Viral Capsid Is a Pathogen-Associated Molecular Pattern in Adenovirus Keratitis


Human adenovirus (HAdV) infection of the human eye, in particular serotypes 8, 19 and 37, induces the formation of corneal subepithelial leukocytic infiltrates. Using a unique mouse model of adenovirus keratitis, we studied the role of various virus-associated molecular patterns in subsequent innate immune responses of resident corneal cells to HAdV-37 infection. We found that neither viral DNA, viral gene expression, or viral replication was necessary for the development of keratitis. In contrast, empty viral capsid induced keratitis and a chemokine profile similar to intact virus. Transfected viral DNA did not induce leukocyte infiltration despite CCL2 expression similar to levels in virus infected corneas. Mice without toll-like receptor 9 (Tlr9) signaling developed clinical keratitis upon HAdV-37 infection similar to wild type mice, although the absolute numbers of activated monocytes in the cornea were less in Tlr9−/− mice. Virus induced leukocytic infiltrates and chemokine expression in mouse cornea could be blocked by treatment with a peptide containing arginine glycine aspartic acid (RGD). These results demonstrate that adenovirus infection of the cornea induces chemokine expression and subsequent infiltration by leukocytes principally through RGD contact between viral capsid and the host cell, possibly through direct interaction between the viral capsid penton base and host cell integrins.


Vyšlo v časopise: Viral Capsid Is a Pathogen-Associated Molecular Pattern in Adenovirus Keratitis. PLoS Pathog 6(4): e32767. doi:10.1371/journal.ppat.1000841
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000841

Souhrn

Human adenovirus (HAdV) infection of the human eye, in particular serotypes 8, 19 and 37, induces the formation of corneal subepithelial leukocytic infiltrates. Using a unique mouse model of adenovirus keratitis, we studied the role of various virus-associated molecular patterns in subsequent innate immune responses of resident corneal cells to HAdV-37 infection. We found that neither viral DNA, viral gene expression, or viral replication was necessary for the development of keratitis. In contrast, empty viral capsid induced keratitis and a chemokine profile similar to intact virus. Transfected viral DNA did not induce leukocyte infiltration despite CCL2 expression similar to levels in virus infected corneas. Mice without toll-like receptor 9 (Tlr9) signaling developed clinical keratitis upon HAdV-37 infection similar to wild type mice, although the absolute numbers of activated monocytes in the cornea were less in Tlr9−/− mice. Virus induced leukocytic infiltrates and chemokine expression in mouse cornea could be blocked by treatment with a peptide containing arginine glycine aspartic acid (RGD). These results demonstrate that adenovirus infection of the cornea induces chemokine expression and subsequent infiltration by leukocytes principally through RGD contact between viral capsid and the host cell, possibly through direct interaction between the viral capsid penton base and host cell integrins.


Zdroje

1. Centers for Disease Control M 2007 Acute respiratory disease associated with adenovirus serotype 14–four states, 2006–2007. MMWR Morb Mortal Wkly Rep 56 1181 1184

2. HierholzerJC

1992 Adenoviruses in the immunocompromised host. Clin Microbiol Rev 5 262 274

3. KojaoghlanianT

FlomenbergP

HorwitzMS

2003 The impact of adenovirus infection on the immunocompromised host. Rev Med Virol 13 155 171

4. ButtAL

ChodoshJ

2006 Adenoviral keratoconjunctivitis in a tertiary care eye clinic. Cornea 25 199 202

5. NatarajanK

RajalaMS

ChodoshJ

2003 Corneal IL-8 expression following adenovirus infection is mediated by c-Src activation in human corneal fibroblasts. J Immunol 170 6234 6243

6. XiaoJ

ChodoshJ

2005 JNK regulates MCP-1 expression in adenovirus type 19-infected human corneal fibroblasts. Invest Ophthalmol Vis Sci 46 3777 3782

7. RajaiyaJ

XiaoJ

RajalaRV

ChodoshJ

2008 Human adenovirus type 19 infection of corneal cells induces p38 MAPK-dependent interleukin-8 expression. Virol J 5 17

8. MuruveDA

2004 The innate immune response to adenovirus vectors. Hum Gene Ther 15 1157 1166

9. ZhuJ

HuangX

YangY

2007 Innate immune response to adenoviral vectors is mediated by both Toll-like receptor-dependent and -independent pathways. J Virol 81 3170 3180

10. MuruveDA

BarnesMJ

StillmanIE

LibermannTA

1999 Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther 10 965 976

11. Iacobelli-MartinezM

NemerowGR

2007 Preferential activation of Toll-like receptor nine by CD46-utilizing adenoviruses. J Virol 81 1305 1312

12. ParkerAL

WaddingtonSN

NicolCG

ShayakhmetovDM

BuckleySM

2006 Multiple vitamin K-dependent coagulation zymogens promote adenovirus-mediated gene delivery to hepatocytes. Blood 108 2554 2561

13. WaddingtonSN

McVeyJH

BhellaD

ParkerAL

BarkerK

2008 Adenovirus serotype 5 hexon mediates liver gene transfer. Cell 132 397 409

14. AkiraS

UematsuS

TakeuchiO

2006 Pathogen recognition and innate immunity. Cell 124 783 801

15. NociariM

OcheretinaO

SchogginsJW

Falck-PedersenE

2007 Sensing infection by adenovirus: Toll-like receptor-independent viral DNA recognition signals activation of the interferon regulatory factor 3 master regulator. J Virol 81 4145 4157

16. MuruveDA

PetrilliV

ZaissAK

WhiteLR

ClarkSA

2008 The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature 452 103 107

17. HaasT

MetzgerJ

SchmitzF

HeitA

MullerT

2008 The DNA sugar backbone 2′ deoxyribose determines toll-like receptor 9 activation. Immunity 28 315 323

18. HemmiH

TakeuchiO

KawaiT

KaishoT

SatoS

2000 A Toll-like receptor recognizes bacterial DNA. Nature 408 740 745

19. TakaokaA

WangZ

ChoiMK

YanaiH

NegishiH

2007 DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448 501 505

20. IshiiKJ

CobanC

KatoH

TakahashiK

ToriiY

2006 A Toll-like receptor-independent antiviral response induced by double-stranded B-form DNA. Nat Immunol 7 40 48

21. StetsonDB

MedzhitovR

2006 Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24 93 103

22. CerulloV

SeilerMP

ManeV

Brunetti-PierriN

ClarkeC

2007 Toll-like receptor 9 triggers an innate immune response to helper-dependent adenoviral vectors. Mol Ther 15 378 385

23. FejerG

DrechselL

LieseJ

SchleicherU

RuzsicsZ

2008 Key role of splenic myeloid DCs in the IFN-alphabeta response to adenoviruses in vivo. PLoS Pathog 4 e1000208 doi:10.1371/journal.ppat.1000208

24. BergelsonJM

CunninghamJA

DroguettG

Kurt-JonesEA

KrithivasA

1997 Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275 1320 1323

25. TamaniniA

NicolisE

BonizzatoA

BezzerriV

MelottiP

2006 Interaction of adenovirus type 5 fiber with the coxsackievirus and adenovirus receptor activates inflammatory response in human respiratory cells. J Virol 80 11241 11254

26. WickhamTJ

MathiasP

ChereshDA

NemerowGR

1993 Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell 73 309 319

27. CashmanSM

MorrisDJ

Kumar-SinghR

2004 Adenovirus type 5 pseudotyped with adenovirus type 37 fiber uses sialic acid as a cellular receptor. Virology 324 129 139

28. LiuQ

MuruveDA

2003 Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther 10 935 940

29. StilwellJL

McCartyDM

NegishiA

SuperfineR

SamulskiRJ

2003 Development and characterization of novel empty adenovirus capsids and their impact on cellular gene expression. J Virol 77 12881 12885

30. HigginbothamJN

SethP

BlaeseRM

RamseyWJ

2002 The release of inflammatory cytokines from human peripheral blood mononuclear cells in vitro following exposure to adenovirus variants and capsid. Hum Gene Ther 13 129 141

31. Di PaoloNC

MiaoEA

IwakuraY

Murali-KrishnaK

AderemA

2009 Virus binding to a plasma membrane receptor triggers interleukin-1 alpha-mediated proinflammatory macrophage response in vivo. Immunity 31 110 121

32. MullerLJ

PelsL

VrensenGF

1995 Novel aspects of the ultrastructural organization of human corneal keratocytes. Invest Ophthalmol Vis Sci 36 2557 2567

33. HamrahP

LiuY

ZhangQ

DanaMR

2003 The corneal stroma is endowed with a significant number of resident dendritic cells. Invest Ophthalmol Vis Sci 44 581 589

34. Brissette-StorkusCS

ReynoldsSM

LepistoAJ

HendricksRL

2002 Identification of a novel macrophage population in the normal mouse corneal stroma. Invest Ophthalmol Vis Sci 43 2264 2271

35. YamagamiS

EbiharaN

UsuiT

YokooS

AmanoS

2006 Bone marrow-derived cells in normal human corneal stroma. Arch Ophthalmol 124 62 69

36. TrelstadRL

CoulombreAJ

1971 Morphogenesis of the collagenous stroma in the chick cornea. J Cell Biol 50 840 858

37. ChodoshJ

AstleyRA

ButlerMG

KennedyRC

2000 Adenovirus keratitis: a role for interleukin-8. Invest Ophthalmol Vis Sci 41 783 789

38. CubittCL

LauschRN

OakesJE

1995 Differences in interleukin-6 gene expression between cultured human corneal epithelial cells and keratocytes. Invest Ophthalmol Vis Sci 36 330 336

39. ChintakuntlawarAV

AstleyR

ChodoshJ

2007 Adenovirus type 37 keratitis in the C57BL/6J mouse. Invest Ophthalmol Vis Sci 48 781 788

40. GordonS

TaylorPR

2005 Monocyte and macrophage heterogeneity. Nat Rev Immunol 5 953 964

41. MatsushimaK

LarsenCG

DuBoisGC

OppenheimJJ

1989 Purification and characterization of a novel monocyte chemotactic and activating factor produced by a human myelomonocytic cell line. J Exp Med 169 1485 1490

42. BozicCR

KolakowskiLFJr

GerardNP

Garcia-RodriguezC

von Uexkull-GuldenbandC

1995 Expression and biologic characterization of the murine chemokine KC. J Immunol 154 6048 6057

43. GinsbergHS

MoldawerLL

SehgalPB

RedingtonM

KilianPL

1991 A mouse model for investigating the molecular pathogenesis of adenovirus pneumonia. Proc Natl Acad Sci U S A 88 1651 1655

44. KrugA

FrenchAR

BarchetW

FischerJA

DzionekA

2004 TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. Immunity 21 107 119

45. KrugA

LukerGD

BarchetW

LeibDA

AkiraS

2004 Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood 103 1433 1437

46. LundJ

SatoA

AkiraS

MedzhitovR

IwasakiA

2003 Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med 198 513 520

47. HuangX

BarrettRP

McClellanSA

HazlettLD

2005 Silencing Toll-like receptor-9 in Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 46 4209 4216

48. WuestT

AustinBA

UematsuS

ThapaM

AkiraS

2006 Intact TRL 9 and type I interferon signaling pathways are required to augment HSV-1 induced corneal CXCL9 and CXCL10. J Neuroimmunol 179 46 52

49. BruderJT

KovesdiI

1997 Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression. J Virol 71 398 404

50. AlcornMJ

BoothJL

CoggeshallKM

MetcalfJP

2001 Adenovirus type 7 induces interleukin-8 production via activation of extracellular regulated kinase 1/2. J Virol 75 6450 6459

51. ChintakuntlawarAV

ChodoshJ

2009 Chemokine CXCL1/KC and its receptor CXCR2 are responsible for neutrophil chemotaxis in adenoviral keratitis. J Interferon Cytokine Res 29 657 666

52. RebetzJ

NaM

SuC

HolmqvistB

EdqvistA

2009 Fiber mediated receptor masking in non-infected bystander cells restricts adenovirus cell killing effect but promotes adenovirus host co-existence. PLoS ONE 4 e8484 doi:10.1371/journal.pone.0008484

53. RobinsonCM

ShariatiF

GillaspyAF

DyerDW

ChodoshJ

2008 Genomic and bioinformatics analysis of human adenovirus type 37: new insights into corneal tropism. BMC Genomics 9 213

54. NemerowGR

StewartPL

1999 Role of alpha(v) integrins in adenovirus cell entry and gene delivery. Microbiol Mol Biol Rev 63 725 734

55. CotterMJ

ZaissAK

MuruveDA

2005 Neutrophils interact with adenovirus vectors via Fc receptors and complement receptor 1. J Virol 79 14622 14631

56. XiaoJ

NatarajanK

RajalaMS

AstleyRA

RamadanRT

2005 Vitronectin: a possible determinant of adenovirus type 19 tropism for human corneal epithelium. Am J Ophthalmol 140 363 369

57. LeopoldPL

FerrisB

GrinbergI

WorgallS

HackettNR

1998 Fluorescent virions: dynamic tracking of the pathway of adenoviral gene transfer vectors in living cells. Hum Gene Ther 9 367 378

58. MohanRR

SchultzGS

HongJW

MohanRR

WilsonSE

2003 Gene transfer into rabbit keratocytes using AAV and lipid-mediated plasmid DNA vectors with a lamellar flap for stromal access. Exp Eye Res 76 373 383

Štítky
Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

Článok vyšiel v časopise

PLOS Pathogens


2010 Číslo 4
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz
Autori: doc. MUDr. Martina Doubková, Ph.D.

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