恶性疟原虫RIFIN蛋白的结构和功能研究进展

doi:10.12140/j.issn.1000-7423.2021.02.019

摘要/Abstract

摘要：

恶性疟原虫感染易引起重症疟疾甚至导致死亡,在其致病机制中,变异表面抗原家族的重复散布蛋白家族（RIFIN）起了重要作用,它们能介导微静脉血管系统中感染红细胞的黏附和玫瑰花环形成,从而阻断血流,堵塞血管导致重症疟疾。RIFIN在感染红细胞的表面表达,是重要的免疫靶点之一,但由于重复散布的基因家族rif的多基因性和基因多态性,RIFIN能够逃避免疫系统的攻击。同时,RIFIN与免疫细胞表面抑制性受体白细胞免疫球蛋白样受体B1（LILRB1）、白细胞相关免疫球蛋白样受体 1（LAIR1）等的结合能下调免疫反应而达到免疫逃避的目的。近年来,随着对恶性疟分子机制研究的日趋深入,研发能够诱导产生有效保护性免疫的疫苗成为预防疟疾、实现疟疾消除计划的关键。本文描述了恶性疟原虫RIFIN的结构,并强调了它们在重症疟疾中的作用以及相关的免疫和疫苗研究进展。

关键词: 恶性疟原虫, RIFIN, 黏附, 玫瑰花环, 免疫逃避

Abstract:

Plasmodium falciparum infection can result in severe malaria and even death. The P. falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), one of the variant surface antigen families, can mediate the adhesion of infected erythrocytes and the formation of rosettes in the venous vascular system, thereby blocking blood flow and leading to severe malaria. RIFINs are expressed on the surface of infected red blood cells and are considered as an important immune target. However, due to the polygenicity and the gene polymorphism of the rif gene family, RIFINs can escape from the attack of immune system. Meanwhile, the binding of RIFINs to immune cell-surface inhibitory receptors such as leukocyte immunoglobulin-like receptor B1 (LILRB1) and leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) can down-regulate the immune response and achieve the immune escape. With recent research on the molecular mechanisms of falciparum malaria, the development of effective vaccines has become the key to preventing malaria and achieving malaria elimination. In this review, we introduce the structure of P. falciparum RIFINs, and highlight their roles in severe malaria and research progress in fields related to immune and vaccine development.

Key words: Plasmodium falciparum, RIFIN, Adhesion, Rosette, Immune escape

中图分类号:

R382.31

史善美, 陈军虎. 恶性疟原虫RIFIN蛋白的结构和功能研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(2): 249-255.

SHI Shan-mei, CHEN Jun-hu. Research progress on the structure and function of RIFIN protein of Plasmodium falciparum[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2021, 39(2): 249-255.

图/表 3

参考文献 52

[1]	WHO. World malaria report 2020[M]. Geneva: WHO, 2020.
[2]	Weiss DJ, Lucas TCD, Nguyen M, et al. Mapping the global prevalence, incidence, and mortality of Plasmodium falciparum, 2000-17: a spatial and temporal modelling study[J]. Lancet, 2019,394(10195):322-331.
[3]	Krief S, Escalante AA, Pacheco MA, et al. On the diversity of malaria parasites in African apes and the origin of Plasmodium falciparum from Bonobos[J]. PLoS Pathog, 2010,6(2):e1000765.
[4]	Cowman AF, Healer J, Marapana D, et al. Malaria: biology and disease[J]. Cell, 2016,167(3):610-624.
[5]	Wahlgren M, Goel S, Akhouri RR. Variant surface antigens of Plasmodium falciparum and their roles in severe malaria[J]. Nat Rev Microbiol, 2017,15(8):479-491.
[6]	Goel S, Palmkvist M, Moll K, et al. RIFINs are adhesins implicated in severe Plasmodium falciparum malaria[J]. Nat Med, 2015,21(4):314-317.
[7]	Tan J, Pieper K, Piccoli L, et al. A LAIR1 insertion generates broadly reactive antibodies against malaria variant antigens[J]. Nature, 2016,529(7584):105-109.
[8]	Saito F, Hirayasu K, Satoh T, et al. Corrigendum: immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors[J]. Nature, 2018,554(7693):554.
[9]	Helmby H, Cavelier L, Pettersson U, et al. Rosetting Plasmodium falciparum-infected erythrocytes express unique strain-specific antigens on their surface[J]. Infect Immun, 1993,61(1):284-288.
[10]	Kyes SA, Rowe JA, Kriek N, et al. Rifins: a second family of clonally variant proteins expressed on the surface of red cells infected with Plasmodium falciparum[J]. Proc Natl Acad Sci USA, 1999,96(16):9333-9338.
[11]	Fernandez V, Hommel M, Chen Q, et al. Small, clonally variant antigens expressed on the surface of the Plasmodium falciparum-infected erythrocyte are encoded by the rif gene family and are the target of human immune responses[J]. J Exp Med, 1999,190(10):1393-1404.
[12]	Petter M, Haeggstr?m M, Khattab A, et al. Variant proteins of the Plasmodium falciparum RIFIN family show distinct subcellular localization and developmental expression patterns[J]. Mol Biochem Parasitol, 2007,156(1):51-61.
[13]	Petter M, Bonow I, Klinkert MQ. Diverse expression patterns of subgroups of the rif multigene family during Plasmodium falciparum gametocytogenesis[J]. PLoS One, 2008,3(11):e3779.
[14]	Joannin N, Abhiman S, Sonnhammer EL, et al. Sub-grouping and sub-functionalization of the RIFIN multi-copy protein family[J]. BMC Genomics, 2008,9:19.
[15]	Joannin N, Kallberg Y, Wahlgren M, et al. RSpred, a set of Hidden Markov Models to detect and classify the RIFIN and STEVOR proteins of Plasmodium falciparum[J]. BMC Genomics, 2011,12:119.
[16]	McRobert L, Preiser P, Sharp S, et al. Distinct trafficking and localization of STEVOR proteins in three stages of the Plasmodium falciparum life cycle[J]. Infect Immun, 2004,72(11):6597-6602.
[17]	Bachmann A, Esser C, Petter M, et al. Absence of erythrocyte sequestration and lack of multicopy gene family expression in Plasmodium falciparum from a splenectomized malaria patient[J]. PLoS One, 2009,4(10):e7459.
[18]	Gardner MJ, Hall N, Fung E, et al. Genome sequence of the human malaria parasite Plasmodium falciparum[J]. Nature, 2002,419(6906):498-511.
[19]	Cheng Q, Cloonan N, Fischer K, et al. Stevor and rif are Plasmodium falciparum multicopy gene families which potentially encode variant antigens[J]. Mol Biochem Parasitol, 1998,97(1/2):161-176.
[20]	Hessa T, Kim H, Bihlmaier K, et al. Recognition of transmembrane helices by the endoplasmic reticulum translocon[J]. Nature, 2005,433(7024):377-381.
[21]	Hiller NL Bhattacharjee S van Ooij C, et al. A host-targeting signal in virulence proteins reveals a secretome in malarial infection[J]. Science, 2004,306(5703):1934-1937.
[22]	Marti M, Good RT, Rug M, et al. Targeting malaria virulence and remodeling proteins to the host erythrocyte[J]. Science, 2004,306(5703):1930-1933.
[23]	Bachmann A, Scholz JA, Jan?en M, et al. A comparative study of the localization and membrane topology of members of the RIFIN, STEVOR and PfMC-2TM protein families in Plasmodium falciparum-infected erythrocytes[J]. Malar J, 2015,14:274.
[24]	Harrison TE, M?rch AM, Felce JH, et al. Structural basis for RIFIN-mediated activation of LILRB1 in malaria[J]. Nature, 2020,587(7833):309-312.
[25]	Scherf A, Lopez-Rubio JJ, Riviere L. Antigenic variation in Plasmodium falciparum[J]. Annu Rev Microbiol, 2008,62(1):445-470.
[26]	Miller LH, Ackerman HC, Su XZ, et al. Malaria biology and disease pathogenesis: insights for new treatments[J]. Nat Med, 2013,19(2):156-167.
[27]	Vigan-Womas I, Guillotte M, Juillerat A, et al. Structural basis for the ABO blood-group dependence of Plasmodium falciparum rosetting[J]. PLoS Pathog, 2012,8(7):e1002781.
[28]	Rowe JA, Handel IG, Thera MA, et al. Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting[J]. Proc Natl Acad Sci USA, 2007,104(44):17471-17476.
[29]	Cserti CM, Dzik WH. The ABO blood group system and Plasmodium falciparum malaria[J]. Blood, 2007,110(7):2250-2258.
[30]	Daniels G. Human Blood Groups,3rd edition[M]. Chichester: Wiley-Blackwell, 2013.
[31]	Albrecht L, Moll K, Blomqvist K, et al. Var gene transcription and PfEMP1 expression in the rosetting and cytoadhesive Plasmodium falciparum clone FCR3S1.2[J]. Malar J, 2011,10:17.
[32]	Stevenson L, Laursen E, Cowan GJ, et al. α2-macroglobulin can crosslink multiple Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) molecules and may facilitate adhesion of parasitized erythrocytes[J]. PLoS Pathog, 2015,11(7):e1005022.
[33]	Treutiger CJ, Scholander C, Carlson J, et al. Rouleaux-forming serum proteins are involved in the rosetting of Plasmodium falciparum-infected erythrocytes[J]. Exp Parasitol, 1999,93(4):215-224.
[34]	Niang M, Bei AK, Madnani KG, et al. STEVOR is a Plasmodium falciparum erythrocyte binding protein that mediates merozoite invasion and rosetting[J]. Cell Host Microbe, 2014,16(1):81-93.
[35]	McLean AR, Ataide R, Simpson JA, et al. Malaria and immunity during pregnancy and postpartum: a tale of two species[J]. Parasitology, 2015,142(8):999-1015.
[36]	Saito F, Hirayasu K, Satoh T, et al. Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors[J]. Nature, 2017,552(7683):101-105.
[37]	Zhou AE, Berry AA, Bailey JA, et al. Antibodies to peptides in semiconserved domains of RIFINs and STEVORs correlate with malaria exposure[J]. mSphere, 2019,4(2):e00097-19.
[38]	Moll K, Palmkvist M, Ch’ng J, et al. Evasion of immunity to Plasmodium falciparum: rosettes of blood group A impair recognition of PfEMP1[J]. PLoS One, 2015,10(12):e0145120.
[39]	Pieper K, Tan J, Piccoli L, et al. Public antibodies to malaria antigens generated by two LAIR1 insertion modalities[J]. Nature, 2017,548(7669):597-601.
[40]	Lanzavecchia A. Dissecting human antibody responses: useful, basic and surprising findings[J]. EMBO Mol Med, 2018,10(3):e8879.
[41]	Naji A, Menier C, Morandi F, et al. Binding of HLA-G to ITIM-bearing Ig-like transcript 2 receptor suppresses B cell responses[J]. J Immunol, 2014,192(4):1536-1546.
[42]	Chan JA, Howell KB, Reiling L, et al. Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity[J]. J Clin Invest, 2012,122(9):3227-3238.
[43]	Kinyanjui SM, Bull P, Newbold CI, et al. Kinetics of antibody responses to Plasmodium falciparum-infected erythrocyte variant surface antigens[J]. J Infect Dis, 2003,187(4):667-674.
[44]	Abdel-Latif MS, Khattab A, Lindenthal C, et al. Recognition of variant Rifin antigens by human antibodies induced during natural Plasmodium falciparum infections[J]. Infect Immun, 2002,70(12):7013-7021.
[45]	Abdel-Latif MS, Cabrera G, K?hler C, et al. Antibodies to rifin: a component of naturally acquired responses to Plasmodium falciparum variant surface antigens on infected erythrocytes[J]. Am J Trop Med Hyg, 2004,71(2):179-186.
[46]	Arora G, Hart GT, Manzella-Lapeira J, et al. NK cells inhibit Plasmodium falciparum growth in red blood cells via antibody-dependent cellular cytotoxicity[J]. Elife, 2018,7:e36806.
[47]	Travassos MA, Niangaly A, Bailey JA, et al. Children with cerebral malaria or severe malarial anaemia lack immunity to distinct variant surface antigen subsets[J]. Sci Rep, 2018,8(1):6281.
[48]	Abdel-Latif MS, Dietz K, Issifou S, et al. Antibodies to Plasmodium falciparum rifin proteins are associated with rapid parasite clearance and asymptomatic infections[J]. Infect Immun, 2003,71(11):6229-6233.
[49]	Quintana MDP, Ch’ng JH, Moll K, et al. Antibodies in children with malaria to PfEMP1, RIFIN and SURFIN expressed at the Plasmodium falciparum parasitized red blood cell surface[J]. Sci Rep, 2018,8(1):3262.
[50]	Kanoi BN, Nagaoka H, White MT, et al. Global repertoire of human antibodies against Plasmodium falciparum RIFINs, SURFINs, and STEVORs in a malaria exposed population[J]. Front Immunol, 2020,11:893.
[51]	Kaur J, Hora R. ‘2TM proteins’: an antigenically diverse superfamily with variable functions and export pathways[J]. Peer J, 2018,6:e4757.
[52]	Beeson JG, Osier FH, Engwerda CR. Recent insights into humoral and cellular immune responses against malaria[J]. Trends Parasitol, 2008,24(12):578-584.