Inadequate Clearance of Translocated Bacterial Products in HIV-Infected Humanized Mice


Bacterial translocation from the gut and subsequent immune activation are hallmarks of HIV infection and are thought to determine disease progression. Intestinal barrier integrity is impaired early in acute retroviral infection, but levels of plasma lipopolysaccharide (LPS), a marker of bacterial translocation, increase only later. We examined humanized mice infected with HIV to determine if disruption of the intestinal barrier alone is responsible for elevated levels of LPS and if bacterial translocation increases immune activation. Treating uninfected mice with dextran sodium sulfate (DSS) induced bacterial translocation, but did not result in elevated plasma LPS levels. DSS-induced translocation provoked LPS elevation only when phagocytic cells were depleted with clodronate liposomes (clodrolip). Macrophages of DSS-treated, HIV-negative mice phagocytosed more LPS ex vivo than those of control mice. In HIV-infected mice, however, LPS phagocytosis was insufficient to clear the translocated LPS. These conditions allowed higher levels of plasma LPS and CD8+ cell activation, which were associated with lower CD4+/CD8+ cell ratios and higher viral loads. LPS levels reflect both intestinal barrier and LPS clearance. Macrophages are essential in controlling systemic bacterial translocation, and this function might be hindered in chronic HIV infection.


Vyšlo v časopise: Inadequate Clearance of Translocated Bacterial Products in HIV-Infected Humanized Mice. PLoS Pathog 6(4): e32767. doi:10.1371/journal.ppat.1000867
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000867

Souhrn

Bacterial translocation from the gut and subsequent immune activation are hallmarks of HIV infection and are thought to determine disease progression. Intestinal barrier integrity is impaired early in acute retroviral infection, but levels of plasma lipopolysaccharide (LPS), a marker of bacterial translocation, increase only later. We examined humanized mice infected with HIV to determine if disruption of the intestinal barrier alone is responsible for elevated levels of LPS and if bacterial translocation increases immune activation. Treating uninfected mice with dextran sodium sulfate (DSS) induced bacterial translocation, but did not result in elevated plasma LPS levels. DSS-induced translocation provoked LPS elevation only when phagocytic cells were depleted with clodronate liposomes (clodrolip). Macrophages of DSS-treated, HIV-negative mice phagocytosed more LPS ex vivo than those of control mice. In HIV-infected mice, however, LPS phagocytosis was insufficient to clear the translocated LPS. These conditions allowed higher levels of plasma LPS and CD8+ cell activation, which were associated with lower CD4+/CD8+ cell ratios and higher viral loads. LPS levels reflect both intestinal barrier and LPS clearance. Macrophages are essential in controlling systemic bacterial translocation, and this function might be hindered in chronic HIV infection.


Zdroje

1. PandreaI

SodoraDL

SilvestriG

ApetreiC

2008 Into the wild: simian immunodeficiency virus (SIV) infection in natural hosts. Trends in Immunology 29 419 428

2. DouekDC

RoedererM

KoupRA

2009 Emerging Concepts in the Immunopathogenesis of AIDS. Annual Review of Medicine 60

3. AncutaP

KamatA

KunstmanKJ

KimE-Y

AutissierP

2008 Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS ONE 3 e2516 doi:10.1371/journal.pone.0002516

4. GregsonJN

SteelA

BowerM

GazzardBG

GotchFM

2009 Elevated plasma lipopolysaccharide is not sufficient to drive natural killer cell activation in HIV-1-infected individuals. AIDS 23 29 34

5. HuntPW

BrenchleyJ

SinclairE

McCuneJM

RolandM

2008 Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis 197 126 133

6. 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

7. PapasavvasE

PistilliM

ReynoldsG

BuckiR

AzzoniL

2009 Delayed loss of control of plasma lipopolysaccharide levels after therapy interruption in chronically HIV-1-infected patients. AIDS 23 369 375

8. BrenchleyJM

PriceDA

SchackerTW

AsherTE

SilvestriG

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

9. 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

10. 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

11. MehandruS

PolesMA

Tenner-RaczK

HorowitzA

HurleyA

2004 Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med 200 761 770

12. HoferU

SpeckRF

2009 Disturbance of the gut-associated lymphoid tissue is associated with disease progression in chronic HIV infection. Semin Immunopathol 31 257 266

13. PaiardiniM

FrankI

PandreaI

ApetreiC

SilvestriG

2008 Mucosal immune dysfunction in AIDS pathogenesis. AIDS Rev 10 36 46

14. 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

15. 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

16. BrenchleyJM

PaiardiniM

KnoxKS

AsherAI

CervasiB

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

17. RaffatelluM

SantosRL

VerhoevenDE

GeorgeMD

WilsonRP

2008 Simian immunodeficiency virus-induced mucosal interleukin-17 deficiency promotes Salmonella dissemination from the gut. Nat Med 14 421 428

18. TraggiaiE

ChichaL

MazzucchelliL

BronzL

PiffarettiJ-C

2004 Development of a Human Adaptive Immune System in Cord Blood Cell-Transplanted Mice. Science 304 104 107

19. BaenzigerS

TussiwandR

SchlaepferE

MazzucchelliL

HeikenwalderM

2006 Disseminated and sustained HIV infection in CD34+ cord blood cell-transplanted Rag2−/−gamma c−/− mice. Proc Natl Acad Sci U S A 103 15951 15956

20. GorantlaS

SnellerH

WaltersL

SharpJG

PirruccelloSJ

2007 Human Immunodeficiency Virus Type 1 Pathobiology Studied in Humanized BALB/c-Rag2−/−{gamma}c−/− Mice. J Virol 81 2700 2712

21. BergesBK

WheatWH

PalmerBE

ConnickE

AkkinaR

2006 HIV-1 infection and CD4 T cell depletion in the humanized Rag2−/−gamma c−/− (RAG-hu) mouse model. Retrovirology 3 76

22. HoferU

BaenzigerS

HeikenwalderM

SchlaepferE

GehreN

2008 RAG2−/− gamma(c)−/− mice transplanted with CD34+ cells from human cord blood show low levels of intestinal engraftment and are resistant to rectal transmission of human immunodeficiency virus. J Virol 82 12145 12153

23. WirtzS

NeufertC

WeigmannB

NeurathMF

2007 Chemically induced mouse models of intestinal inflammation. Nat Protocols 2 541

24. VetuschiA

LatellaG

SferraR

CaprilliR

GaudioE

2002 Increased Proliferation and Apoptosis of Colonic Epithelial Cells in Dextran Sulfate Sodium-Induced Colitis in Rats. Digestive Diseases and Sciences 47 1447 1457

25. TessnerTG

CohnSM

SchloemannS

StensonWF

1998 Prostaglandins prevent decreased epithelial cell proliferation associated with dextran sodium sulfate injury in mice. Gastroenterology 115 874 882

26. 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

27. HopfU

RamadoriG

MollerB

GalanosC

1984 Hepatocellular clearance function of bacterial lipopolysaccharides and free lipid A in mice with endotoxic shock. Am J Emerg Med 2 13 19

28. FreudenbergMA

FreudenbergN

GalanosC

1982 Time course of cellular distribution of endotoxin in liver, lungs and kidneys of rats. Br J Exp Pathol 63 56 65

29. GitterA

BendfeldtK

SchulzkeJ

FrommM

2000 Leaks in the epithelial barrier caused by spontaneous and TNF-{alpha}-induced single-cell apoptosis. FASEB J 14 1749 1753

30. SmithAM

RahmanFZ

HayeeBH

GrahamSJ

MarksDJB

2009 Disordered macrophage cytokine secretion underlies impaired acute inflammation and bacterial clearance in Crohn's disease. J Exp Med 206 1883 1897

31. BiswasSK

Lopez-CollazoE

2009 Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends in Immunology 30 475 487

32. Adib-ConquyM

CavaillonJ-M

2002 Gamma Interferon and Granulocyte/Monocyte Colony-stimulating Factor Prevent Endotoxin Tolerance in Human Monocytes by Promoting Interleukin-1 Receptor-associated Kinase Expression and Its Association to MyD88 and Not by Modulating TLR4 Expression. Journal of Biological Chemistry 277 27927 27934

33. SchuchmannM

HermannF

HerkelJ

van der ZeeR

GallePR

2004 HSP60 and CpG-DNA-oligonucleotides differentially regulate LPS-tolerance of hepatic Kupffer cells. Immunology Letters 93 199 204

34. DalpkeAH

LehnerMD

HartungT

HeegK

2005 Differential effects of CpG-DNA in Toll-like receptor-2/-4/-9 tolerance and cross-tolerance. Immunology 116 203 212

35. DolganiucA

NorkinaO

KodysK

CatalanoD

BakisG

2007 Viral and Host Factors Induce Macrophage Activation and Loss of Toll-Like Receptor Tolerance in Chronic HCV Infection. Gastroenterology 133 1627 1636

36. LesterRT

YaoX-D

BallTB

McKinnonLR

OmangeWR

2009 HIV-1 RNA Dysregulates the Natural TLR Response to Subclinical Endotoxemia in Kenyan Female Sex-Workers. PLoS ONE 4 e5644 doi:10.1371/journal.pone.0005644

37. MuthumaniK

HwangDS

ChooAY

MayilvahananS

DayesNS

2005 HIV-1 Vpr inhibits the maturation and activation of macrophages and dendritic cells in vitro. Int Immunol 17 103 116

38. BiggsBA

HewishM

KentS

HayesK

CroweSM

1995 HIV-1 infection of human macrophages impairs phagocytosis and killing of Toxoplasma gondii. J Immunol 154 6132 6139

39. KedzierskaK

AzzamR

ElleryP

MakJ

JaworowskiA

2003 Defective phagocytosis by human monocyte/macrophages following HIV-1 infection: underlying mechanisms and modulation by adjunctive cytokine therapy. Journal of Clinical Virology 26 247 263

40. KafKedzierska

JagMak

AaeJaworowski

AbgGreenway

AaViolo

2001 nef-deleted HIV-1 inhibits phagocytosis by monocyte-derived macrophages in vitro but not by peripheral blood monocytes in vivo. AIDS 15 945 955

41. BaquiAA

MeillerTF

ZhangM

FalklerWAJr

1999 The effects of HIV viral load on the phagocytic activity of monocytes activated with lipopolysaccharide from oral microorganisms. Immunopharmacol Immunotoxicol 21 421 438

42. MarshallJD

ChehimiJ

GriG

KostmanJR

MontanerLJ

1999 The Interleukin-12-Mediated Pathway of Immune Events Is Dysfunctional in Human Immunodeficiency Virus-Infected Individuals. Blood 94 1003 1011

43. RockstrohJK

KreuzerKA

SauerbruchT

SpenglerU

1998 Protein levels of interleukin-12 p70 Holomer, its p40 chain and interferon-gamma during advancing HIV infection. Journal of Infection 37 282 286

44. ByrnesAA

HarrisDM

AtabaniSF

SabundayoBP

LanganSJ

2008 Immune activation and IL-12 production during acute/early HIV infection in the absence and presence of highly active, antiretroviral therapy. J Leukoc Biol 84 1447 1453

45. AyehunieS

SonnerborgA

Yemane-BerhanT

ZewdieDW

BrittonS

1993 Raised levels of tumour necrosis factor-alpha and neopterin, but not interferon-alpha, in serum of HIV-1-infected patients from Ethiopia. Clin Exp Immunol 91 37 42

46. von SydowM

SonnerborgA

GainesH

StrannegardO

1991 Interferon-alpha and tumor necrosis factor-alpha in serum of patients in various stages of HIV-1 infection. AIDS Res Hum Retroviruses 7 375 380

47. ShenR

RichterHE

ClementsRH

NovakL

HuffK

2009 Macrophages in Vaginal but Not Intestinal Mucosa Are Monocyte-Like and Permissive to Human Immunodeficiency Virus Type 1 Infection. J Virol 83 3258 3267

48. EmbretsonJ

ZupancicM

RibasJL

BurkeA

RaczP

1993 Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 362 359 362

49. OrensteinJM

FoxC

WahlSM

1997 Macrophages as a Source of HIV During Opportunistic Infections. Science 276 1857 1861

50. BaenzigerS

HeikenwalderM

JohansenP

SchlaepferE

HoferU

2009 Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology. Blood 113 377 388

51. 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

52. HeilF

HemmiH

HochreinH

AmpenbergerF

KirschningC

2004 Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8. Science 303 1526 1529

53. LiuZ

CumberlandWG

HultinLE

PrinceHE

DetelsR

1997 Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol 16 83 92

54. PerelsonAS

NeumannAU

MarkowitzM

LeonardJM

HoDD

1996 HIV-1 Dynamics in Vivo: Virion Clearance Rate, Infected Cell Life-Span, and Viral Generation Time. Science 271 1582 1586

55. WolthersKC

WismanGBA

OttoSA

de Roda HusmanA-M

SchaftN

1996 T Cell Telomere Length in HIV-1 Infection: No Evidence for Increased CD4+ T Cell Turnover. Science 274 1543 1547

56. CullenBR

GreeneWC

1989 Regulatory pathways governing HIV-1 replication. Cell 58 423 426

57. ZeisbergerSM

OdermattB

MartyC

Zehnder-FjallmanAH

Ballmer-HoferK

2006 Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95 272 281

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