic cell development. Cell 135 37 48

29. SwieckiM

ColonnaM

2010 Unraveling the functions of plasmacytoid dendritic cells during viral infections, autoimmunity, and tolerance. Immunol Rev 234 142 162

30. ErikssonKK

Cervantes-BarraganL

LudewigB

ThielV

2008 Mouse hepatitis virus liver pathology is dependent on ADP-ribose-1″-phosphatase, a viral function conserved in the alpha-like supergroup. J Virol 82 12325 12334

31. MarsdenPA

NingQ

FungLS

LuoX

ChenY

2003 The Fgl2/fibroleukin prothrombinase contributes to immunologically mediated thrombosis in experimental and human viral hepatitis. J Clin Invest 112 58 66

32. GermainRN

2001 The art of the probable: system control in the adaptive immune system. Science 293 240 245

33. TanSL

GanjiG

PaeperB

ProllS

KatzeMG

2007 Systems biology and the host response to viral infection. Nat Biotechnol 25 1383 1389

34. GardyJL

LynnDJ

BrinkmanFS

HancockRE

2009 Enabling a systems biology approach to immunology: focus on innate immunity. Trends Immunol 30 249 262

35. ZakDE

AderemA

2009 Systems biology of innate immunity. Immunol Rev 227 264 282

36. KirschnerDE

LindermanJJ

2009 Mathematical and computational approaches can complement experimental studies of host-pathogen interactions. Cell Microbiol 11 531 539

37. Meier-SchellersheimM

FraserIDC

KlauschenF

2009 Multiscale modeling for biologists. WIREs Systems Biology and Medicine 1 4 14

38. PerelsonAS

2002 Modelling viral and immune system dynamics. Nat Rev Immunol 2 28 36

39. AntiaR

GanusovVV

AhmedR

2005 The role of models in understanding CD8+ T-cell memory. Nat Rev Immunol 5 101 111

40. BeltmanJB

MareeAF

De BoerRJ

2009 Analysing immune cell migration. Nat Rev Immunol 9 789 798

41. BocharovGA

RomanyukhaAA

1994 Mathematical model of antiviral immune response. III. Influenza A virus infection. J Theor Biol 167 323 360

42. HowatTJ

BarrecaC

O'HareP

GogJR

GrenfellBT

2006 Modelling dynamics of the type I interferon response to in vitro viral infection. J R Soc Interface 3 699 709

43. TegnerJ

NilssonR

BajicVB

BjorkegrenJ

RavasiT

2006 Systems biology of innate immunity. Cell Immunol 244 105 109

44. MullerU

SteinhoffU

ReisLF

HemmiS

PavlovicJ

1994 Functional role of type I and type II interferons in antiviral defense. Science 264 1918 1921

45. ColeySE

LaviE

SawickiSG

FuL

SchelleB

2005 Recombinant mouse hepatitis virus strain A59 from cloned, full-length cDNA replicates to high titers in vitro and is fully pathogenic in vivo. J Virol 79 3097 3106

46. JohnsonJB

OmlandKS

2004 Model selection in ecology and evolution. Trends Ecol Evol 19 101 108

47. PittMA

MyungIJ

2002 When a good fit can be bad. Trends Cogn Sci 6 421 425

48. LudewigB

KrebsP

JuntT

MettersH

FordNJ

2004 Determining control parameters for dendritic cell-cytotoxic T lymphocyte interaction. Eur J Immunol 34 2407 2418