Programmed Death (PD)-1-Deficient Mice Are Extremely Sensitive to Murine Hepatitis Virus Strain-3 (MHV-3) Infection


The inhibitory receptor programmed death-1 (PD-1) has the capacity to maintain peripheral tolerance and limit immunopathological damage; however, its precise role in fulminant viral hepatitis (FH) has yet to be described. Here, we investigated the functional mechanisms of PD-1 as related to FH pathogenesis induced by the murine hepatitis virus strain-3 (MHV-3). High levels of PD-1-positive CD4+, CD8+ T cells, NK cells and macrophages were observed in liver, spleen, lymph node and thymus tissues following MHV-3 infection. PD-1-deficient mice exhibited significantly higher expression of the effector molecule which initiates fibrinogen deposition, fibrinogen-like protein 2 (FGL2), than did their wild-type (WT) littermates. As a result, more severe tissue damage was produced and mortality rates were higher. Fluorescence double-staining revealed that FGL2 and PD-1 were not co-expressed on the same cells, while quantitative RT-PCR demonstrated that higher levels of IFN-γ and TNF-α mRNA transcription occurred in PD-1-deficient mice in response to MHV-3 infection. Conversely, in vivo blockade of IFN-γ and TNF-α led to efficient inhibition of FGL2 expression, greatly attenuated the development of tissue lesions, and ultimately reduced mortality. Thus, the up-regulation of FGL2 in PD-1-deficient mice was determined to be mediated by IFN-γ and TNF-α. Taken together, our results suggest that PD-1 signaling plays an essential role in decreasing the immunopathological damage induced by MHV-3 and that manipulation of this signal might be a useful strategy for FH immunotherapy.


Vyšlo v časopise: Programmed Death (PD)-1-Deficient Mice Are Extremely Sensitive to Murine Hepatitis Virus Strain-3 (MHV-3) Infection. PLoS Pathog 7(7): e32767. doi:10.1371/journal.ppat.1001347
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001347

Souhrn

The inhibitory receptor programmed death-1 (PD-1) has the capacity to maintain peripheral tolerance and limit immunopathological damage; however, its precise role in fulminant viral hepatitis (FH) has yet to be described. Here, we investigated the functional mechanisms of PD-1 as related to FH pathogenesis induced by the murine hepatitis virus strain-3 (MHV-3). High levels of PD-1-positive CD4+, CD8+ T cells, NK cells and macrophages were observed in liver, spleen, lymph node and thymus tissues following MHV-3 infection. PD-1-deficient mice exhibited significantly higher expression of the effector molecule which initiates fibrinogen deposition, fibrinogen-like protein 2 (FGL2), than did their wild-type (WT) littermates. As a result, more severe tissue damage was produced and mortality rates were higher. Fluorescence double-staining revealed that FGL2 and PD-1 were not co-expressed on the same cells, while quantitative RT-PCR demonstrated that higher levels of IFN-γ and TNF-α mRNA transcription occurred in PD-1-deficient mice in response to MHV-3 infection. Conversely, in vivo blockade of IFN-γ and TNF-α led to efficient inhibition of FGL2 expression, greatly attenuated the development of tissue lesions, and ultimately reduced mortality. Thus, the up-regulation of FGL2 in PD-1-deficient mice was determined to be mediated by IFN-γ and TNF-α. Taken together, our results suggest that PD-1 signaling plays an essential role in decreasing the immunopathological damage induced by MHV-3 and that manipulation of this signal might be a useful strategy for FH immunotherapy.


Zdroje

1. RosenHR

MartinP

2000 Viral hepatitis in the liver transplant recipient. Infect Dis Clin North Am 14 761 784

2. PopeM

RotsteinO

ColeE

SinclairS

ParrR

1995 Pattern of disease after murine hepatitis virus strain 3 infection correlates with macrophage activation and not viral replication. J Virol 69 5252 60

3. LevyGA

LeibowitzJL

EdgingtonTS

1981 Induction of monocyte procoagulant activity by murine hepatitis virus type 3 parallels disease susceptibility in mice. J Exp Med 154 1150 63

4. LucchiariMA

MartinJP

ModollelM

PereiraCA

1991 Acquired immunity of A/J mice to mouse hepatitis virus 3 infection: dependence on interferon gamma synthesis and macrophage sensitivity to interferon gamma. J Gen Virol 72 1317 1322

5. 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

6. KeirME

ButteMJ

FreemanGJ

SharpeAH

2008 PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26 677 704

7. SheppardKA

FitzLJ

LeeJM

BenanderC

GeorgeJA

2004 PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett 574 37 41

8. ChemnitzJM

ParryRV

NicholsKE

JuneCH

RileyJL

2004 SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173 945 54

9. IwaiY

TerawakiS

IkegawaM

OkazakiT

HonjoT

2003 PD-1 inhibits antiviral immunity at the effector phase in the liver. J Exp Med 198 39 50

10. JunH

SeoSK

JeongHY

SeoHM

ZhuG

2005 B7-H1 (CD274) inhibits the development of herpetic stromal keratitis (HSK). FEBS Lett 579 6259 64

11. BarberDL

WherryEJ

MasopustD

ZhuB

AllisonJP

2006 Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439 682 87

12. VeluV

TitanjiK

ZhuB

HusainS

PladevegaA

2009 Enhancing SIV-specific immunity in vivo by PD-1 blockade. Nature 458 206 10

13. TrautmannL

JanbazianL

ChomontN

SaidEA

GimmigS

2006 Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 12 1198 202

14. PennaA

PilliM

ZerbiniA

OrlandiniA

MezzadriS

2007 Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 45 588 601

15. SaidEA

DupuyFP

TrautmannL

ZhangY

ShiY

2010 Programmed death-1-induced interleukin-10 production by monocytes impairs CD4(+) T cell activation during HIV infection. Nat Med 16 452 9

16. DasS

SuarezG

BeswickEJ

SierraJC

GrahamDY

2006 Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J Immunol 176 3000 9

17. SmithP

WalshCM

ManganNE

FallonRE

SayersJR

2004 Schistosoma mansoni worms induce anergy of T cells via selective up-regulation of programmed death ligand on macrophages. J Immunol 173 1240 48

18. Lázár-MolnárE

GácserA

FreemanGJ

AlmoSC

NathensonSG

2008 The PD-1/PD-L costimulatory pathway critically affects host resistance to the pathogenic fungus Histoplasma capsulatum. Proc Natl Acad Sci U S A 105 2658 63

19. TerrazasLI

MonteroD

TerrazasCA

ReyesJL

Rodriguez-SosaM

2005 Role of the programmed Death-1 pathway in the suppressive activity of alternatively activated macrophages in experimental cysticercosis. Int J Parasitol 35 1349 58

20. MartinicMM

von HerrathMG

2008 Novel strategies to eliminate persistent viral infections. Trends Immunol 29 116 24

21. LiuM

MendicinoM

NingQ

GhanekarA

HeW

2006 Cytokine-induced hepatic apoptosis is dependent on FGL2/fibroleukin: the role of Sp1/Sp3 and STAT1/PU.1 composite cis elements. J Immunol 176 7028 38

22. HancockWW

SzabaFM

BerggrenKN

ParentMA

MullarkyIK

2004 Intact type 1 immunity and immune-associated coagulative responses in mice lacking IFN gamma-inducible fibrinogen-like protein 2. Proc Natl Acad Sci U S A 101 3005 10

23. BrownKE

FreemanGJ

WherryEJ

SharpeAH

2010 Role of PD-1 in regulating acute infections. Curr Opinion Immunol 22 397 401

24. HuangX

VenetF

WangYL

LepapeA

YuanZ

2009 PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc Natl Acad Sci USA 106 6303 6308

25. FuseS

TsaiCY

MolloyMJ

AllieSR

ZhangW

2009 Recall responses by helpless memory CD8+ T cells are restricted by the upregulation of PD-1. J Immunol 182 4244 4254

26. YaoS

WangS

ZhuY

LuoL

ZhuG

2009 PD-1 on dendritic cells impedes innate immunity against bacterial infection. Blood 113 5811 5818

27. DickGA

NivenJF

GledhillAN

1956 A virus related to that causing hepatitis in mice (MHV). Br J Exp Pathol 37 90 98

28. DingJW

NingQ

LiuMF

LaiA

PeltekianK

1998 Expression of the fgl2 and its protein product (prothrombinase) in tissues during murine hepatitis virus strain-3 (MHV-3) infection. Adv Exp Med Biol 440 609 18

29. DingJW

NingQ

LiuMF

LaiA

LeibowitzJ

1997 Fulminant hepatic failure in murine hepatitis virus strain 3 infection: tissue-specific expression of a novel fgl2 prothrombinase. J Virol 71 9223 30

30. ShalevI

WongKM

FoersterK

ZhuY

ChanC

2009 The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis. Hepatology 49 387 97

31. MarazziS

BlumS

HartmannR

GundersenD

SchreyerM

1998 Characterization of human fibroleukin, a fibrinogen-like protein secreted by T lymphocytes. J Immunol 161 138 47

32. ShalevI

LiuH

KoscikC

BartczakA

JavadiM

2008 Targeted deletion of fgl2 leads to impaired regulatory T cell activity and development of autoimmune glomerulonephritis. J Immunol 180 249 60

33. FranceschiniD

ParoliM

FrancavillaV

VidettaM

MorroneS

2009 PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 119 551 64

34. FranciscoLM

SalinasVH

BrownKE

VanguriVK

FreemanGJ

2009 PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 206 3015 29

35. LivakKJ

SchmittgenTD

2001 Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25 402 8

36. ChenY

ZhangJ

LiJ

ZhaoT

ZouL

2006 Triptolide inhibits B7-H1 expression on proinflammatory factor activated renal tubular epithelial cells by decreasing NF-kappaB transcription. Mol Immunol 43 1088 98

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2011 Číslo 7
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Aktuální možnosti diagnostiky a léčby litiáz
nový kurz
Autori: MUDr. Tomáš Ürge, PhD.

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