固有免疫在微小隐孢子虫感染中的作用

摘要/Abstract

摘要：

微小隐孢子虫（Cryptosporidium parvum）是引起人类尤其是2岁以下婴幼儿腹泻的重要病原体。由于该病原体具有“微创”的特性,上皮细胞作为固有免疫的第一道屏障,在抵抗微小隐孢子虫感染中发挥着重要的作用。本文从上皮细胞分泌的效应分子、模式识别受体的激活、miRNA的调节、外泌体的释放以及补体系统等几个方面进行综述,以阐明固有免疫在抵抗微小隐孢子虫感染中的作用机制。

关键词: 微小隐孢子虫, 上皮细胞, 固有免疫, NF-κB信号通路

Abstract:

Cryptosporidium parvum is an important pathogen that causes diarrhea in humans, especially in children < 2 years. Because of the“minimally invasive” nature of Cryptosporidium parasites, the innate immune responses mediated by epithelial cells are critical for the host to defend against infection, particularly infection with Cryptosporidium. In this review, we focus on the effector molecules secreted by epithelial cells, pattern recognition receptor activation, miRNA regulation, exosome release, and the complement system, in order to elucidate the mechanisms underlying the role of innate immunity in defending against infection with Cryptosporidium parvum.

Key words: Cryptosporidium parvum, Epithelial cell, Innate immunity, NF-κB signaling pathway

中图分类号:

R382.3

刘晓洁, 毛铁波, 周蕊. 固有免疫在微小隐孢子虫感染中的作用[J]. 中国寄生虫学与寄生虫病杂志, 2017, 35(2): 185-192.

Xiao-jie LIU, Tie-bo MAO, Rui ZHOU. The role of innate immunity in defending against infection with Cryptosporidium parvum[J]. Chinese Journal of Parasitology and Parasitic Diseases, 2017, 35(2): 185-192.

图/表 1

参考文献 86

[1]	顾有方, 汪凯, 刘德义, 等. 宠物犬蓝氏贾第鞭毛虫和隐孢子虫感染的分子检测[J].中国寄生虫学与寄生虫病杂志, 2015, 33(5): 362-367.
[2]	王东, 张媛媛.隐孢子虫感染昆明小鼠后肠道病理变化及螺旋霉素治疗效果[J]. 中国寄生虫学与寄生虫病杂志, 2014, 32(3): 225-228.
[3]	孙涛, 刘维, 王菊花, 等. 合肥地区奶牛源隐孢子虫的分离与鉴定[J]. 中国寄生虫学与寄生虫病杂志, 2011, 29(6):447-452.
[4]	Striepen B.Parasitic infections: time to tackle cryptosporidiosis[J]. Nature, 2013, 503(7475): 189-191.
[5]	Kotloff KL, Nataro JP, Blackwelder WC, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries(the Global Enteric Multicenter Study, GEMS): a prospective, case-control study[J]. Lancet, 2013, 382(9888): 209-222.
[6]	Goodgame RW.Understanding intestinal spore-forming protozoa: cryptosporidia, microsporidia, isospora, and cyclospora[J]. Ann Intern Med, 1996, 124(4): 429-441.
[7]	Pierce KK, Kirkpatrick BD.Update on human infections caused by intestinal protozoa[J]. Curr Opin Gastroenterol, 2009, 25(1): 12-17.
[8]	Putignani L, Menichella D.Global distribution, public health and clinical impact of the protozoan pathogen Cryptosporidium[J]. Interdiscip Perspect Infect Dis, 2010, 2010: 366-366.
[9]	O’Donoghue PJ. Cryptosporidium and cryptosporidiosis in man and animals[J]. Int J Parasitol, 1995, 25(2): 139-195.
[10]	宋军澎, 赵继学, 高虹, 等. 长春地区医院就诊患者隐孢子虫感染的血清学检测[J]. 中国寄生虫学与寄生虫病杂志, 2011, 29(3): 239-243, 封3.
[11]	张小萍, 何艳燕, 朱倩, 等. 上海市饮用水和环境水中隐孢子虫和蓝氏贾第鞭毛虫污染状况调查[J]. 中国寄生虫学与寄生虫病杂志, 2010, 28(6): 435-438.
[12]	高姗姗, 吴绍强, 罗静,等. IMS-qPCR检测水源性微小隐孢子虫方法的建立[J]. 中国寄生虫学与寄生虫病杂志, 2013, 31(3): 180-184.
[13]	Chen XM, Keithly JS, Paya CV, et al. Cryptosporidiosis[J]. N Engl J Med, 2002, 346(22): 1723-1731.
[14]	Chen XM, O’Hara SP, Nelson JB, et al. Multiple TLRs are expressed in human cholangiocytes and mediate host epithelial defense responses to Cryptosporidium parvum via activation of NF-kappaB[J]. J Immunol, 2005, 175(11): 7447-7456.
[15]	Pantenburg B, Dann SM, Wang HC, et al. Intestinal immune response to human Cryptosporidium sp. infection[J]. Infect Immun, 2008, 76(1): 23-29.
[16]	周庆新, 李锦春, 徐前明, 等. 感染隐孢子虫奶牛血液免疫和抗氧化指标的变化[J].中国寄生虫学与寄生虫病杂志, 2012, 30(4): 301-304.
[17]	Petry F, Jakobi V, Tessema TS.Host immune response to Cryptosporidium parvum infection[J]. Exp Parasitol, 2010, 126(3): 304-309.
[18]	Kagnoff MF, Eckmann L.Epithelial cells as sensors for microbial infection[J]. J Clin Invest, 1997, 100(1): 6-10.
[19]	Wang HC, Dann SM, Okhuysen PC, et al. High levels of CXCL10 are produced by intestinal epithelial cells in AIDS patients with active cryptosporidiosis but not after reconstitution of immunity[J]. Infect Immun, 2007, 75(1): 481-487.
[20]	Harada K, Nakanuma Y.Cholangiopathy with respect to biliary innate immunity[J]. Int J Hepatol, 2012, 2012: 793569.
[21]	Okazawa A, Kanai T, Nakamaru K, et al. Human intestinal epithelial cell-derived interleukin(IL)-18, along with IL-2, IL-7 and IL-15, is a potent synergistic factor for the proliferation of intraepithelial lymphocytes[J]. Clin Exp Immunol, 2004, 136(2): 269-276.
[22]	Tessema TS, Schwamb B, Lochner M, et al. Dynamics of gut mucosal and systemic Th1/Th2 cytokine responses in interferon-gamma and interleukin-12p40 knock out mice during primary and challenge Cryptosporidium parvum infection[J]. Immunobiology, 2009, 214(6): 454-466.
[23]	Muller WA.Mechanisms of transendothelial migration of leukocytes[J]. Circ Res, 2009, 105(3): 223-230.
[24]	Gong AY, Hu G, Zhou R, et al. MicroRNA-221 controls expression of intercellular adhesion molecule-1 in epithelial cells in response to Cryptosporidium parvum infection[J]. Int J Parasitol, 2011, 41(3-4): 397-403.
[25]	Gong AY, Zhou R, Hu G, et al. MicroRNA-513 regulates B7-H1 translation and is involved in IFN-gamma-induced B7-H1 expression in cholangiocytes[J]. J Immunol, 2009, 182(3): 1325-1333.
[26]	Gong AY, Zhou R, Hu G, et al. Cryptosporidium parvum induces B7-H1 expression in cholangiocytes by down-regulating microRNA-513[J]. J Infect Dis, 2010, 201(1): 160-169.
[27]	Ricciardolo FL, Sterk PJ, Gaston B, et al. Nitric oxide in health and disease of the respiratory system[J]. Physiol Rev, 2004, 84(3): 731-765.
[28]	Leitch GJ, He Q.Reactive nitrogen and oxygen species ameliorate experimental cryptosporidiosis in the neonatal BALB/c mouse model[J]. Infect Immun, 1999, 67(11): 5885-5891
[29]	Gookin JL, Allen J, Chiang S, et al. Local peroxynitrite formation contributes to early control of Cryptosporidium parvum infection[J]. Infect Immun, 2005, 73(7): 3929-3936.
[30]	Gookin JL, Chiang S, Allen J, et al. NF-kappaB-mediated expression of iNOS promotes epithelial defense against infection by Cryptosporidium parvum in neonatal piglets[J]. Am J Physiol Gastrointest Liver Physiol, 2006, 290(1): G164-G174.
[31]	Zhou R, Gong AY, Eischeid AN, et al. miR-27b targets KSRP to coordinate TLR4-mediated epithelial defense against Cryptosporidium parvum infection[J]. PLoS Pathog, 2012, 8(5): e1002702.
[32]	Dommett R, Zilbauer M, George JT, et al. Innate immune defence in the human gastrointestinal tract[J]. Mol Immunol, 2005, 42(8): 903-912.
[33]	Zaalouk TK, Bajaj-Elliott M, George JT, et al. Differential regulation of beta-defensin gene expression during Cryptosporidium parvum infection[J]. Infect Immun, 2004, 72(5): 2772-2779.
[34]	Tarver AP, Clark DP, Diamond G, et al. Enteric beta-defensin: molecular cloning and characterization of a gene with inducible intestinal epithelial cell expression associated with Cryptosporidium parvum infection[J]. Infect Immun, 1998, 66(3): 1045-1056.
[35]	Marin F, Luquet G, Marie B, et al. Molluscan shell proteins: primary structure, origin, and evolution[J]. Curr Top Dev Biol, 2008, 80: 209-276.
[36]	Cevallos AM, Bhat N, Verdon R, et al. Mediation of Cryptosporidium parvum infection in vitro by mucin-like glycoproteins defined by a neutralizing monoclonal antibody[J]. Infect Immun, 2000, 68(9): 5167-5175.
[37]	Maynard CL, Elson CO, Hatton RD, et al. Reciprocal interactions of the intestinal microbiota and immune system[J]. Nature, 2012, 489(7415): 231-241.
[38]	Taylor BC, Zaph C, Troy AE, et al. TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis[J]. J Exp Med, 2009, 206(3): 655-667.
[39]	Reigstad CS, Lundén GO, Felin J, et al. Regulation of serum amyloid A3(SAA3)in mouse colonic epithelium and adipose tissue by the intestinal microbiota[J]. PLoS One, 2009, 4(6): e5842.
[40]	Choi SM, McAleer JP, Zheng M, et al. Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia[J]. J Exp Med, 2013, 210(3): 551-561.
[41]	Hayden MS, Ghosh S.Shared principles in NF-kappaB signaling[J]. Cell, 2008, 132(3): 344-362.
[42]	Zhou R, Hu G, Liu J, et al. NF-kappaB p65-dependent transactivation of miRNA genes following Cryptosporidium parvum infection stimulates epithelial cell immune responses[J]. PLoS Pathog, 2009, 5(12): e1000681.
[43]	Zhou R, O’Hara SP, Chen XM. MicroRNA regulation of innate immune responses in epithelial cells[J]. Cell Mol Immunol, 2011, 8(5): 371-379.
[44]	Pöppelmann B, Klimmek K, Strozyk E, et al. NF{kappa}B-dependent down-regulation of tumor necrosis factor receptor-associated proteins contributes to interleukin-1-mediated enhancement of ultraviolet B-induced apoptosis[J]. J Biol Chem, 2005, 280(16): 15635-15643.
[45]	Oeckinghaus A, Hayden MS, Ghosh S.Crosstalk in NF-κB signaling pathways[J]. Nat Immunol, 2011, 12(8): 695-708.
[46]	Chen XM, Levine SA, Splinter PL, et al. Cryptosporidium parvum activates nuclear factor kappaB in biliary epithelia preventing epithelial cell apoptosis[J]. Gastroenterology, 2001, 120(7): 1774-1783.
[47]	Abrahamsen MS.Complete genome sequence of the apicomplexan, Cryptosporidium parvum[J]. Science, 2004, 304(5669): 441-445.
[48]	Carpenter S, Aiello D, Atianand MK, et al. A long noncoding RNA mediates both activation and repression of immune response genes[J]. Science, 2013, 341(6147): 789-792.
[49]	Liu N, Olson EN.MicroRNA regulatory networks in cardiovascular development[J]. Dev Cell, 2010, 18(4): 510-525.
[50]	Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing data[J]. Nucl Acid Res, 2011, 39: D152-D157.
[51]	Kincaid RP, Sullivan CS.Virus-encoded microRNAs: an overview and a look to the future[J]. PLoS Pathog, 2012, 8(12): e1003018.
[52]	Zhou R, Feng Y, Chen XM.Non-coding RNAs in epithelial immunity to Cryptosporidium infection[J]. Parasitology, 2014, 141(10): 1233-1243.
[53]	Zhou R, Hu G, Gong AY, et al. Binding of NF-kappaB p65 subunit to the promoter elements is involved in LPS-induced transactivation of miRNA genes in human biliary epithelial cells[J]. Nucl Acid Res, 2010, 38(10): 3222-3232.
[54]	O’Hara SP, Splinter PL, Gajdos GB, et al. NFkappaB p50-CCAAT/enhancer-binding protein beta(C/EBPbeta)-mediated transcriptional repression of microRNA let-7i following microbial infection[J]. J Biol Chem, 2010, 285(1): 216-225.
[55]	Chen XM, Splinter PL, O’Hara SP, et al. A cellular micro-RNA, let-7i, regulates Toll-like receptor 4 expression and contributes to cholangiocyte immune responses against Cryptosporidium parvum infection[J]. J Biol Chem, 2007, 282(39): 28929-28938.
[56]	Hu G, Zhou R, Liu J, et al. MicroRNA-98 and let-7 confer cholangiocyte expression of cytokine-inducible Src homology 2-containing protein in response to microbial challenge[J]. J Immunol, 2009, 183(3): 1617-1624.
[57]	Hu G, Zhou R, Liu J, et al. MicroRNA-98 and let-7 regulate expression of suppressor of cytokine signaling 4 in biliary epithelial cells in response to Cryptosporidium parvum infection[J]. J Infect Dis, 2010, 202(1): 125-135.
[58]	Sheedy FJ, Palsson-McDermott E, Hennessy EJ, et al. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21[J]. Nat Immunol, 2010, 11(2): 141-147.
[59]	Asirvatham AJ, Gregorie CJ, Hu Z, et al. MicroRNA targets in immune genes and the Dicer/Argonaute and ARE machinery components[J]. Mol Immunol, 2008, 45(7): 1995-2006.
[60]	Ueda R, Kohanbash G, Sasaki K, et al. Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1[J]. Proc Natl Acad Sci USA, 2009, 106(26): 10746-10751.
[61]	Hu G, Gong AY, Liu J, et al. miR-221 suppresses ICAM-1 translation and regulates interferon-gamma-induced ICAM-1 expression in human cholangiocytes[J]. Am J Physiol Gastrointest Liver Physiol, 2010, 298(4): G542-G550.
[62]	Kawahigashi Y, Mishima T, Mizuguchi Y, et al. MicroRNA profiling of human intrahepatic cholangiocarcinoma cell lines reveals biliary epithelial cell-specific microRNAs[J]. Nippon Ika Daigaku Zasshi, 2009, 76(4): 188-197.
[63]	Stievano L, Piovan E, Amadori A.C and CX3C chemokines: cell sources and physiopathological implications[J]. Crit Rev Immunol, 2004, 24(3): 205-228.
[64]	Zhou R, Gong AY, Chen D, et al. Histone deacetylases and NF-kB signaling coordinate expression of CX3CL1 in epithelial cells in response to microbial challenge by suppressing miR-424 and miR-503[J]. PLoS One, 2013, 8(5): e65153.
[65]	Chen CY, Shyu AB.AU-rich elements: characterization and importance in mRNA degradation[J]. Trends Biochem Sci, 1995, 20(11): 465-470.
[66]	Dean JL, Sully G, Clark AR, et al. The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilization[J]. Cell Signal, 2004, 16(10): 1113-1121.
[67]	Anderson P.Post-transcriptional control of cytokine production[J]. Nat Immunol, 2008, 9(4): 353-359.
[68]	Stoecklin G, Anderson P.Post transcriptional mechanisms regulating the inflammatory response[J]. Adv Immun, 2006, 89(89): 1-37.
[69]	Winzen R, Thakur BK, Dittrich-Breiholz O, et al.Functional analysis of KSRP interaction with the AU-rich element of interleukin-8 and identification of inflammatory mRNA targets[J]. Mol Cell Biol, 2007, 27(23): 8388-8400.
[70]	Subramaniam D, Ramalingam S, May R, et al.Gastrin-mediated interleukin-8 and cyclooxygenase-2 gene expression: differential transcriptional and post transcriptional mechanisms[J]. Gastroenterology, 2008, 134(4): 1070-1082.
[71]	Pautz A, Art J, Hahn S, et al.Regulation of the expression of inducible nitric oxide synthase[J]. Nitric Oxide, 2010, 23(2): 75-93.
[72]	Théry C.Exosomes: secreted vesicles and intercellular communications[J]. Biol Rep, 2011, 3: 15.
[73]	Hu G, Drescher KM, Chen XM.Exosomal miRNAs: biological properties and therapeutic potential[J]. Front Genet, 2012, 3: 56.
[74]	Smalheiser NR.Exosomal transfer of proteins and RNAs at synapses in the nervous system[J]. Biol Direct, 2007, 2: 35.
[75]	Valadi H, Ekström K, Bossios A, et al.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells[J]. Nat Cell Biol, 2007, 9(6): 654-659.
[76]	Théry C, Ostrowski M, Segura E.Membrane vesicles as conveyors of immune responses[J]. Nat Rev Immunol, 2009, 9(8): 581-593.
[77]	Hu G, Gong AY, Roth AL, et al.Release of luminal exosomes contributes to TLR4-mediated epithelial antimicrobialdefense[J]. PLoS Pathog, 2013, 9(4): e1003261.
[78]	Mallegol J, Van Niel G, Lebreton C, et al.T84-intestinal epithelial exosomes bear MHC class Ⅱ/peptide complexes potentiating antigen presentation by dendritic cells[J]. Gastroenterology, 2007, 132(5): 1866-1876.
[79]	Robbins PD, Morelli AE.Regulation of immune responses by extracellular vesicles[J]. Nat Rev Immunol, 2014, 14(3): 195-208.
[80]	Barakat FM, McDonald V, Di Santo JP, et al. Roles for NK cells and an NK cell-independent source of intestinal gamma interferon for innate immunity to Cryptosporidium parvum infection[J]. Infect Immun, 2009, 77(11): 5044-5049.
[81]	McDonald V, Korbel DS, Barakat FM, et al. Innate immune responses against Cryptosporidium parvum infection[J]. Parasite Immunol, 2013, 35(2): 55-64.
[82]	Ungar BL, Kao TC, Burris JA, et al.Cryptosporidium infection in an adult mouse model independent roles for IFN-gammaand CD4+ T lymphocytesin protectiveimmunity[J]. J Immunol, 1991, 147(3): 1014-1022.
[83]	McDonald V, Bancroft GJ. Mechanisms of innate and acquired resistance to Cryptosporidium parvum infection in SCID mice[J]. Parasite Immunol, 1994, 16(6): 315-320.
[84]	Chen W, Harp JA, Harmsen AG.Requirements for CD4+ cells and gamma interferon in resolution of established Cryptosporidium parvum infection in mice[J]. Infect Immun, 1993, 61(9): 3928-3932.
[85]	Takeuchi D, Jones VC, Kobayashi M, et al.Cooperative role of macrophages and neutrophils in host antiprotozoan resistance in mice acutely infected with Cryptosporidium parvum[J]. Infect Immun, 2008, 76(8): 3657-3663.
[86]	Petry F, Jakobi V, Wagner S, et al.Binding and activation of human and mouse complement by Cryptosporidium parvum(Apicomplexa) and susceptibility of C1q- and MBL-deficient mice toinfection[J]. Mol Immunol, 2008, 45(12): 3392-3400.