Role of CD40-CD40L in Mouse Severe Malaria

P Piguet

C Kan

C Vesin

A Rochat

Y Donati

C Barazzone

From the Department of Pathology, University of Geneva, Geneva, Switzerland

Accepted 2001 Apr 30.

Abstract

We explored the role of CD40-CD40L (CD154) in the severe malaria elicited by Plasmodium berghei anka infection in mice. Mortality was >90% by day 8 after infection in +/+ mice, but markedly decreased in CD40−/− or in CD40L−/− mice, as well as in +/+ mice treated with anti-CD40L monoclonal antibody. Parasitemia was similar in the different conditions. Breakdown of the blood-brain barrier was evident in infected +/+, but not in CD40−/− mice. Thrombocytopenia was less severe in CD40−/− mice than in the +/+ controls. Sequestration of macrophages in brain venules and alveolar capillaries was reduced in CD40−/− or in CD40L−/− mice, whereas sequestration of parasitized red blood cells or polymorphonuclear leukocytes in alveolar capillaries was CD40-CD40L-independent. CD40 mRNA was increased in the brain and lung of infected mice whereas CD40L was increased in the lung. Tumor necrosis factor plasma levels were similarly increased in infected +/+ or CD40−/− mice. Expression of CD54 and its mRNA levels in the brain were moderately decreased in CD40-deficient mice. Thus the mortality associated with severe malaria requires CD40-CD40L interaction that contributes to the breakdown of the blood-brain barrier, macrophage sequestration, and platelet consumption.

Abstract

Infection of mice by Plasmodium berghei anka (PbA) results, in susceptible strains, to a lethal syndrome, commonly named cerebral malaria, in which mice die 7 to 9 days after infection in a state of coma associated with neurological manifestations,^1,2 Prominent in this syndrome are a breakdown of the blood-brain barrier, microhemorrhages, and sequestration of macrophages and platelets in the cortical venules.^3-6 In addition, there is a sequestration of macrophages, polymorphonuclear leukocytes (PMNs), parasitized red blood cells (pRBCs), and platelets in other organs, notably the lung.^5-7 Hence, because this syndrome is not limited to the brain, it is also referred as severe malaria (SM). Various studies using antibodies, recombinant cytokines, or knock-out mice have shown that the secretion of tumor necrosis factor (TNF) is an important effector of the mortality of SM.^8-10 Further studies with TNF receptor (TNFR)-deficient mice have shown that mortality is dependent on the TNFR2 and not the TNFR1,¹¹ whereas the reverse is true in the majority of immunological and/or infectious diseases.¹²

TNF production is induced by an immune response, elicited by the presence of the parasite in the blood.¹³ Indeed, depletion of CD4 T lymphocyte prevents the acute mortality of PbA infection in mice, apparently by decreasing TNF production.^1,13 TNF might be responsible for some of the manifestations of SM, such as the hypoglycemia and the sequestration of cells in the microcirculation. TNF is known to increase the expression of the adhesion molecules CD54 (ICAM-1) and CD106 (VCAM) on endothelia,^14-16 which might contribute to increasing the adhesion of leukocytes and other cells and thereby disturbing the microcirculation in the brain and other organs. This pathogenic hypothesis is supported by the increased expression of CD54 and CD106 in the brain microcirculation during SM and the delayed mortality seen in mice treated with anti-CD11a mAb (LFA-1, a β2 integrin determinant)^6,17 or in CD54-deficient mice.¹⁸

CD40 is a cell receptor belonging to the TNF receptor superfamily that can modulate cell proliferation, differentiation, and death.¹⁹ Studies based on mice genetically deficient in CD40 or its ligand CD40L (CD154) as well as the use of anti-CD40L mAb have demonstrated that this system plays an important role in both humoral and cell-mediated immunity.^20,21 Presence of CD40 has been reported on B lymphocytes, platelets, mast cells, endothelial cells, and dendritic cells, whereas the source of CD40L includes T lymphocytes, macrophages, and platelets.^21,22 Response to infectious agents; rejection of allograft; autoimmune diseases, such as encephalitis, arthritis, atherosclerosis and pulmonary fibrosis, are attenuated in mice with a perturbation of the CD40-CD40L signaling.²¹ Understanding of the role of CD40-CD40L in cell-mediated immunity is presently incomplete because CD40-CD40L seems to be critical for the resistance to some intracellular parasites such as Leishmania,²³ but not others such as mycobacteria.²⁴ CD40-CD40L signaling has been reported to induce the expression of adhesion molecules CD54, CD62E, and CD106 on endothelial cells from the umbilical vein,²⁵ that might be relevant to the pathogenesis of SM, as discussed above.

In this report, we explored the role of CD40-CD40L in the course of PbA-induced SM. Mortality was completely abrogated in CD40−/−, CD40L−/−, as well as in mice treated with the anti-CD40L mAb, indicating an essential role of this system in the pathogenesis of SM.

Footnotes

Address reprint requests to Pierre F. Piguet, MD, Department of Pathology, 1 rue M. Servet, CMU, 1211 Geneva, Switzerland. pierre. .hc.eginu.enicedem@teugip

This study was supported by grant no. 31-56839.99 from the Swiss National Science Foundation.

Footnotes

References

1. Wright DH: The effect of neonatal thymectomy on the survival of golden hamsters infected with Plasmodium berghei. Br J Exp Pathol 1968, 49:379-384
2. White NJ, Ho M: Advances in parasitology. The Pathophysiology of Malaria. 1992:pp 84-173 Academic Press, New York
3. Thumwood CM, Hunt NH, Clark IA, Cowden WB: Breakdown of the blood-brain barrier in murine cerebral malaria. Parasitology 1988, 96:579-589 [[PubMed]
4. Clark IA, Macmicking JD, Gray KM, Rockett KA, Cowden WB: Malaria mimicry with tumor necrosis factorContrasts between species of murine malaria and plasmodium falciparum. Am J Pathol 1992, 140:325-336 [Google Scholar]
5. Senaldi G, Vesin C, Chang R, Grau G, Piguet PF: An effector role of neutrophils in the pathogenesis of murine severe malaria. Infect Immun 1994, 62:1144-1149
6. Favre N, Willimann K, Ryffel B, Weiss N, Imhof BA, Rudin W, Lucas R, Piguet PF: Role of ICAM-1 in the development of murine cerebral malaria. Microbes Infect 1999, 1:961-968 [[PubMed]
7. Coquelin F, Boulard Y, Mora-Silvera E, Richard F, Chabaud AG, Landau I: Final stage maturation of the erythrocytic schizonts of rodent Plasmodium in the lungs. C R Acad Sci (III) 1999, 322:55-62 [[PubMed]
8. Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P: Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 1987, 237:1210-1212 [[PubMed]
9. Grau GE, Heremans H, Piguet PF, Pointaire P, Lambert PH, Billiau A, Vassalli P: Monoclonal antibody against interferon-gamma can prevent experimental cerebral malaria and its associated overproduction of tumor necrosis factor. Proc Natl Acad Sci USA 1989, 86:5572-5574
10. Rudin W, Eugster HP, Bordmann G, Bonato J, Muller M, Yamage M, Ryffel B: Resistance to cerebral malaria in tumor necrosis factor-alpha/beta-deficient mice is associated with a reduction of intercellular adhesion molecule-1 up-regulation and T helper type 1 response. Am J Pathol 1997, 150:257-266
11. Lucas R, Juillard P, Decoster E, Redard M, Burger D, Donati Y, Giroud C, Monso Hinard C, De Kesel T, Buurman WA, et al: Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria. Eur J Immunol 1997, 27:1719-1725 [[PubMed]
12. Rothe J, Lesslauer W, Lotscher H, Lang Y, Koebel P, Kontgen F, Althage A, Zinkernagel R, Steinmetz M, Bluethman H: Mice lacking the tumor necrosis receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 1993, 364:798-802 [[PubMed]
13. Grau GE, Piguet PF, Engers HD, Louis JA, Vassalli P, Lambert PH: L3T4+ T lymphocytes play a major role in the pathogenesis of murine cerebral malaria. J Immunol 1986, 137:2348-2354 [[PubMed]
14. Lucas R, Lou JN, Juillard P, Moore M, Bluethmann H, Grau GE: Respective role of TNF receptors in the development of experimental cerebral malaria. J Neuroimmunol 1997, 72:143-148 [[PubMed]
15. Imhof BA, Dunon D: Leukocyte migration and adhesion. Adv Immunol 1995, 58:345-416 [[PubMed]
16. Ma N, Hunt NH, Madigan MC, Chan Ling T: 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 1996, 149:1745-1762
17. Grau GE, Pointaire P, Piguet PF, Vesin C, Rosen H, Stamenkovic I, Takei F, Vassalli P: Late administration of monoclonal antibody to leukocyte function antigen 1 abrogates incipient murine cerebral malaria. Eur J Immunol 1991, 21:2265-2267 [[PubMed]
18. Falanga PB, Butcher EC: Late treatment with anti-LFA-1(CD11a) antibody prevents cerebral malaria in a mouse model. Eur J Immunol 1991, 21:2259-2263 [[PubMed]
19. Grell M, Zimmermann G, Gottfried E, Chen CM, Grunwald U, Huang DCS, Lee YHW, Durkop H, Engelmann H, Scheurich P, et al: Induction of cell death by tumor necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by endogenous membrane-anchored TNF. EMBO J 1999, 18:3034-3043
20. Kawabe T, Naka T, Yoshida K, Tanaka T, Fujiwara H, Suematsu S, Yoshida N, Kishimoto T, Kikutani H: The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1994, 1:167-178 [[PubMed]
21. Grewal IS, Flawell RA: CD40 and CD154 in cell-mediated immunity. Ann Rev Immunol 1998, 16:111-135 [[PubMed]
22. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Mueller-Berghaus G, Kroczek R: CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998, 391:591-594 [[PubMed]
23. Kamanaka M, Yu P, Yasui T, Yoshida K, Kawabe T, Hori T, Kishimoto T, Kitutani H: Protective role of CD40 in Leishmania major infection at two distinct phases of cell-mediated immunity. Immunity 1996, 4:275-281 [[PubMed]
24. Campos-Neto A, Ovendale P, Bement T, Koppi TA, Fanslow WC, Rossi MA, Alderson MR: CD40 ligand is not essential for the development of cell-mediated immunity and resistance to mycobacterium tuberculosis. J Immunol 1998, 160:2037-2041 [[PubMed]
25. Yellin MJ, Brett J, Baum D, Matsushima A, Szabolcs M, Stern D, Chess L: Functional interactions of T cells with endothelial cells: the role of CD40L-CD40-mediated signals. J Exp Med 1995, 182:1857-1864
26. Castigli E, Alt FW, Davidson L, Bottaro A, Mizoguchi E, Bhan A, Geha RS: CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. Proc Natl Acad Sci USA 1994, 91:12135-12139
27. Noelle RJ, Roy M, Shepherd DM, Stamenkovic I, Ledbetter JA, Aruffo A: A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci USA 1992, 89:6550-6554
28. Piguet PF, Vesin C, Laperousaz CD, Rochat A: Role of plasminogen activators and of urokinase receptor (uPAR, CD87) in platelet kinetics in mice. Hematol J 2000, 1:199-205 [[PubMed]
29. Rolink A, Melchers F, Andersson J: The Scid but not the Rag-2 gene product is required for S mu-S epsilon heavy chain class switching. Immunity 1996, 5:319-330 [[PubMed]
30. Piguet PF, Collart MA, Grau GE, Kapanci Y, Vassalli P: Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med 1989, 170:655-663
31. Mendoza RB, Cantwell MJ, Kipps TJ: Immunostimulatory effects of a plasmid expressing CD40 ligand (CD154) on gene immunization. J Immunol 1997, 159:5777-5781 [[PubMed]
32. Grimaldi JC, Torres R, Kozak CA, Chang R, Clark EA, Howard M, Cockayne DA: Genomic structure and chromosomal mapping of the murine CD40 gene. J Immunol 1992, 149:3921-3926 [[PubMed]
33. Horley KJ, Carpeinto C, Baker B, Takei F: Molecular cloning of murine intercellular adhesion molecule (ICAM-1). EMBO J 1989, 8:2889.
34. Barazzone C, Horowitz S, Donati Y, Vesin C, Rochat A, Rodriguez I, Piguet PF: Oxygen toxicity in mouse lung: pathways to cell death. Am J Respir Cell Mol Biol 1998, 19:573-581 [[PubMed]
35. Mann HB, Whitney DR: On a test of whether one or two random variables is stochastically larger than the other. Ann Math Statist 1947, 18:50-60 [PubMed]
36. Grau GE, Piguet PF, Gretener D, Vesin C, Lambert PH: Immunopathology of thrombocytopenia in experimental malaria. Immunology 1988, 65:501-506
37. Hearn J, Rayment N, Landon DN, Katz DR, de Souza JB: Immunopathology of cerebral malaria: morphological evidence of parasite sequestration in murine brain vasculature. Infect Immun 2000, 68:5364-5376
38. Piguet PF, Laperrousaz CD, Vesin C, Donati Y: Incidence of apoptosis in the lymphoid organs of normal or malaria infected mice is decreased in CD18 and urokinase-receptor (UPAR, CD87) deficient mice. Dev Immunol 2000, 8:1-9
39. Hermsen CC, Mommers E, van de Wiel T, Sauerwein RW, Eling WM: Convulsions due to increased permeability of the blood-brain barrier in experimental cerebral malaria can be prevented by splenectomy or anti-T cell treatment. J Infect Dis 1998, 178:1225-1227 [[PubMed]
40. Kato K, Santana-Sahagun E, Rassenti LZ, Weisman MH, Tamura N, Kobayashi S, Hashimoto H, Kipps TJ: The soluble CD40 ligand sCD154 in systemic lupus erythematosus. J Clin Invest 1999, 104:947-955
41. Younes A, Snell V, Consoli U, Clodi K, Zhao S, Palmer JL, Thomas EK, Armitage RJ, Andreeff M: Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia. Br J Haematol 1998, 100:135-141 [[PubMed]
42. Dinarello CA, Thompson RC: Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today 1991, 12:404-410 [[PubMed]
43. Howard LM, Amy AJ, Vanderlugt CL, Dal Canto MC, Laman JD, Noelle RJ, Miller SD: Mechanisms of immunotherapeutic intervention by anti-CD40L (CD154) antibody in an animal model of multiple sclerosis. J Clin Invest 1999, 103:281-290
44. Schofield L, Hackett F: Signal transduction in host cells by a glycosylphatidylinositol toxin of malaria parasites. J Exp Med 1993, 177:145-153
45. Heffner JE, Repine JE, Crystal RGE (Eds): Platelets. The Lung: Scientific Foundations. New York, Raven Press, 1991, pp 617–627
46. Piguet PF, Laperousaz CD, Vesin C, Tacchini-Cottier F, Senaldi G, Grau GE: Delayed mortality and attenuated thrombocytopenia associated with severe malaria in urokinase and urokinase-receptor (UPAR, CD87) deficient mice. Infect Immun 2000, 68:3822-3829
47. Hughes M, Hayward CP, Warkentin TE, Horsewood P, Chorneyko LA, Kelton JG: Morphological analysis of microparticles generation in heparin-induced thrombocytopenia. Blood 2000, 96:188-194 [[PubMed]
48. Tacchini-Cottier F, Vesin C, Redard M, Buurman W, Piguet PF: Role of TNF receptors I and II in TNF-induced platelets consumption in mice. J Immunol 1998, 160:6182-6186 [[PubMed]
49. Stewart PA, Hayakawa K, Farrell CL: Quantitation of blood-brain barrier ultrastructure. Microsc Res Tech 1994, 27:516-527 [[PubMed]
50. Brett J, Gerlach H, Nawroth P, Steinberg S, Godman G, Stern D: Tumor necrosis factor cachectin increases permeability of endothelial cell monolayers by a mechanism involving regulatory G-proteins. J Exp Med 1989, 169:1977-1991
51. Eunhee SY, Ulich TR: Endotoxin, interleukin-1, and tumor necrosis factor cause neutrophil-dependant microvascular leakage in postcapillary venules. Am J Pathol 1992, 140:659-663