Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections

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The chronic phase of HIV infection is marked by pathological activation of the immune system, the extent of which better predicts disease progression than either plasma viral load or CD4⁺ T cell count. Recently, translocation of microbial products from the gastrointestinal tract has been proposed as an underlying cause of this immune activation, based on indirect evidence including the detection of microbial products and specific immune responses in the plasma of chronically HIV-infected humans or SIV-infected Asian macaques. We analyzed tissues from SIV-infected rhesus macaques (RMs) to provide direct in situ evidence for translocation of microbial constituents from the lumen of the intestine into the lamina propria and to draining and peripheral lymph nodes and liver, accompanied by local immune responses in affected tissues. In chronically SIV-infected RMs this translocation is associated with breakdown of the integrity of the epithelial barrier of the gastrointestinal (GI) tract and apparent inability of lamina propria macrophages to effectively phagocytose translocated microbial constituents. By contrast, in the chronic phase of SIV infection in sooty mangabeys, we found no evidence of epithelial barrier breakdown, no increased microbial translocation and no pathological immune activation. Because immune activation is characteristic of the chronic phase of progressive HIV/SIV infections, these findings suggest that increased microbial translocation from the GI tract, in excess of capacity to clear the translocated microbial constituents, helps drive pathological immune activation. Novel therapeutic approaches to inhibit microbial translocation and/or attenuate chronic immune activation in HIV-infected individuals may complement treatments aimed at direct suppression of viral replication.

Vyšlo v časopise: Damaged Intestinal Epithelial Integrity Linked to Microbial Translocation in Pathogenic Simian Immunodeficiency Virus Infections. PLoS Pathog 6(8): e32767. doi:10.1371/journal.ppat.1001052
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1001052

Souhrn

Zdroje

1. LaneHC

1984 Polyclonal activation of B cells in homosexual men. New Engl J Med 31 536 537

2. HellersteinM

HanleyMB

CesarD

SilerS

PapageorgopoulosC

1999 Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 5 83 89

3. HazenbergMD

OttoSA

van BenthemBH

RoosMT

CoutinhoRA

2003 Persistent immune activation in HIV-1 infection is associated with progression to AIDS. Aids 17 1881 1888

4. ValdezH

LedermanMM

1997 Cytokines and cytokine therapies in HIV infection. AIDS Clin Rev 187 228

5. GiorgiJV

HultinLE

McKeatingJA

JohnsonTD

OwensB

1999 Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 179 859 870

6. SilvestriG

SodoraDL

KoupRA

PaiardiniM

O'NeilSP

2003 Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 18 441 452

7. BrenchleyJM

PriceDA

DouekDC

2006 HIV disease: fallout from a mucosal catastrophe? Nat Immunol 7 235 239

8. GrossmanZ

Meier-SchellersheimM

PaulWE

PickerLJ

2006 Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med 12 289 295

9. BrenchleyJM

PriceDA

SchackerTW

AsherTE

SilvestriG

2006 Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12 1365 1371

10. MarchettiG

BellistriGM

BorghiE

TincatiC

FerramoscaS

2008 Microbial translocation is associated with sustained failure in CD4+ T-cell reconstitution in HIV-infected patients on long-term highly active antiretroviral therapy. AIDS 22 2035 2038

11. AncutaP

KamatA

KunstmanKJ

KimEY

AutissierP

2008 Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS ONE 3 e2516

12. AnselmiA

VendrameD

RamponO

GiaquintoC

ZanchettaM

2007 Immune reconstitution in human immunodeficiency virus type 1-infected children with different virological responses to anti-retroviral therapy. Clin Exp Immunol 150 442 450

13. BalagopalA

PhilpFH

AstemborskiJ

BlockTM

MehtaA

2008 Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C. Gastroenterology

14. JiangW

LedermanMM

HuntP

SiegSF

HaleyK

2009 Plasma Levels of Bacterial DNA Correlate with Immune Activation and the Magnitude of Immune Restoration in Persons with Antiretroviral-Treated HIV Infection. J Infect Dis 199 1177 1185

15. CookeKR

OlkiewiczK

EricksonN

FerraraJL

2002 The role of endotoxin and the innate immune response in the pathophysiology of acute graft versus host disease. J Endotoxin Res 8 441 448

16. BaystonK

BaumgartnerJD

ClarkP

CohenJ

1991 Anti-endotoxin antibody for prevention of acute GVHD. Bone Marrow Transplant 8 426 427

17. LangrehrJM

MachensC

ZillE

LederK

NusslerA

2000 Bacterial translocation during graft-versus-host disease after small bowel transplantation is reduced following inhibition of inducible nitric oxide synthesis. Transplantation 69 2415 2421

18. CookeKR

GerbitzA

CrawfordJM

TeshimaT

HillGR

2001 LPS antagonism reduces graft-versus-host disease and preserves graft-versus-leukemia activity after experimental bone marrow transplantation. J Clin Invest 107 1581 1589

19. CaradonnaL

AmatiL

MagroneT

PellegrinoNM

JirilloE

2000 Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance. J Endotoxin Res 6 205 214

20. SchietromaM

CarleiF

CappelliS

AmicucciG

2006 Intestinal permeability and systemic endotoxemia after laparotomic or laparoscopic cholecystectomy. Ann Surg 243 359 363

21. SchietromaM

CarleiF

CappelliS

PescosolidoA

LygidakisNJ

2007 Effects of cholecystectomy (laparoscopic versus open) on PMN-elastase. Hepatogastroenterology 54 342 345

22. AmmoriBJ

FitzgeraldP

HawkeyP

McMahonMJ

2003 The early increase in intestinal permeability and systemic endotoxin exposure in patients with severe acute pancreatitis is not associated with systemic bacterial translocation: molecular investigation of microbial DNA in the blood. Pancreas 26 18 22

23. LiQ

EstesJD

DuanL

JessurunJ

PambuccianS

2008 Simian immunodeficiency virus-induced intestinal cell apoptosis is the underlying mechanism of the regenerative enteropathy of early infection. J Infect Dis 197 420 429

24. VeazeyRS

DeMariaM

ChalifouxLV

ShvetzDE

PauleyDR

1998 Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280 427 431

25. CecchinatoV

TrindadeC

LaurenceA

HeraudJ

BrenchleyJ

2008 Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficienty virus-infected macaques. Mucosal Immunology 1 279 288

26. BrenchleyJM

PaiardiniM

KnoxKS

AsherAI

CervasiB

2008 Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood 112 2826 2835

27. SchackerTW

NguyenPL

BeilmanGJ

WolinskyS

LarsonM

2002 Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest 110 1133 1139

28. NakanishiK

YoshimotoT

TsutsuiH

OkamuraH

2001 Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 19 423 474

29. AhmadR

SindhuST

TomaE

MorissetR

AhmadA

2002 Elevated levels of circulating interleukin-18 in human immunodeficiency virus-infected individuals: role of peripheral blood mononuclear cells and implications for AIDS pathogenesis. J Virol 76 12448 12456

30. GroismanGM

AmarM

LivneE

2002 CD10: a valuable tool for the light microscopic diagnosis of microvillous inclusion disease (familial microvillous atrophy). Am J Surg Pathol 26 902 907

31. SankaranS

GuadalupeM

ReayE

GeorgeMD

FlammJ

2005 Gut mucosal T cell responses and gene expression correlate with protection against disease in long-term HIV-1-infected nonprogressors. Proc Natl Acad Sci U S A 102 9860 9865

32. KotlerDP

GaetzHP

LangeM

KleinEB

HoltPR

1984 Enteropathy associated with the acquired immunodeficiency syndrome. Ann Intern Med 101 421 428

33. KapembwaMS

FlemingSC

SewankamboN

SerwaddaD

LucasS

1991 Altered small-intestinal permeability associated with diarrhoea in human-immunodeficiency-virus-infected Caucasian and African subjects. Clin Sci (Lond) 81 327 334

34. BjarnasonI

SharpstoneDR

FrancisN

MarkerA

TaylorC

1996 Intestinal inflammation, ileal structure and function in HIV. Aids 10 1385 1391

35. SharpstoneD

NeildP

CraneR

TaylorC

HodgsonC

1999 Small intestinal transit, absorption, and permeability in patients with AIDS with and without diarrhoea. Gut 45 70 76

36. BatmanPA

MillerAR

ForsterSM

HarrisJR

PinchingAJ

1989 Jejunal enteropathy associated with human immunodeficiency virus infection: quantitative histology. J Clin Pathol 42 275 281

37. HeiseC

MillerCJ

LacknerA

DandekarS

1994 Primary acute simian immunodeficiency virus infection of intestinal lymphoid tissue is associated with gastrointestinal dysfunction. J Infect Dis 169 1116 1120

38. BatmanPA

KotlerDP

KapembwaMS

BoothD

PottenCS

2007 HIV enteropathy: crypt stem and transit cell hyperproliferation induces villous atrophy in HIV/Microsporidia-infected jejunal mucosa. Aids 21 433 439

39. EstesJ

BakerJV

BrenchleyJM

KhorutsA

BartholdJL

2008 Collagen deposition limits immune reconstitution in the gut. J Infect Dis 198 456 464

40. SmythiesLE

SellersM

ClementsRH

Mosteller-BarnumM

MengG

2005 Human intestinal macrophages display profound inflammatory anergy despite avid phagocytic and bacteriocidal activity. J Clin Invest 115 66 75

41. PandreaI

ApetreiC

DufourJ

DillonN

BarbercheckJ

2006 Simian immunodeficiency virus SIVagm.sab infection of Caribbean African green monkeys: a new model for the study of SIV pathogenesis in natural hosts. J Virol 80 4858 4867

42. ChakrabartiLA

LewinSR

ZhangL

GettieA

LuckayA

2000 Normal T-cell turnover in sooty mangabeys harboring active simian immunodeficiency virus infection. J Virol 74 1209 1223

43. SumpterB

DunhamR

GordonS

EngramJ

HennessyM

2007 Correlates of preserved CD4(+) T cell homeostasis during natural, nonpathogenic simian immunodeficiency virus infection of sooty mangabeys: implications for AIDS pathogenesis. J Immunol 178 1680 1691

44. PandreaI

OnangaR

KornfeldC

RouquetP

BourryO

2003 High levels of SIVmnd-1 replication in chronically infected Mandrillus sphinx. Virology 317 119 127

45. PandreaIV

GautamR

RibeiroRM

BrenchleyJM

ButlerIF

2007 Acute Loss of Intestinal CD4+ T Cells Is Not Predictive of Simian Immunodeficiency Virus Virulence. J Immunol 179 3035 3046

46. GordonSN

KlattNR

BosingerSE

BrenchleyJM

MilushJM

2007 Severe Depletion of Mucosal CD4+ T Cells in AIDS-Free Simian Immunodeficiency Virus-Infected Sooty Mangabeys. J Immunol 179 3026 3034

47. EstesJD

GordonSN

ZengM

ChahroudiAM

DunhamRM

2008 Early resolution of acute immune activation and induction of PD-1 in SIV-infected sooty mangabeys distinguishes nonpathogenic from pathogenic infection in rhesus macaques. J Immunol 180 6798 6807

48. MandlJN

BarryAP

VanderfordTH

KozyrN

ChavanR

2008 Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med 14 1077 1087

49. KaoCY

ChenY

ThaiP

WachiS

HuangF

2004 IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kappaB signaling pathways. J Immunol 173 3482 3491

50. LiangSC

TanXY

LuxenbergDP

KarimR

Dunussi-JoannopoulosK

2006 Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203 2271 2279

51. KollsJK

LindenA

2004 Interleukin-17 family members and inflammation. Immunity 21 467 476

52. FavreD

LedererS

KanwarB

MaZM

ProllS

2009 Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog 5 e1000295

53. KedzierskaK

AzzamR

ElleryP

MakJ

JaworowskiA

2003 Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy. J Clin Virol 26 247 263

54. BaquiAA

Jabra-RizkMA

KelleyJI

ZhangM

FalklerWAJr

2000 Enhanced interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha production by LPS stimulated human monocytes isolated from HIV+ patients. Immunopharmacol Immunotoxicol 22 401 421

55. SchulbinH

BodeH

StockerH

SchmidtW

ZippelT

2008 Cytokine expression in the colonic mucosa of human immunodeficiency virus-infected individuals before and during 9 months of antiretroviral therapy. Antimicrob Agents Chemother 52 3377 3384

56. MillerCJ

LiQ

AbelK

KimEY

MaZM

2005 Propagation and dissemination of infection after vaginal transmission of simian immunodeficiency virus. J Virol 79 9217 9227

57. ClineAN

BessJW

PiatakMJr

LifsonJD

2005 Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS. J Med Primatol 34 303 312

58. LiQ

DuanL

EstesJD

MaZM

RourkeT

2005 Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature 434 1148 1152