疟原虫表达的巨噬细胞迁移抑制因子同源分子的功能研究
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摘要
疟疾是世界上最严重的传染性疾病之一,全球每年有200万人死亡。一方面,疟疾的发病机理非常复杂,人们对其仍然缺乏了解。另一方面,迄今为止疟原虫逃逸宿主免疫攻击的机理还不清楚,并且目前没有任何疟原虫来源的分子被认为直接参与了对宿主免疫系统的调节。
本研究鉴定了2个来源于疟原虫的巨噬细胞迁移抑制因子同源分子:PfMIF和PyMIF,它们分别来源于恶性疟原虫(Plasmodium falciparum)和约氏疟原虫(Plasmodium yoelii)。
本研究发现,疟原虫来源的MIF分子在氨基酸序列上与MIF家族成员的一致性在27-30%,Proline 2等主要氨基酸位点高度保守,三维结构与MIF家族成员高度相似。PfMIF具有互变异构酶活性,但是与HuMIF相比活力较低。PfMIF在趋化方面具有与HuMIF相当的活性。PfMIF分子能够从体外培养的感染红细胞或者转染的哺乳动物细胞系中释放。感染恶性疟的病人血清中能检测到PfMIF分子,感染约氏疟的小鼠体内Pymif转录水平在感染后第四天开始持续升高,而血清中的PyMIF分子持续升高至30%虫血率后下降,最高浓度在40-50ng/ml。
本研究结果表明,PfMIF和PyMIF是MIF家族的两个新成员,并且可能调节宿主免疫反应、在感染过程中扮演一定角色。本研究有助于进一步理解寄生虫逃逸宿主免疫反应和感染的机理,并对这些方面的研究提供了新的思路。
Malaria is one of the most severe infectious diseases in the world and responsible for 2 millions of deaths every year.The pathogenesis of malaria is complicated,multifactor and poorly understood.And up to now,mechanisms for malaria parasite escaping from host immune attack have not been understood clearly.No malaria-derived molecule has been found in regulating the host immune response directly.
In this research work,we identified two malaria-derived MIF homologues(PfMIF and PyMIF) from Plasmodium falciparum and Plasmodium yoelii,did preliminary functional analysis and investigated their levels in both human and rodent animal.
First,we have identified the sequence and structure character of PfMIF and PyMIF molecules.The Pfmif gene includes one intron(280bp) and two exons(79bp and 272bp), of which coding a 351 nucleotides Pfmif gene and encodes a 116 amino acid polypeptide. By comparing its amino acid sequences within other 9 organisms,we found that the PfMIF protein sequence is 27%to 30%identical to the MIF family sequences as 17 residues are highly conserved especially the proline at position 2,which is critical for isomerase function of vertebrate MIF.In the evolutional tree analysis,Pfmif has relative far relationship to the mammalian and nematode MIF.The three-dimensional structures of PfMIF and PyMIF predicted by Geno3D soft were same to HuMIF to have two antiparallel a-helixes and sixβ-sheets,forming aβαβββαββstructure(1).We also identified the polymorphism of Pfmif genome in Plasmodium falciparum from 9 strains and there is no difference in exon and only a microsatellite in the middle of the single intron.
The gene sequence of Pymif identified from P.yoelii is 484bp,encoding a 351bp open reading frame.The amino acid sequence of it is highly conserved,76%identical and 91% positive to that of Pfmif.Besides these,we found 7 homologues of mif genes from other 7 Plasmodium species and there is no much different intraspecies.Specially,all these sequences have 4 cysteines and forming a typical structure of CC chemokine family:CC (-C-C).However,all of them have no C-X-X-C motif,which is the sequence feature of MIF family.
Then we have made the functional comparison of PfMIF with HuMIF in enzymatic and chemotactic activities.When we identified the tautomerase of PfMIF with three substrates,_L-Dopachrome methyl ester,Phenylpyruvate and p-Hydroxyphenylpyruvate,we found that the PfMIF was active in tautomerizing all of the substrates,but the specific activities of them were less than 5%of the HuMIF.The mutant PfMIF didn't have any measurable catalytic activity on the three substrates.For chemotaxis assay,we found that PfMIF had such a significant chemotactic activity to human monocytes as the efficient concentration was as low as 0.1ng/ml,which was greatly comparable to HuMIF. Furthermore,the chemotactic index of PfMIF was obviously not dose-dependent.
For analysis of the role of malaria derived MIF in infection,we have made some primary functional research of them in vivo and in vitro.PfMIF molecule can be detected in the supernatant of cultured PRBC in vitro without stimulated and the level of it increases from 0 to 48h after synchronization.When we transfected the pEGFP vector with Pfmif encoding region into Cos7 cells,the rPfmif molecules can also be detected in the supernatant and the secretion level increased from 24h to 72h after transfection.By PfMIF-specific sandwich ELISA,3 serum samples of Plasmodium falciparum infected-patients were confirmed to have PfMIF molecule.Besides the study of PfMIF,we have detected the transcription and expression of PyMIF in vivo.After we infected mice with P.yoelii,the mRNA of Pymif was detectable from day 4~(th),when the parasitemia was about 3%,and the up-regulation of Pymif mRNA in peripheral blood of mice remained till death.Meanwhile,the PyMIF protein was detected from day 4,enhanced each day till day 7~(th) when the parasitemia was about 30%but fall down on the day of death(day 8).
Since the first nematode-derived MIF homologue was reported in 1998,more and more parasite-derived molecules were paid attention.It provides a new conception of study the relationship between host and parasite.For malaria parasite which is in symbiosis with host during a long period of evolution,this definitely exists a mechanism that benefits for them and also did not lead the host died out.Here we first reported the primary functions of the homologues of MIF in malaria parasite in vitro and in vivo.Our results provide a new sight in escaping host immune attack and also provide a new clue in the research of malaria pathogenesis.
本研究鉴定了2个来源于疟原虫的巨噬细胞迁移抑制因子同源分子:PfMIF和PyMIF,它们分别来源于恶性疟原虫(Plasmodium falciparum)和约氏疟原虫(Plasmodium yoelii)。
本研究发现,疟原虫来源的MIF分子在氨基酸序列上与MIF家族成员的一致性在27-30%,Proline 2等主要氨基酸位点高度保守,三维结构与MIF家族成员高度相似。PfMIF具有互变异构酶活性,但是与HuMIF相比活力较低。PfMIF在趋化方面具有与HuMIF相当的活性。PfMIF分子能够从体外培养的感染红细胞或者转染的哺乳动物细胞系中释放。感染恶性疟的病人血清中能检测到PfMIF分子,感染约氏疟的小鼠体内Pymif转录水平在感染后第四天开始持续升高,而血清中的PyMIF分子持续升高至30%虫血率后下降,最高浓度在40-50ng/ml。
本研究结果表明,PfMIF和PyMIF是MIF家族的两个新成员,并且可能调节宿主免疫反应、在感染过程中扮演一定角色。本研究有助于进一步理解寄生虫逃逸宿主免疫反应和感染的机理,并对这些方面的研究提供了新的思路。
Malaria is one of the most severe infectious diseases in the world and responsible for 2 millions of deaths every year.The pathogenesis of malaria is complicated,multifactor and poorly understood.And up to now,mechanisms for malaria parasite escaping from host immune attack have not been understood clearly.No malaria-derived molecule has been found in regulating the host immune response directly.
In this research work,we identified two malaria-derived MIF homologues(PfMIF and PyMIF) from Plasmodium falciparum and Plasmodium yoelii,did preliminary functional analysis and investigated their levels in both human and rodent animal.
First,we have identified the sequence and structure character of PfMIF and PyMIF molecules.The Pfmif gene includes one intron(280bp) and two exons(79bp and 272bp), of which coding a 351 nucleotides Pfmif gene and encodes a 116 amino acid polypeptide. By comparing its amino acid sequences within other 9 organisms,we found that the PfMIF protein sequence is 27%to 30%identical to the MIF family sequences as 17 residues are highly conserved especially the proline at position 2,which is critical for isomerase function of vertebrate MIF.In the evolutional tree analysis,Pfmif has relative far relationship to the mammalian and nematode MIF.The three-dimensional structures of PfMIF and PyMIF predicted by Geno3D soft were same to HuMIF to have two antiparallel a-helixes and sixβ-sheets,forming aβαβββαββstructure(1).We also identified the polymorphism of Pfmif genome in Plasmodium falciparum from 9 strains and there is no difference in exon and only a microsatellite in the middle of the single intron.
The gene sequence of Pymif identified from P.yoelii is 484bp,encoding a 351bp open reading frame.The amino acid sequence of it is highly conserved,76%identical and 91% positive to that of Pfmif.Besides these,we found 7 homologues of mif genes from other 7 Plasmodium species and there is no much different intraspecies.Specially,all these sequences have 4 cysteines and forming a typical structure of CC chemokine family:CC (-C-C).However,all of them have no C-X-X-C motif,which is the sequence feature of MIF family.
Then we have made the functional comparison of PfMIF with HuMIF in enzymatic and chemotactic activities.When we identified the tautomerase of PfMIF with three substrates,_L-Dopachrome methyl ester,Phenylpyruvate and p-Hydroxyphenylpyruvate,we found that the PfMIF was active in tautomerizing all of the substrates,but the specific activities of them were less than 5%of the HuMIF.The mutant PfMIF didn't have any measurable catalytic activity on the three substrates.For chemotaxis assay,we found that PfMIF had such a significant chemotactic activity to human monocytes as the efficient concentration was as low as 0.1ng/ml,which was greatly comparable to HuMIF. Furthermore,the chemotactic index of PfMIF was obviously not dose-dependent.
For analysis of the role of malaria derived MIF in infection,we have made some primary functional research of them in vivo and in vitro.PfMIF molecule can be detected in the supernatant of cultured PRBC in vitro without stimulated and the level of it increases from 0 to 48h after synchronization.When we transfected the pEGFP vector with Pfmif encoding region into Cos7 cells,the rPfmif molecules can also be detected in the supernatant and the secretion level increased from 24h to 72h after transfection.By PfMIF-specific sandwich ELISA,3 serum samples of Plasmodium falciparum infected-patients were confirmed to have PfMIF molecule.Besides the study of PfMIF,we have detected the transcription and expression of PyMIF in vivo.After we infected mice with P.yoelii,the mRNA of Pymif was detectable from day 4~(th),when the parasitemia was about 3%,and the up-regulation of Pymif mRNA in peripheral blood of mice remained till death.Meanwhile,the PyMIF protein was detected from day 4,enhanced each day till day 7~(th) when the parasitemia was about 30%but fall down on the day of death(day 8).
Since the first nematode-derived MIF homologue was reported in 1998,more and more parasite-derived molecules were paid attention.It provides a new conception of study the relationship between host and parasite.For malaria parasite which is in symbiosis with host during a long period of evolution,this definitely exists a mechanism that benefits for them and also did not lead the host died out.Here we first reported the primary functions of the homologues of MIF in malaria parasite in vitro and in vivo.Our results provide a new sight in escaping host immune attack and also provide a new clue in the research of malaria pathogenesis.
引文
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1.Sun,H.W.,J.Bernhagen,R.Bucala,and E.Lolis.1996.Crystal structure at 2.6-A resolution of human macrophage migration inhibitory factor.Proc Nail Acad Sci U S A 93:5191-5196.
2.Chaiyaroj,S.C.,A.S.Rutta,K.Muenthaisong,P.Watkins,M.Na Ubol,and S.Looareesuwan.2004.Reduced levels of transforming growth factor-betal,interleukin-12 and increased migration inhibitory factor are associated with severe malaria.Acta Trop 89:319-327.
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4. Ocana-Morgner, C, M.M. Mota, and A. Rodriguez. 2003. Malaria blood stage suppression of liver stage immunity by dendritic cells. J Exp Med 197:143-151.
5. Hirunpetcharat, C, and M.F. Good. 1998. Deletion of Plasmodium berghei-specific CD4+ T cells adoptively transferred into recipient mice after challenge with homologous parasite. Proc Natl Acad Sci U S A 95: 1715-1720.
6. Hisaeda, H., Y. Maekawa, D. Iwakawa, H. Okada, K. Himeno, K. Kishihara, S. Tsukumo, and K. Yasutomo. 2004. Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells. Nat Med 10:29-30.
7. Gomez-Escobar, N., W.F. Gregory, and R.M. Maizels. 2000. Identification of tgh-2, a filarial nematode homolog of Caenorhabditis elegans daf-7 and human transforming growth factor beta, expressed in microfilarial and adult stages of Brugia malayi. Infect Immun 68:6402-6410.
8. Grencis, R.K., and G.M. Entwistle. 1997. Production of an interferon-gamma homologue by an intestinal nematode: functionally significant or interesting artefact? Parasitology 115 Suppl:S 101-106.
9. Gomez-Escobar, N., A. van den Biggelaar, and R. Maizels. 1997. A member of the TGF-beta receptor gene family in the parasitic nematode Brugia pahangi. Gene 199:101-109.
10. Davies, S.J., C.B. Shoemaker, and E.J. Pearce. 1998. A divergent member of the transforming growth factor beta receptor family from Schistosoma mansoni is expressed on the parasite surface membrane. J Biol Chem 273:11234-11240.
11. Pastrana, D.V., N. Raghavan, P. FitzGerald, S.W. Eisinger, C. Metz, R. Bucala, R.P. Schleimer, C. Bickel, and A.L. Scott. 1998. Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor. Infect Immun 66:5955-5963.
12. Zang, X., P. Taylor, J.M. Wang, D.J. Meyer, A.L. Scott, M.D. Walkinshaw, and R.M. Maizels. 2002. Homologues of human macrophage migration inhibitory factor from a parasitic nematode. Gene cloning, protein activity, and crystal structure. J Biol Chem 277: 44261-44267.
13. Wu, Z., T. Boonmars, I. Nagano, T. Nakada, and Y. Takahashi. 2003. Molecular expression and characterization of a homologue of host cytokine macrophage migration inhibitory factor from Trichinella spp. J Parasitol 89:507-515.
14. Tan, T.H., S.A. Edgerton, R. Kumari, M.S. McAlister, S.M. Roe, S. Nagl, L.H. Pearl, M.E. Selkirk, A.E. Bianco, N.F. Totty, C. Engwerda, C.A. Gray, D.J. Meyer, and S.M. Rowe. 2001. Macrophage migration inhibitory factor of the parasitic nematode Trichinella spiralis. Biochem J 357:373-383.
15. David, J.R. 1966. Delayed hypersensitivity in vitro: its mediation by cell-free substances formed by lymphoid cell-antigen interaction. Proc Natl Acad Sci U S A 56:72-77.
16. Bloom, B.R., and B. Bennett. 1966. Mechanism of a reaction in vitro associated with delayed-type hypersensitivity. Science 153:80-82.
17. Chaisavaneeyakorn, S., J.M. Moore, C. Othoro, J. Otieno, S.C. Chaiyaroj, Y.P. Shi, B.L. Nahlen, A.A. Lal, and V. Udhayakumar. 2002. Immunity to placental malaria. IV. Placental malaria is associated with up-regulation of macrophage migration inhibitory factor in intervillous blood. J Infect Dis 186:1371-1375.
18. Calandra, T., J. Bernhagen, C.N. Metz, L.A. Spiegel, M. Bacher, T. Donnelly, A. Cerami, and R. Bucala. 1995. MIF as a glucocorticoid-induced modulator of cytokine production. Nature 377:68-71.
19. Bacher, M., C.N. Metz, T. Calandra, K. Mayer, J. Chesney, M. Lohoff, D. Gemsa, T. Donnelly, and R. Bucala. 1996. An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci U S A 93:7849-7854.
20. Calandra, T., J. Bernhagen, R.A. Mitchell, and R. Bucala. 1994. The macrophage is an important and previously unrecognized source of macrophage migration inhibitory factor. J Exp Med 179:1895-1902.
21. Rossi, A.G., C. Haslett, N. Hirani, A.P. Greening, I. Rahman, C.N. Metz, R. Bucala, and S.C. Donnelly. 1998. Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma. J Clin Invest 101:2869-2874.
22. Lue, H., R. Kleemann, T. Calandra, T. Roger, and J. Bernhagen. 2002. Macrophage migration inhibitory factor (MIF): mechanisms of action and role in disease. Microbes Infect 4:449-460.
23. Mikayama, T., T. Nakano, H. Gomi, Y. Nakagawa, Y.C. Liu, M. Sato, A. Iwamatsu, Y. Ishii, W.Y. Weiser, and K. Ishizaka. 1993. Molecular cloning and functional expression of a cDNA encoding glycosylation-inhibiting factor. Proc Natl Acad Sci USA 90:10056-10060.
24. Apte, R.S., D. Sinha, E. Mayhew, G.J. Wistow, and J.Y. Niederkorn. 1998. Cutting edge: role of macrophage migration inhibitory factor in inhibiting NK. cell activity and preserving immune privilege. J Immunol 160:5693-5696.
25. Mitchell, R.A., H. Liao, J. Chesney, G. Fingerle-Rowson, J. Baugh, J. David, and R. Bucala. 2002. Macrophage migration inhibitory factor (MIF) sustains macrophage proinfiammatory function by inhibiting p53: regulatory role in the innate immune response. Proc Natl Acad Sci U S A 99:345-350.
26. Abe, R., T. Peng, J. Sailors, R. Bucala, and C.N. Metz. 2001. Regulation of the CTL response by macrophage migration inhibitory factor. J Immunol 166:747-753.
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