Real-Time Imaging Reveals the Dynamics of Leukocyte Behaviour during Experimental Cerebral Malaria Pathogenesis
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that takes a significant toll on human life. Blockage of the brain blood vessels contributes to the clinical signs of CM, however we know little about the precise pathological events that lead to this disease. To this end, studies in Plasmodium-infected mice, that also develop a similar fatal disease, have proven useful. These studies have revealed an important role for leukocytes not so much in protecting but rather promoting pathology in the brain. To better understand leukocyte behaviour during experimental CM, we established a brain-imaging model that allows us to ‘peek’ into the brain of living mice and watch immunological events as they unfold. We found that worsening of disease was accompanied by an accumulation of monocytes in the blood vessels. Monocyte accumulation was regulated by activated CD8+ T cells but only when present in critical numbers. Monocyte depletion resulted in reduced T cell trafficking to the brain, but this did not result in improved disease outcome. Our studies reveal the orchestration of leukocyte accumulation in real time during CM, and demonstrate that CD8+ T cells play a crucial role in promoting clinical signs in this disease.
Vyšlo v časopise:
Real-Time Imaging Reveals the Dynamics of Leukocyte Behaviour during Experimental Cerebral Malaria Pathogenesis. PLoS Pathog 10(7): e32767. doi:10.1371/journal.ppat.1004236
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004236
Souhrn
Cerebral malaria (CM) is a severe complication of Plasmodium falciparum infection that takes a significant toll on human life. Blockage of the brain blood vessels contributes to the clinical signs of CM, however we know little about the precise pathological events that lead to this disease. To this end, studies in Plasmodium-infected mice, that also develop a similar fatal disease, have proven useful. These studies have revealed an important role for leukocytes not so much in protecting but rather promoting pathology in the brain. To better understand leukocyte behaviour during experimental CM, we established a brain-imaging model that allows us to ‘peek’ into the brain of living mice and watch immunological events as they unfold. We found that worsening of disease was accompanied by an accumulation of monocytes in the blood vessels. Monocyte accumulation was regulated by activated CD8+ T cells but only when present in critical numbers. Monocyte depletion resulted in reduced T cell trafficking to the brain, but this did not result in improved disease outcome. Our studies reveal the orchestration of leukocyte accumulation in real time during CM, and demonstrate that CD8+ T cells play a crucial role in promoting clinical signs in this disease.
Zdroje
1. World Health Organisation. WHO Global Malaria Program: World Malaria Report 2013. WHO Press. Geneva, Switzerland.
2. TurnerGD, MorrisonH, JonesM, DavisTM, LooareesuwanS, et al. (1994) An immunohistochemical study of the pathology of fatal malaria. Evidence for widespread endothelial activation and a potential role for intercellular adhesion molecule-1 in cerebral sequestration. Am J Pathol 145: 1057–1069.
3. ColtelN, CombesV, HuntNH, GrauGE (2004) Cerebral malaria – a neurovascular pathology with many riddles still to be solved. Curr Neurovasc Res 1: 91–110.
4. FernandezV, WahlgrenM (2002) Rosetting and autoagglutination in Plasmodium falciparum. Chem Immunol 80: 163–187.
5. DondorpAM, PongponratnE, WhiteNJ (2004) Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology. Acta Trop 89: 309–317.
6. PenetM-F, ViolaA, Confort-GounyS, Le FurY, DuhamelG, et al. (2005) Imaging Experimental Cerebral Malaria In Vivo: Significant Role of Ischemic Brain Edema. J Neurosci 25: 7352–7358.
7. BeareNA, HardingSP, TaylorTE, LewallenS, MolyneuxME (2009) Perfusion abnormalities in children with cerebral malaria and malarial retinopathy. J Infect Dis 199: 263–271.
8. von Zur MuhlenC, SibsonNR, PeterK, CampbellSJ, WilainamP, et al. (2008) A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI. J Clin Invest 118: 1198–1207.
9. HermsenC, van de WielT, MommersE, SauerweinR, ElingW (1997) Depletion of CD4+ or CD8+ T-cells prevents Plasmodium berghei induced cerebral malaria in end-stage disease. Parasitology 114 (Pt 1) 7–12.
10. de SouzaJB, HafallaJC, RileyEM, CouperKN (2010) Cerebral malaria: why experimental murine models are required to understand the pathogenesis of disease. Parasitology 137: 755–772.
11. WykesMN, GoodMF (2009) What have we learnt from mouse models for the study of malaria? Eur J Immunol 39: 2004–2007.
12. HuntNH, GrauGE (2003) Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria. Trends Immunol 24: 491–499.
13. NitcheuJ, BonduelleO, CombadiereC, TefitM, SeilheanD, et al. (2003) Perforin-dependent brain-infiltrating cytotoxic CD8+ T lymphocytes mediate experimental cerebral malaria pathogenesis. J Immunol 170: 2221–2228.
14. BelnoueE, KayibandaM, DescheminJ-C, ViguierM, MackM, et al. (2003) CCR5 deficiency decreases susceptibility to experimental cerebral malaria. Blood 101: 4253–4259.
15. BelnoueE, KayibandaM, VigarioAM, DescheminJC, van RooijenN, et al. (2002) On the pathogenic role of brain-sequestered alphabeta CD8+ T cells in experimental cerebral malaria. J Immunol 169: 6369–6375.
16. NieCQ, BernardNJ, NormanMU, AmanteFH, LundieRJ, et al. (2009) IP-10-mediated T cell homing promotes cerebral inflammation over splenic immunity to malaria infection. PLoS Pathog 5: e1000369.
17. CabralesP, CarvalhoLJ (2010) Intravital microscopy of the mouse brain microcirculation using a closed cranial window. J Vis Exp Nov 18; (45) p11 2184.
18. GermainRN, MillerMJ, DustinML, NussenzweigMC (2006) Dynamic imaging of the immune system: progress, pitfalls and promise. Nat Rev Immunol 6: 497–507.
19. FinleyRW, MackeyLJ, LambertPH (1982) Virulent P. berghei malaria: prolonged survival and decreased cerebral pathology in cell-dependent nude mice. J Immunol 129: 2213–2218.
20. YanezDM, ManningDD, CooleyAJ, WeidanzWP, van der HeydeHC (1996) Participation of lymphocyte subpopulations in the pathogenesis of experimental murine cerebral malaria. J Immunol 157: 1620–1624.
21. HaqueA, BestSE, UnossonK, AmanteFH, de LabastidaF, et al. (2011) Granzyme B expression by CD8+ T cells is required for the development of experimental cerebral malaria. J Immunol 186: 6148–6156.
22. TaniguchiT, TachikawaS, KandaY, KawamuraT, Tomiyama-MiyajiC, et al. (2007) Malaria protection in beta 2-microglobulin-deficient mice lacking major histocompatibility complex class I antigens: essential role of innate immunity, including gammadelta T cells. Immunology 122: 514–521.
23. PotterS, ChaudhriG, HansenA, HuntNH (1999) Fas and perforin contribute to the pathogenesis of murine cerebral malaria. Redox Report 4: 333–335.
24. LundieRJ, de Koning-WardTF, DaveyGM, NieCQ, HansenDS, et al. (2008) Blood-stage Plasmodium infection induces CD8+ T lymphocytes to parasite-expressed antigens, largely regulated by CD8alpha+ dendritic cells. Proc Natl Acad Sci U S A 105: 14509–14514.
25. PaisTF, ChatterjeeS (2005) Brain macrophage activation in murine cerebral malaria precedes accumulation of leukocytes and CD8(+) T cell proliferation. J Neuroimmunol 163: 73–83.
26. BagotS, NogueiraF, ColletteA, do RosarioV, LemonierF, et al. (2004) Comparative study of brain CD8+ T cells induced by sporozoites and those induced by blood-stage Plasmodium berghei ANKA involved in the development of cerebral malaria. Infect Immun 72: 2817–2826.
27. PaiS, DanneKJ, QinJ, CavanaghLL, SmithA, et al. (2012) Visualizing leukocyte trafficking in the living brain with 2-photon intravital microscopy. Front Cell Neurosci 6: 67.
28. NeillAL, HuntNH (1995) Effects of endotoxin and dexamethasone on cerebral malaria in mice. Parasitology 111 (Pt 4) 443–454.
29. CurfsJH, SchettersTP, HermsenCC, JerusalemCR, van ZonAA, et al. (1989) Immunological aspects of cerebral lesions in murine malaria. Clin Exp Immunol 75: 136–140.
30. SasmonoRT, OceandyD, PollardJW, TongW, PavliP, et al. (2003) A macrophage colony-stimulating factor receptor-green fluorescent protein transgene is expressed throughout the mononuclear phagocyte system of the mouse. Blood 101: 1155–1163.
31. SasmonoRT, EhrnspergerA, CronauSL, RavasiT, KandaneR, et al. (2007) Mouse neutrophilic granulocytes express mRNA encoding the macrophage colony-stimulating factor receptor (CSF-1R) as well as many other macrophage-specific transcripts and can transdifferentiate into macrophages in vitro in response to CSF-1. J Leukoc Biol 82: 111–123.
32. MombaertsP, IacominiJ, JohnsonRS, HerrupK, TonegawaS, et al. (1992) RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68: 869–877.
33. AmanteFH, HaqueA, StanleyAC, RiveraFdL, RandallLM, et al. (2010) Immune-Mediated Mechanisms of Parasite Tissue Sequestration during Experimental Cerebral Malaria. J Immunol 185: 3632–3642.
34. NgLG, QinJS, RoedigerB, WangY, JainR, et al. (2011) Visualizing the neutrophil response to sterile tissue injury in mouse dermis reveals a three-phase cascade of events. J Invest Dermatol 131: 2058–2068.
35. WeningerW, UlfmanLH, ChengG, SouchkovaN, QuackenbushEJ, et al. (2000) Specialized contributions by alpha(1,3)-fucosyltransferase-IV and FucT-VII during leukocyte rolling in dermal microvessels. Immunity 12: 665–676.
36. Carvalho-TavaresJ, HickeyMJ, HutchisonJ, MichaudJ, SutcliffeIT, et al. (2000) A role for platelets and endothelial selectins in tumor necrosis factor-alpha-induced leukocyte recruitment in the brain microvasculature. Circ Res 87: 1141–1148.
37. GrangerDN, KubesP (1994) The microcirculation and inflammation: modulation of leukocyte-endothelial cell adhesion. J Leukoc Biol 55: 662–675.
38. KimJV, KangSS, DustinML, McGavernDB (2009) Myelomonocytic cell recruitment causes fatal CNS vascular injury during acute viral meningitis. Nature 457: 191–195.
39. SchlueterAJ, GlasgowJK (2006) Phenotypic comparison of multiple monocyte-related populations in murine peripheral blood and bone marrow. Cytometry A 69: 281–290.
40. GrauGE, FajardoLF, PiguetPF, AlletB, LambertPH, et al. (1987) Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 237: 1210–1212.
41. MempelTR, PittetMJ, KhazaieK, WeningerW, WeisslederR, et al. (2006) Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25: 129–141.
42. AbtinA, JainR, MitchellAJ, RoedigerB, BrzoskaAJ, et al. (2014) Perivascular macrophages mediate neutrophil recruitment during bacterial skin infection. Nat Immunol 15: 45–53.
43. BaptistaFG, PamplonaA, PenaAC, MotaMM, PiedS, et al. (2010) Accumulation of Plasmodium-infected red blood cells in the brain is crucial for the development of cerebral malaria in mice. Infect Immun Sep 78 (9) 4033–9.
44. MiuJ, MitchellAJ, MullerM, CarterSL, MandersPM, et al. (2008) Chemokine gene expression during fatal murine cerebral malaria and protection due to CXCR3 deficiency. J Immunol 180: 1217–1230.
45. SunderkotterC, NikolicT, DillonMJ, Van RooijenN, StehlingM, et al. (2004) Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol 172: 4410–4417.
46. WhiteNJ, TurnerGDH, MedanaIM, DondorpAM, DayNPJ (2010) The murine cerebral malaria phenomenon. Trends in Parasitology 26: 11–15.
47. CraigAG, GrauGE, JanseC, KazuraJW, MilnerD, et al. (2012) The role of animal models for research on severe malaria. PLoS Pathog Feb; 8 (2) e1002401.
48. OngPK, MeaysD, FrangosJA, CarvalhoLJ (2013) A chronic scheme of cranial window preparation to study pial vascular reactivity in murine cerebral malaria. Microcirculation July;20 (5) 394–404.
49. HoltmaatA, BonhoefferT, ChowDK, ChuckowreeJ, De PaolaV, et al. (2009) Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nat Protoc 4: 1128–1144.
50. YangG, PanF, ParkhurstCN, GrutzendlerJ, GanWB (2010) Thinned-skull cranial window technique for long-term imaging of the cortex in live mice. Nat Protoc 5: 201–208.
51. FrevertU, NacerA, CabreraM, MovilaA, LeberlM (2014 Feb) Imaging Plasmodium immunobiology in the liver, brain, and lung. Parasitol Int 63: 171–186.
52. BoubouMI, ColletteA, VoegtleD, MazierD, CazenavePA, et al. (1999) T cell response in malaria pathogenesis: selective increase in T cells carrying the TCR V(beta)8 during experimental cerebral malaria. Int Immunol 11: 1553–1562.
53. ClaserC, MalleretB, GunSY, WongAYW, ChangZW, et al. (2011) CD8+ T Cells and IFN-g Mediate the Time-Dependent Accumulation of Infected Red Blood Cells in Deep Organs during Experimental Cerebral Malaria. PLoS ONE Apr 11, 6 (4) e18720.
54. PorcherieA, MathieuC, PeronetR, SchneiderE, ClaverJ, et al. (2011) Critical role of the neutrophil-associated high-affinity receptor for IgE in the pathogenesis of experimental cerebral malaria. The Journal of Experimental Medicine 208: 2225–2236.
55. FalangaP, ButcherE (1991) Late treatment with anti-LFA-1 (CD11a) antibody prevents cerebral malaria in a mouse model. Eur J Immunol 21: 2259–2263.
56. GrauG, PointaireP, PiguetPF, VesinC, RosenH, et al. (1991) Late administration of monoclonal antibody to leukocyte function-antigen 1 abrogates incipient murine cerebral malaria. Eur J Immunol 21: 2265–2267.
57. CabralesP, ZaniniGM, MeaysD, FrangosJA, CarvalhoLJM (2010) Murine Cerebral Malaria Is Associated with a Vasospasm-Like Microcirculatory Dysfunction, and Survival upon Rescue Treatment Is Markedly Increased by Nimodipine. Am J Pathol Mar; 176 (3) 1306–15.
58. SchofieldL, GrauGE (2005) Immunological processes in malaria pathogenesis. Nat Rev Immunol 5: 722–735.
59. NacerA, MovilaA, BaerK, MikolajczakSA, KappeSH, et al. (2012) Neuroimmunological blood brain barrier opening in experimental cerebral malaria. PLoS Pathog 8 (10) e1002982.
60. CampanellaGS, TagerAM, El KhouryJK, ThomasSY, AbrazinskiTA, et al. (2008) Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria. Proc Natl Acad Sci U S A 105: 4814–4819.
61. HowlandSW, PohCM, GunSY, ClaserC, MalleretB, et al. (2013) Brain microvessel cross-presentation is a hallmark of experimental cerebral malaria. EMBO Mol Med 5: 916–931.
62. McQuillanJA, MitchellAJ, HoYF, CombesV, BallHJ, et al. (2011) Coincident parasite and CD8 T cell sequestration is required for development of experimental cerebral malaria. Int J Parasitol 41: 155–163.
63. HansenDS, BernardNJ, NieCQ, SchofieldL (2007) NK cells stimulate recruitment of CXCR3+ T cells to the brain during Plasmodium berghei-mediated cerebral malaria. J Immunol 178: 5779–5788.
64. Villegas-MendezA, GreigR, ShawTN, de SouzaJB, Gwyer FindlayE, et al. (2012) IFN-γ–Producing CD4+ T Cells Promote Experimental Cerebral Malaria by Modulating CD8+ T Cell Accumulation within the Brain. The Journal of Immunology 189: 968–979.
65. OakleyMS, SahuBR, Lotspeich-ColeL, SolankiNR, MajamV, et al. (2013) The Transcription Factor T-bet Regulates Parasitemia and Promotes Pathogenesis during Plasmodium berghei ANKA Murine Malaria. J Immunol Nov1;19 (9) 4699–708.
66. MaN, HuntNH, MadiganMC, Chan-LingT (1996) Correlation between enhanced vascular permeability, up-regulation of cellular adhesion molecules and monocyte adhesion to the endothelium in the retina during the development of fatal murine cerebral malaria. Am J Pathol 149: 1745–1762.
67. SrivastavaK, FieldDJ, AggreyA, YamakuchiM, MorrellCN (2010) Platelet factor 4 regulation of monocyte KLF4 in experimental cerebral malaria. PLoS One May 3, 5 (5) e10413.
68. BelnoueE, CostaFT, VigarioAM, VozaT, GonnetF, et al. (2003) Chemokine receptor CCR2 is not essential for the development of experimental cerebral malaria. Infect Immun 71: 3648–3651.
69. PivaL, TetlakP, ClaserC, KarjalainenK, ReniaL, et al. (2012) Cutting edge: Clec9A+ dendritic cells mediate the development of experimental cerebral malaria. J Immunol 189: 1128–1132.
70. RandallLM, AmanteFH, ZhouY, StanleyAC, HaqueA, et al. (2008) Cutting edge: selective blockade of LIGHT-lymphotoxin beta receptor signaling protects mice from experimental cerebral malaria caused by Plasmodium berghei ANKA. J Immunol 181: 7458–7462.
71. WangJ, FuYX (2004) The role of LIGHT in T cell-mediated immunity. Immunol Res 30: 201–214.
72. WeiserS, MiuJ, BallHJ, HuntNH (2007) Interferon-gamma synergises with tumour necrosis factor and lymphotoxin-alpha to enhance the mRNA and protein expression of adhesion molecules in mouse brain endothelial cells. Cytokine 37: 84–91.
73. ThumwoodCM, HuntNH, ClarkIA, CowdenWB (1988) Breakdown of the blood-brain barrier in murine cerebral malaria. Parasitology 96 (Pt 3) 579–589.
74. FaustN, VarasF, KellyLM, HeckS, GrafT (2000) Insertion of enhanced green fluorescent protein into the lysozyme gene creates mice with green fluorescent granulocytes and macrophages. Blood 96: 719–726.
75. MombaertsP, IacominiJ, JohnsonRS, HerrupK, TonegawaS, et al. (1992) RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68: 869–877.
76. GrauGE, PiguetPF, EngersHD, LouisJA, VassalliP, et al. (1986) L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria. J Immunol 137: 2348–2354.
77. KondermannC (2007) Blood vessel classification into arteries and veins in retinal images. Medical Imaging 2007: Image Processing 651247.
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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