弓形虫致密颗粒蛋白的生物学功能研究进展

doi:10.11843/j.issn.0366-6964.2022.10.008

Abstract

Abstract: Toxoplasma gondii is an important zoonotic parasite with a wide range of intermediate hosts, complex life history, diverse modes of transmission and global distribution, which can infect almost all warm-blood animals, including humans, causing zoonotic toxoplasmosis. About one third of the world human population are chronically infected with T. gondii, which poses a serious health threat to immune deficiency patients, pregnant women and pregnant animals. Therefore, T. gondii is an important zoonotic parasite. Dense granule protein family secreted by the dense granules, one of the important subcellular secretory organelles of T. gondii, plays important roles in many biological processes, such as regulating the host cell cycle and immune response by modulating the signal pathways, gene expression, participating in the protein transport and localization, nutrient uptake, the formation and stability maintenance of intravacuolar network (IVN), as well as egress and chronic infection of T. gondii. In this review, the basic biological functions of the dense granule proteins are summarized in order to provide new research ideas for the pathogenesis of T. gondii, the discovery of potential drug targets against T. gondii and the development of anti-T. gondii vaccines.

Key words: Toxoplasma gondii, toxoplasmosis, dense granule proteins, biological function

CLC Number:

ZHENG Xiaonan, LI Tingting, WANG Jinlei, ZHENG Wenbin, ZHU Xingquan. Research Progress on Biological Functions of Dense Granule Proteins of Toxoplasma gondii[J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(10): 3345-3357.

References 73

[1]	ELSHEIKHA H M, MARRA C M, ZHU X Q. Epidemiology, pathophysiology, diagnosis, and management of cerebral toxoplasmosis[J]. Clin Microbiol Rev, 2021, 34(1):e00115-19.
[2]	YAROVINSKY F. Innate immunity to Toxoplasma gondii infection[J]. Nat Rev Immunol, 2014, 14(2):109-121.
[3]	WANG Z D, WANG S C, LIU H H, et al. Prevalence and burden of Toxoplasma gondii infection in HIV-infected people:a systematic review and meta-analysis[J]. Lancet HIV, 2017, 4(4):e177-e88.
[4]	DUNAY I R, GAJUREL K, DHAKAL R, et al. Treatment of Toxoplasmosis:historical perspective, animal models, and current clinical practice[J]. Clin Microbiol Rev, 2018, 31(4):e00057-17.
[5]	ZHANG N Z, CHEN J, WANG M, et al. Vaccines against Toxoplasma gondii:new developments and perspectives[J]. Expert Rev Vaccines, 2013, 12(11):1287-1299.
[6]	WANG J L, ZHANG N Z, LI T T, et al. Advances in the development of anti-Toxoplasma gondii vaccines:challenges, opportunities, and perspectives[J]. Trends Parasitol, 2019, 35(3):239-253.
[7]	SIBLEY L D, NIESMAN I R, PARMLEY S F, et al. Regulated secretion of multi-lamellar vesicles leads to formation of a tubulo-vesicular network in host-cell vacuoles occupied by Toxoplasma gondii[J]. J Cell Sci, 1995, 108(4):1669-1677.
[8]	BLADER I J, COLEMAN B I, CHEN C T, et al. Lytic cycle of Toxoplasma gondii:15 years later[J]. Annu Rev Microbiol, 2015, 69:463-485.
[9]	MA J S, SASAI M W, OHSHIMA J, et al. Selective and strain-specific NFAT4 activation by the Toxoplasma gondii polymorphic dense granule protein GRA6[J]. J Exp Med, 2014, 211(10):2013-2032.
[10]	HAKIMI M A, OLIAS P, SIBLEY L D. Toxoplasma effectors targeting host signaling and transcription[J]. Clin Microbiol Rev, 2017, 30(3):615-645.
[11]	ROSOWSKI E E, LU D N, JULIEN L, et al. Strain-specific activation of the NF-κB pathway by GRA15, a novel Toxoplasma gondii dense granule protein[J]. J Exp Med, 2011, 208(1):195-212.
[12]	GOV L, KARIMZADEH A, UENO N, et al. Human innate immunity to Toxoplasma gondii is mediated by host caspase-1 and ASC and parasite GRA15[J]. mBio, 2013, 4(4):e00255-13.
[13]	PERNAS L, ADOMAKO-ANKOMAH Y, SHASTRI A J, et al. Toxoplasma effector MAF1 mediates recruitment of host mitochondria and impacts the host response[J]. PLoS Biol, 2014, 12(4):e1001845.
[14]	BLANK M L, PARKER M L, RAMASWAMY R, et al. A Toxoplasma gondii locus required for the direct manipulation of host mitochondria has maintained multiple ancestral functions[J]. Mol Microbiol, 2018, 108(5):519-535.
[15]	BRAUN L, BRENIER-PINCHART M P, YOGAVEL M, et al. A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation[J]. J Exp Med, 2013, 210(10):2071-2086.
[16]	OLIAS P, ETHERIDGE R D, ZHANG Y, et al. Toxoplasma effector recruits the Mi-2/NuRD complex to repress STAT1 transcription and block IFN-γ-dependent gene expression[J]. Cell Host Microbe, 2016, 20(1):72-82.
[17]	MATTA S K, OLIAS P, HUANG Z, et al. Toxoplasma gondii effector TgIST blocks type I interferon signaling to promote infection[J]. Proc Natl Acad Sci U S A, 2019, 116(35):17480-17491.
[18]	GAY G, BRAUN L, BRENIER-PINCHART M P, et al. Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ-mediated host defenses[J]. J Exp Med, 2016, 213(9):1779-1798.
[19]	BRAUN L, BRENIER-PINCHART M P, HAMMOUDI P M, et al. The Toxoplasma effector TEEGR promotes parasite persistence by modulating NF-κB signalling via EZH2[J]. Nat Microbiol, 2019, 4(7):1208-1220.
[20]	HE H, BRENIER-PINCHART M P, BRAUN L, et al. Characterization of a Toxoplasma effector uncovers an alternative GSK3/β-catenin-regulatory pathway of inflammation[J]. Elife, 2018, 7:e39887.
[21]	TOMITA T, MUKHOPADHYAY D, HAN B, et al. Toxoplasma gondii matrix antigen 1 is a secreted immunomodulatory effector[J]. mBio, 2021, 12(3):e00603-21.
[22]	SHASTRI A J, MARINO N D, FRANCO M, et al. GRA25 is a novel virulence factor of Toxoplasma gondii and influences the host immune response[J]. Infect Immun, 2014, 82(6):2595-2605.
[23]	HERMANNS T, MVLLER U B, KÖNEN-WAISMAN S, et al. The Toxoplasma gondii rhoptry protein ROP18 is an Irga6-specific kinase and regulated by the dense granule protein GRA7[J]. Cell Microbiol, 2016, 18(2):244-259.
[24]	NYONDA M A, HAMMOUDI P M, YE S, et al. Toxoplasma gondii GRA60 is an effector protein that modulates host cell autonomous immunity and contributes to virulence[J]. Cell Microbiol, 2021, 23(2):e13278.
[25]	WANG J L, BAI M J, ELSHEIKHA H M, et al. Novel roles of dense granule protein 12 (GRA12) in Toxoplasma gondii infection[J]. FASEB J, 2020, 34(2):3165-3178.
[26]	GUEVARA R B, FOX B A, FALLA A, et al. Toxoplasma gondii intravacuolar-network-associated dense granule proteins regulate maturation of the cyst matrix and cyst wall[J]. mSphere, 2019, 4(5):e00487-19.
[27]	FOX B A, GUEVARA R B, ROMMEREIM L M, et al. Toxoplasma gondii parasitophorous vacuole membrane-associated dense granule proteins orchestrate chronic infection and GRA12 underpins resistance to host gamma interferon[J]. mBio, 2019, 10(4):e00589-19.
[28]	KRAVETS E, DEGRANDI D, MA Q J, et al. Guanylate binding proteins directly attack Toxoplasma gondii via supramolecular complexes[J]. Elife, 2016, 5:e11479.
[29]	ZHAO Y O, KHAMINETS A, HUNN J P, et al. Disruption of the Toxoplasma gondii parasitophorous vacuole by IFNγ-inducible immunity-related GTPases (IRG proteins) triggers necrotic cell death[J]. PLoS Pathog, 2009, 5(2):e1000288.
[30]	BOUGDOUR A, DURANDAU E, BRENIER-PINCHART M P, et al. Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression[J]. Cell Host Microbe, 2013, 13(4):489-500.
[31]	KIM S G, SEO S H, SHIN J H, et al. Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53-dependent apoptosis and anticancer effect[J]. J Cell Mol Med, 2019, 23(5):3234-3245.
[32]	PANAS M W, NAOR A, CYGAN A M, et al. Toxoplasma controls host cyclin E expression through the use of a novel MYR1-dependent effector protein, HCE1[J]. mBio, 2019, 10(2):e00674-19.
[33]	CYGAN A M, THEISEN T C, MENDOZA A G, et al. Coimmunoprecipitation with MYR1 identifies three additional proteins within the Toxoplasma gondii parasitophorous vacuole required for translocation of dense granule effectors into host cells[J]. mSphere, 2020, 5(1):e00858-19.
[34]	BLAKELY W J, HOLMES M J, ARRIZABALAGA G. The Secreted acid phosphatase domain-containing GRA44 from Toxoplasma gondii is required for c-Myc induction in infected cells[J]. mSphere, 2020, 5(1):e00877-19.
[35]	FRANCO M, PANAS M W, MARINO N D, et al. A novel secreted protein, MYR1, is central to Toxoplasma's manipulation of host cells[J]. mBio, 2016, 7(1):e02231-15.
[36]	MARINO N D, PANAS M W, FRANCO M, et al. Identification of a novel protein complex essential for effector translocation across the parasitophorous vacuole membrane of Toxoplasma gondii[J]. PLoS Pathog, 2018, 14(1):e1006828.
[37]	WANG Y F, SANGARÉ L O, PAREDES-SANTOS T C, et al. Genome-wide screens identify Toxoplasma gondii determinants of parasite fitness in IFNγ-activated murine macrophages[J]. Nat Commun, 2020, 11(1):5258.
[38]	MAYORAL J, TOMITA T, TU V, et al. Toxoplasma gondii PPM3C, a secreted protein phosphatase, affects parasitophorous vacuole effector export[J]. PLoS Pathog, 2020, 16(12):e1008771.
[39]	WANG Y F, CIRELLI K M, BARROS P D C, et al. Three Toxoplasma gondii dense granule proteins are required for induction of lewis rat macrophage pyroptosis[J]. mBio, 2019, 10(1):e02388-18.
[40]	NAOR A, PANAS M W, MARINO N, et al. MYR1-dependent effectors are the major drivers of a host cell's early response to Toxoplasma, including counteracting MYR1-independent effects[J]. mBio, 2018, 9(2):e02401-17.
[41]	FRANCO M, SHASTRI A J, BOOTHROYD J C. Infection by Toxoplasma gondii specifically induces host c-Myc and the genes this pivotal transcription factor regulates[J]. Eukaryot Cell, 2014, 13(4):483-493.
[42]	COFFEY M J, SLEEBS B E, UBOLDI A D, et al. An aspartyl protease defines a novel pathway for export of Toxoplasma proteins into the host cell[J]. Elife, 2015, 4:e10809.
[43]	HAMMOUDI P M, JACOT D, MUELLER C, et al. Fundamental roles of the golgi-associated Toxoplasma Aspartyl protease, ASP5, at the host-parasite interface[J]. PLoS Pathog, 2015, 11(10):e1005211.
[44]	GOLD D A, KAPLAN A D, LIS A, et al. The Toxoplasma dense granule proteins GRA17 and GRA23 mediate the movement of small molecules between the host and the parasitophorous vacuole[J]. Cell Host Microbe, 2015, 17(5):642-652.
[45]	WANG J L, ELSHEIKHA H M, ZHU W N, et al. Immunization with Toxoplasma gondii GRA17 deletion mutant induces partial protection and survival in challenged mice[J]. Front Immunol, 2017, 8:730.
[46]	MASATANI T, MATSUO T, TANAKA T, et al. TgGRA23, a novel Toxoplasma gondii dense granule protein associated with the parasitophorous vacuole membrane and intravacuolar network[J]. Parasitol Int, 2013, 62(4):372-379.
[47]	PAREDES-SANTOS T, WANG Y F, WALDMAN B, et al. The GRA17 parasitophorous vacuole membrane permeability pore contributes to bradyzoite viability[J]. Front Cell Infect Microbiol, 2019, 9:321.
[48]	LI T T, WANG J L, LIANG Q L, et al. Effect of deletion of gra17 and gra23 genes on the growth, virulence, and immunogenicity of type II Toxoplasma gondii[J]. Parasitol Res, 2020, 119(9):2907-2916.
[49]	LIANG Q L, SUN L X, ELSHEIKHA H M, et al. RHΔgra17Δnpt1 strain of Toxoplasma gondii elicits protective immunity against acute, chronic and congenital Toxoplasmosis in mice[J]. Microorganisms, 2020, 8(3):352.
[50]	MERCIER C, DUBREMETZ J F, RAUSCHER B, et al. Biogenesis of nanotubular network in Toxoplasma parasitophorous vacuole induced by parasite proteins[J]. Mol Biol Cell, 2002, 13(7):2397-2409.
[51]	ROMANO J D, NOLAN S J, PORTER C, et al. The parasite Toxoplasma sequesters diverse Rab host vesicles within an intravacuolar network[J]. J Cell Biol, 2017, 216(12):4235-4254.
[52]	ROMMEREIM L M, BELLINI V, FOX B, et al. Phenotypes associated with knockouts of eight dense granule gene loci (GRA2-9) in virulent Toxoplasma gondii[J]. PLoS One, 2016, 11(7):e0159306.
[53]	LAFAVERS K A, MÁRQUEZ-NOGUERAS K M, COPPENS I, et al. A novel dense granule protein, GRA41, regulates timing of egress and calcium sensitivity in Toxoplasma gondii[J]. Cell Microbiol, 2017, 19(9):e12749.
[54]	BERAKI T, HU X Y, BRONCEL M, et al. Divergent kinase regulates membrane ultrastructure of the Toxoplasma parasitophorous vacuole[J]. Proc Natl Acad Sci U S A, 2019, 116(13):6361-6370.
[55]	DEFFIEU M S, ALAYI T D, SLOMIANNY C, et al. The Toxoplasma gondii dense granule protein TgGRA3 interacts with host Golgi and dysregulates anterograde transport[J]. Biol Open, 2019, 8(3):bio039818.
[56]	COPPENS I, DUNN J D, ROMANO J D, et al. Toxoplasma gondii sequesters lysosomes from mammalian hosts in the vacuolar space[J]. Cell, 2006, 125(2):261-274.
[57]	DUNN J D, RAVINDRAN S, KIM S K, et al. The Toxoplasma gondii dense granule protein GRA7 is phosphorylated upon invasion and forms an unexpected association with the rhoptry proteins ROP2 and ROP4[J]. Infect Immun, 2008, 76(12):5853-5861.
[58]	NADIPURAM S M, KIM E W, VASHISHT A A, et al. In vivo biotinylation of the Toxoplasma parasitophorous vacuole reveals novel dense granule proteins important for parasite growth and pathogenesis[J]. mBio, 2016, 7(4):e00808-16.
[59]	RIVERA-CUEVAS Y, MAYORAL J, DI CRISTINA M, et al. Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins[J]. PLoS Pathog, 2021, 17(12):e1010138.
[60]	SCHWAB J C, BECKERS C J, JOINER K A. The parasitophorous vacuole membrane surrounding intracellular Toxoplasma gondii functions as a molecular sieve[J]. Proc Natl Acad Sci U S A, 1994, 91(2):509-513.
[61]	DOU Z C, MCGOVERN O L, DI CRISTINA M, et al. Toxoplasma gondii ingests and digests host cytosolic proteins[J]. mBio, 2014, 5(4):e01188-14.
[62]	GUÉRIN A, CORRALES R M, PARKER M L, et al. Efficient invasion by Toxoplasma depends on the subversion of host protein networks[J]. Nat Microbiol, 2017, 2(10):1358-1366.
[63]	CYGAN A M, JEAN BELTRAN P M, MENDOZA A G, et al. Proximity-Labeling reveals novel host and parasite proteins at the Toxoplasma parasitophorous vacuole membrane[J]. mBio, 2021, 12(6):e0026021.
[64]	ROME M E, BECK J R, TURETZKY J M, et al. Intervacuolar transport and unique topology of GRA14, a novel dense granule protein in Toxoplasma gondii[J]. Infect Immun, 2008, 76(11):4865-4875.
[65]	OKADA T, MARMANSARI D, LI Z M, et al. A novel dense granule protein, GRA22, is involved in regulating parasite egress in Toxoplasma gondii[J]. Mol Biochem Parasitol, 2013, 189(1-2):5-13.
[66]	DÍAZ-MARTÍN R D, MERCIER C, GÓMEZ DE LEÓN C T, et al. The dense granule protein 8 (GRA8) is a component of the sub-pellicular cytoskeleton in Toxoplasma gondii[J]. Parasitol Res, 2019, 118(6):1899-1918.
[67]	GUEVARA R B, FOX B A, BZIK D J. Toxoplasma gondii parasitophorous vacuole membrane-associated dense granule proteins regulate maturation of the cyst wall[J]. mSphere, 2020, 5(1):e00851-19.
[68]	GUEVARA R B, FOX B A, BZIK D J. A family of Toxoplasma gondii genes related to GRA12 regulate cyst burdens and cyst reactivation[J]. mSphere, 2021, 6(2):e00182-21.
[69]	TU V, TOMITA T, SUGI T, et al. The Toxoplasma gondii cyst wall interactome[J]. mBio, 2020, 11(1):e02699-19.
[70]	NADIPURAM S M, THIND A C, RAYATPISHEH S, et al. Proximity biotinylation reveals novel secreted dense granule proteins of Toxoplasma gondii bradyzoites[J]. PLoS One, 2020, 15(5):e0232552.
[71]	TOMITA T, BZIK D J, MA Y F, et al. The Toxoplasma gondii cyst wall protein CST1 is critical for cyst wall integrity and promotes bradyzoite persistence[J]. PLoS Pathog, 2013, 9(12):e1003823.
[72]	TU V, MAYORAL J, SUGI T, et al. Enrichment and proteomic characterization of the cyst wall from in vitro Toxoplasma gondii cysts[J]. mBio, 2019, 10(2):e00469-19.
[73]	YOUNG J C, BRONCEL M, TEAGUE H, et al. Phosphorylation of Toxoplasma gondii secreted proteins during acute and chronic stages of infection[J]. mSphere, 2020, 5(5):e00792-20.

Research Progress on Biological Functions of Dense Granule Proteins of Toxoplasma gondii

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References 73

Related Articles 15

Recommended Articles

Metrics

Comments

[1]	GUO Yanli, LI Keqiang, BAI Shaochuan, WANG Tao, WANG Dehe, WANG Qi, LI Lanhui. The Structure, Activity Regulation of ALV-E and Its Effects on Host Function [J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(7): 2683-2691.
[2]	SUN Xiaojing, ZHANG Lei, TIAN Tian, MA Xi, YAO Jia, WANG Yang. Unravelling Toxoplasma Treatment: Conventional Drugs toward Nanomedicine [J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(5): 1834-1844.
[3]	XIA Chunqiu, WAN Fachun, LIU Lei, SHEN Weijun, XIAO Dingfu. Valine: Biological Function and Application in Livestock and Poultry Diets [J]. Acta Veterinaria et Zootechnica Sinica, 2023, 54(11): 4502-4513.
[4]	CHEN Huixian, CHEN Yajie, WANG Xianmei, WANG Lifang, LIU Qun, LIU Jing. Identification of the Cross-reacting Antigen MIC17A of Toxoplasma gondii and Neospora caninum and the Study of Its Cross-immune Protective Efficacy in Mice [J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(7): 2300-2306.
[5]	FU Ming, HE Junjun, ZHU Xingquan, CONG Wei. Proteomic Analysis of Changes in the Mouse Brain Tissue Infected with Toxoplasma gondii Oocysts during the Acute and Chronic Stage [J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(2): 556-566.
[6]	WANG Pei, WANG Meng, LI Tingting, ZHENG Xiaonan, LIANG Qinli, CHEN Xiaoqing. Generation and Basic Functional Characterization of Four Hypothetical Protein Genes Deletion Strains of Toxoplasma gondii [J]. Acta Veterinaria et Zootechnica Sinica, 2022, 53(10): 3598-3608.
[7]	WANG Weizhen, DENG Zhanzhao, XIN Guosheng, CAI Zhengyun, GU Yaling, ZHANG Juan. The Biological Function of Circular RNA and Its Research Progress in Poultry [J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(7): 1778-1788.
[8]	LIU Yibing, WU Dequn, LIN Zheguang, JI Ting. Review on Biological Function of Royal Jelly [J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(6): 1498-1510.
[9]	YIN Deqi, WEI Ziwei, ZHANG Yiwei, SANG Xiaoyu, YANG Na, FENG Ying, CHEN Ran, JIANG Ning. Research Progress in Protein Post-translational Modifications of Toxoplasma gondii [J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(11): 2995-3005.
[10]	QIU Yanhua, ZHAI Bintao, SHANG Xiaofei, ZHOU Xuzheng, LI Bing, ZHANG Jiyu. Evaluation of the Activity of Sabinene against Toxoplasma gondii in vitro [J]. Acta Veterinaria et Zootechnica Sinica, 2021, 52(10): 2915-2923.
[11]	LI Yi, WANG Xianmei, YANG Xu, DENG Junhua, WANG Fei, LIU Qun, XU Jianhai, LIU Jing. Establishment of Double-antibody Sandwich ELISA to Diagnose Acute Toxoplasmosis [J]. Acta Veterinaria et Zootechnica Sinica, 2020, 51(12): 3101-3110.
[12]	ZHANG Jin-wei, LONG Ke-ren, WANG Xun, LI Ming-zhou, MA Ji-deng. The Research Advance of Circular RNA [J]. ACTA VETERINARIA ET ZOOTECHNICA SINICA, 2016, 47(11): 2151-2158.
[13]	JIANG Wei, CHEN Yong-jun, ZHANG Hua-jing, LIU Ying-chun, JING Zhen-yu, XUE Jun-xin, WANG Quan. Treatment Effects of Sulfachloropyrazine-sodium with Scutellaria Baicalensis and Glycyrrhiza against Acute Murine Toxoplasmosis [J]. ACTA VETERINARIA ET ZOOTECHNICA SINICA, 2013, 44(12): 2022-2028.
[14]	ZHANG Song-lin, SHEN Zhi-qiang, LIU Lei, MA Yong-biao, LIU Ji-shan. Advance on Biological Functions of Structural and Non-structural Proteins of Porcine Reproductive and Respiratory Syndrome Virus [J]. ACTA VETERINARIA ET ZOOTECHNICA SINICA, 2012, 43(11): 1683-1696.
[15]	CHEN Jia;;WU Songming;;ZHU Xingquan;HUANG Siyang. Advances on the Studies of Parasite Proteasomes [J]. ACTA VETERINARIA ET ZOOTECHNICA SINICA, 2012, 43(1): 7-13.