恶性疟原虫var基因的表达调控机制研究进展

doi:10.12140/j.issn.1000-7423.2021.06.001

摘要/Abstract

摘要：

疟疾是由疟原虫感染引起的传染性疾病。var基因编码的红细胞膜表面蛋白1（PfEMP1）是恶性疟原虫致病过程中最主要的毒力因子,与疟原虫感染红细胞的抗原变异及细胞黏附过程密切相关。var基因表达受严格的时空调控,一般来说,单个疟原虫在红内期只表达一个var基因,遵循相互排斥的表达策略。本文综述了恶性疟原虫var基因调控的研究进展以加深人们对疟疾致病机制的理解。

关键词: 恶性疟原虫, 毒力因子, var基因, 表达调控, 表观修饰

Abstract:

Malaria is an infectious disease caused by Plasmodium infection. The erythrocyte membrane surface protein 1 (PfEMP1) encoded by the var gene family is the key virulence factor in the pathogenic process of P. falciparum, which is closely related with the antigen variation and cytoadhesion. The expression of var genes is strictly controlled by time and space. Generally, a single Plasmodium parasite expresses only one var gene in the erythrocytic stage, following a mutually exclusive expression strategy. Based upon current researches, we make a comprehensive summary on var gene expression regulation mechanism to improve the understanding of the pathogenesis of malaria.

Key words: Plasmodium falciparum, Virulence factor, var genes, Expression regulation, Epigenetic modification

中图分类号:

R382.312

石明丽, 肖波, 江陆斌. 恶性疟原虫var基因的表达调控机制研究进展[J]. 中国寄生虫学与寄生虫病杂志, 2021, 39(6): 719-724.

SHI Ming-li, XIAO Bo, JIANG Lu-bin. Research progress on the expression regulation of var genes in Plasmodium falciparum[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2021, 39(6): 719-724.

图/表 1

参考文献 55

[1]	World Health Organization. World malaria report 2021[R]. Geneva: WHO, 2021.
[2]	Cowman AF, Healer J, Marapana D, et al. Malaria: biology and disease[J]. Cell, 2016, 167(3): 610-624.
[3]	Roberts DJ, Craig AG, Berendt AR, et al. Rapid switching to multiple antigenic and adhesive phenotypes in malaria[J]. Nature, 1992, 357(6380): 689-692.
[4]	Kyes S, Pinches R, Newbold C. A simple RNA analysis method shows var and rif multigene family expression patterns in Plasmodium falciparum[J]. Mol Biochem Parasitol, 2000, 105(2): 311-315.
[5]	Lopez-Rubio JJ, Gontijo AM, Nunes MC, et al. 5′ flanking region of var genes nucleate histone modification patterns linked to phenotypic inheritance of virulence traits in malaria parasites[J]. Mol Microbiol, 2007, 66(6): 1296-1305.
[6]	Scherf A, Hernandez-Rivas R, Buffet P, et al. Antigenic variation in malaria: in situ switching, relaxed and mutually exclusive transcription of var genes during intra-erythrocytic development in Plasmodium falciparum[J]. EMBO J, 1998, 17(18): 5418-5426.
[7]	Hollin T, Le Roch KG. From genes to transcripts, a tightly regulated journey in Plasmodium[J]. Front Cell Infect Microbiol, 2020, 10: 618454.
[8]	Chookajorn T, Dzikowski R, Frank M, et al. Epigenetic memory at malaria virulence genes[J]. Proc Nalt Acad Sci USA, 2007, 104(3): 899-902.
[9]	Lopez-Rubio JJ, Mancio-Silva L, Scherf A. Genome-wide analysis of heterochromatin associates clonally variant gene regulation with perinuclear repressive centers in malaria parasites[J]. Cell Host Microbe, 2009, 5(2): 179-190.
[10]	Flueck C, Bartfai R, Volz J, et al. Plasmodium falciparum heterochromatin protein 1 marks genomic loci linked to phenotypic variation of exported virulence factors[J]. PLoS Pathog, 2009, 5(9): e1000569.
[11]	Pérez-Toledo K, Rojas-Meza AP, Mancio-Silva L, et al. Plasmodium falciparum heterochromatin protein 1 binds to tri-methylated histone 3 lysine 9 and is linked to mutually exclusive expression of var genes[J]. Nucleic Acids Res, 2009, 37(8): 2596-2606.
[12]	Brancucci NMB, Bertschi NL, Zhu L, et al. Heterochromatin protein 1 secures survival and transmission of malaria parasites[J]. Cell Host Microbe, 2014, 16(2): 165-176.
[13]	Jiang L, Mu J, Zhang Q, et al. PfSETvs methylation of histone H3K36 represses virulence genes in Plasmodium falciparum[J]. Nature, 2013, 499(7457): 223-227.
[14]	Duraisingh MT, Voss TS, Marty AJ, et al. Heterochromatin silencing and locus repositioning linked to regulation of virulence genes in Plasmodium falciparum[J]. Cell, 2005, 121(1): 13-24.
[15]	Tonkin CJ, Carret CK, Duraisingh MT, et al. Sir2 paralogues cooperate to regulate virulence genes and antigenic variation in Plasmodium falciparum[J]. PLoS Biol, 2009, 7(4): e84.
[16]	Coleman BI, Skillman KM, Jiang RHY, et al. A Plasmodium falciparum histone deacetylase regulates antigenic variation and gametocyte conversion[J]. Cell Host Microbe, 2014, 16(2): 177-186.
[17]	Volz JC, Bártfai R, Petter M, et al. PfSET10, a Plasmodium falciparum methyltransferase, maintains the active var gene in a poised state during parasite division[J]. Cell Host Microbe, 2012, 11(1): 7-18.
[18]	Ngwa CJ, Gross MR, Musabyimana JP, et al. The role of the histone methyltransferase PfSET10 in antigenic variation by malaria parasites: a cautionary tale[J]. mSphere, 2021, 6(1): e01217-20.
[19]	Chen PB, Ding S, Zanghì G, et al. Plasmodium falciparum PfSET7: enzymatic characterization and cellular localization of a novel protein methyltransferase in sporozoite, liver and erythrocytic stage parasites[J]. Sci Rep, 2016, 6: 21802.
[20]	Fraschka SA, Henderson RW, Bártfai R. H3.3 demarcates GC-rich coding and subtelomeric regions and serves as potential memory mark for virulence gene expression in Plasmodium falciparum[J]. Sci Rep, 2016, 6: 31965.
[21]	Bártfai R, Hoeijmakers WA, Salcedo-Amaya AM, et al. H2A.Z demarcates intergenic regions of the Plasmodium falciparum epigenome that are dynamically marked by H3K9ac and H3K4me3[J]. PLoS Pathog, 2010, 6(12): e1001223.
[22]	Petter M, Lee CC, Byrne TJ, et al. Expression of P. falciparum var genes involves exchange of the histone variant H2A.Z at the promoter[J]. PLoS Pathog, 2011, 7(2): e1001292.
[23]	Petter M, Selvarajah SA, Lee CC, et al. H2A.Z and H2B.Z double-variant nucleosomes define intergenic regions and dynamically occupyvargene promoters in the malaria parasite Plasmodium falciparum[J]. Mol Microbiol, 2013, 87(6): 1167-1182.
[24]	Ma H, Hao Y, Dong X, et al. Molecular mechanisms and function prediction of long noncoding RNA[J]. Sci World J, 2012, 2012: 541786.
[25]	Calderwood MS, Gannoun-Zaki L, Wellems TE, et al. Plasmodium falciparum var genes are regulated by two regions with separate promoters, one upstream of the coding region and a second within the intron[J]. J Biol Chem, 2003, 278(36): 34125-34132.
[26]	Militello KT, Patel V, Chessler AD, et al. RNA polymerase II synthesizes antisense RNA in Plasmodium falciparum[J]. RNA, 2005, 11(4): 365-370.
[27]	Epp C, Li F, Howitt CA, et al. Chromatin associated sense and antisense noncoding RNAs are transcribed from the var gene family of virulence genes of the malaria parasite Plasmodium falciparum[J]. RNA, 2009, 15(1): 116-127.
[28]	Kyes SA, Christodoulou Z, Raza A, et al. A well-conserved Plasmodium falciparum var gene shows an unusual stage-specific transcript pattern[J]. Mol Microbiol, 2003, 48(5): 1339-1348.
[29]	Amit-Avraham I, Pozner G, Eshar S, et al. Antisense long noncoding RNAs regulate var gene activation in the malaria parasite Plasmodium falciparum[J]. Proc Nalt Acad Sci USA, 2015, 112(9): E982-E991.
[30]	Jing Q, Cao L, Zhang L, et al. Plasmodium falciparum var gene is activated by its antisense long noncoding RNA[J]. Front Microbiol, 2018, 9: 3117.
[31]	Guizetti J, Guizetti J, Barcons-Simon A, et al. Trans-acting GC-rich non-coding RNA at var expression site modulates gene counting in malaria parasite[J]. Nucleic Acids Res, 2016, 44(20): 9710-9718.
[32]	Wei G, Zhao Y, Zhang Q, et al. Dual regulatory effects of non-coding GC-rich elements on the expression of virulence genes in malaria parasites[J]. Infect Genet Evol, 2015, 36: 490-499.
[33]	Barcons-Simon A, Cordon-Obras C, Guizetti J, et al. CRISPR interference of a clonally variant GC-rich noncoding RNA family leads to general repression of var genes in Plasmodium falciparum[J]. mBio, 2020, 11(1): e03054-19.
[34]	Ralph SA, Scheidig-Benatar C, Scherf A. Antigenic variation in Plasmodium falciparum is associated with movement of var loci between subnuclear locations[J]. Proc Nalt Acad Sci USA, 2005, 102(15): 5414-5419.
[35]	Mok BW, Ribacke U, Rasti N, et al. Default pathway of var2csa switching and translational repression in Plasmodium falciparum[J]. PLoS One, 2008, 3(4): e1982.
[36]	Voss TS, Tonkin CJ, Marty AJ, et al. Alterations in local chromatin environment are involved in silencing and activation of subtelomericvar genes in Plasmodium falciparum[J]. Mol Microbiol, 2007, 66(1): 139-150.
[37]	Callebaut I, Prat K, Meurice E, et al. Prediction of the general transcription factors associated with RNA polymerase Ⅱin Plasmodium falciparum: conserved features and differences relative to other eukaryotes[J]. BMC Genomics, 2005, 6: 100.
[38]	Gissot M, Briquet S, Refour P, et al. PfMyb1, a Plasmodium falciparum transcription factor, is required for intra-erythrocytic growth and controls key genes for cell cycle regulation[J]. J Mol Biol, 2005, 346(1): 29-42.
[39]	Komaki-Yasuda K, Okuwaki M, Nagata K, et al. Identification of a novel and unique transcription factor in the intraerythrocytic stage of Plasmodium falciparum[J]. PLoS One, 2013, 8(9): e74701.
[40]	Briquet S, Boschet C, Gissot M, et al. High-mobility-group box nuclear factors of Plasmodium falciparum[J]. Eukaryot Cell, 2006, 5(4): 672-682.
[41]	Balaji S, Babu MM, Iyer LM, et al. Discovery of the principal specific transcription factors of Apicomplexa and their implication for the evolution of the AP2-integrase DNA binding domains[J]. Nucleic Acids Res, 2005, 33(13): 3994-4006.
[42]	Campbell TL, De Silva EK, Olszewski KL, et al. Identification and genome-wide prediction of DNA binding specificities for the ApiAP2 family of regulators from the malaria parasite[J]. PLoS Pathog, 2010, 6(10): e1001165.
[43]	Flueck C, Bartfai R, Niederwieser I, et al. A major role for the Plasmodium falciparum ApiAP2 protein PfSIP2 in chromosome end biology[J]. PLoS Pathog, 2010, 6(2): e1000784.
[44]	Cubillos EFG, Prata IO, Fotoran WL, et al. The transcription factor PfAP2-O influences virulence gene transcription and sexual development in Plasmodium falciparum[J]. Front Cell Infect Microbiol, 2021, 11: 669088.
[45]	Han ST, Zhang QF, Pan WQ. In vivo identification of the interaction between var intron and an ApiAP2 transcription factor in Plasmodium falciparum[J]. Chin J Parasitol Parasit Dis, 2014, 32(1): 1-5. (in Chinese)
[45]	(韩世通, 张青锋, 潘卫庆. 恶性疟原虫ApiAP2蛋白与var基因内含子序列相互作用的体内鉴定[J]. 中国寄生虫学与寄生虫病杂志, 2014, 32(1): 1-5.)
[46]	Zhang Q, Huang Y, Zhang Y, et al. A critical role of perinuclear filamentous actin in spatial repositioning and mutually exclusive expression of virulence genes in malaria parasites[J]. Cell Host Microbe, 2011, 10(5): 451-463.
[47]	Painter HJ, Chung NC, Sebastian A, et al. Genome-wide real-time in vivo transcriptional dynamics during Plasmodium falciparum blood-stage development[J]. Nat Commun, 2018, 9(1): 2656.
[48]	Lu XM, Batugedara G, Lee M, et al. Nascent RNA sequencing reveals mechanisms of gene regulation in the human malaria parasite Plasmodium falciparum[J]. Nucleic Acids Res, 2017, 45(13): 7825-7840.
[49]	Toenhake CG, Fraschka SA, Vijayabaskar MS, et al. Chromatin accessibility-based characterization of the gene regulatory network underlying Plasmodium falciparum blood-stage development[J]. Cell Host Microbe, 2018, 23(4): 557-569.e9.
[50]	Ruiz JL, Tena JJ, Bancells C, et al. Characterization of the accessible genome in the human malaria parasite Plasmodium falciparum[J]. Nucleic Acids Res, 2018, 46(18): 9414-9431.
[51]	Zhang QF, Siegel TN, Martins RM, et al. Exonuclease-mediated degradation of nascent RNA silences genes linked to severe malaria[J]. Nature, 2014, 513(7518): 431-435.
[52]	Fan YT, Shen SJ, Wei GY, et al. Rrp6 regulates heterochromatic gene silencing via ncRNA RUF6 decay in malaria parasites[J]. mBio, 2020, 11(3): e01110-20.
[53]	Claessens A, Harris LM, Stanojcic S, et al. RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics[J]. PLoS Genet, 2018, 14(7): e1007490.
[54]	Li Z, Yin S, Sun M, et al. DNA helicase RecQ1 regulates mutually exclusive expression of virulence genes in Plasmodium falciparum via heterochromatin alteration[J]. Proc Nalt Acad Sci USA, 2019, 116(8): 3177-3182.
[55]	Bryant JM, Baumgarten S, Dingli F, et al. Exploring the virulence gene interactome with CRISPR/dCas9 in the human malaria parasite[J]. Mol Syst Biol, 2020, 16(8): e9569.