摘要
栉孔扇贝是我国重要的海水养殖优势品种之一。然而近年来养殖病害频发，特别是扇贝育苗期间苗种的病害问题，严重制约着扇贝养殖业健康持续的发展。从个体发育早期免疫系统入手，深入研究扇贝免疫系统发生与发育的调控过程及母源免疫的作用机制，探讨提高扇贝苗种免疫力的有效方法和途径，创新苗种养殖方式，是保障扇贝养殖业健康持续发展的重要途径。本论文以栉孔扇贝为研究对象，采用分子生物学和免疫学技术，分析了扇贝造血相关转录因子的结构和功能及其与免疫分子在扇贝早期发育中的时空表达模式，初步探讨了扇贝免疫系统发生过程；并研究了母源免疫分子的传递及传代免疫效应，揭示了母源免疫及其传代效应在扇贝发育早期免疫防御中的重要作用。
1.栉孔扇贝造血相关转录因子结构和功能的鉴定与分析
克隆获得栉孔扇贝造血相关转录因子CfRunt、CfCBFβ和CfGATA基因的cDNA序列。它们分别含有保守的runt同源结构域、CBF_beta结构域和两个ZnF_GATA锌指结构域，分别属于runx、CBFβ和GATA123家族成员。体外重组蛋白CfRunt和CfGATA均能与特异DNA基序相结合，而CfCBFβ能够显著促进CfRunt的DNA结合活性。鳗弧菌刺激后，栉孔扇贝循环血细胞数量在6h时显著下降至最低值，48h时与对照组差异不显著；而CfRunt和CfCBFβmRNA的表达分别于6-48h和6-96h显著上调，CfGATA mRNA表达于6-12h时显著下调。CfRunt和CfGATA基因干扰能够引起栉孔扇贝血细胞新生率和循环血细胞数量的显著下降。在CfRunt基因干扰后，LPS刺激能够显著诱导CfRunt mRNA表达，并且血细胞新生率及循环血细胞数量均显著升高；而CfGATA基因干扰后，LPS刺激未能引起CfGATA mRNA表达、血细胞新生率及循环血细胞数量的显著变化。以上研究结果表明造血相关转录因子CfRunt、CfCBFβ和CfGATA在扇贝血细胞生成中发挥重要作用。
2.造血相关转录因子在个体早期发育中的时空表达及对菌刺激的响应模式
在栉孔扇贝早期个体发育过程中，CfRunt和CfCBFβ mRNA的表达分别在32细胞期、D形幼虫期或面盘幼虫后期显著升高，而CfGATA mRNA表达在原肠期时达到最大值。整体免疫荧光定位研究发现CfRunt蛋白最早表达于32细胞期的整个胚胎中，随后其分布逐渐特化，分别位于桑葚胚的植物极细胞、原肠胚的中胚层和早期担轮幼虫的腹侧原担轮中。在担轮幼虫早期，CfRunt、CfCBFβ和CfGATA均出现于幼虫原担轮基部两侧对称细胞中。在D形幼虫期CfRunt和CfGATA主要分布于面盘基部两侧细胞，CfCBFβ在面盘基部的表达消失，而在幼虫背侧后部出现一个有造血相关转录因子较强表达的囊状区域。在面盘幼虫中期造血相关转录因子在面盘基部的表达均消失，主要表达于幼虫背侧后部的囊状区域中。鳗弧菌刺激后，担轮、D形和面盘后期幼虫中CfRunt和CfGATA mRNA的表达分别于6、12或24h时显著上调；而CfCBFβ在D形和面盘后期幼虫中的表达分别于12h时显著下调和上调。以上研究结果表明在早期个体发育过程中，扇贝可能经历了两次造血过程，分别发生在早期担轮幼虫原担轮基部的两侧对称细胞中和D形幼虫背侧后部的囊状区域。
3.免疫分子在个体早期发育中的时空表达及对菌刺激的响应模式
研究发现PRR分子（CfPGRP-S1、CfLGBP、CfLec-1和CfLec-3）和免疫效应分子（CfLYZ和CfLBP/BPI）mRNA分别于担轮幼虫期和D形幼虫期开始大量表达，在随后发育过程中均保持较高表达水平，而CfCu/Zn-SOD和CfCATmRNA表达水平均在面盘幼虫早期时显著升高。整体免疫荧光定位显示PRR和免疫效应分子的表达均最早出现于担轮幼虫原担轮基部的两侧对称细胞或D形幼虫面盘基部两侧细胞中。在面盘幼虫期各分子分布出现差异，PRR分子和CfLBP/BPI主要位于幼虫的面盘、口、食道或胃部，而CfLYZ、CfCAT和CfCu/Zn-SOD主要位于消化腺、胃或面盘中。鳗弧菌刺激后，担轮幼虫后期中免疫效应分子在6或12h时显著上调，在D形幼虫后期，除CfCAT外，其它免疫分子mRNA表达均显著上调或下调；在面盘幼虫后期，除CfLGBP显著下调外，其它免疫分子mRNA表达均在6或12h显著上调。说明在个体发育过程中，扇贝免疫系统最早形成于担轮幼虫原担轮基部的两侧对称细胞中，在D形幼虫时期逐渐发育，到面盘幼虫早期时其发育较为成熟，免疫分子功能性的分布在各个组织中，并具有较完善的免疫应答能力。
4.母源免疫分子传递及传代免疫效应
研究发现栉孔扇贝卵细胞中CfCu/Zn-SOD mRNA的表达水平最高，其它免疫分子（CfLBP/BPI、CfLGBP、CfLec-3和CfLYZ）mRNA水平相对较低。相比之下，除CfLec-3外，卵细胞中其它免疫分子的蛋白均有较高表达，其中CfCu/Zn-SOD蛋白含量最高。扇贝卵细胞蛋白提取液对大肠杆菌、鳗弧菌和酵母菌具有较明显的凝集和损伤作用，而对金黄色葡萄球菌无凝集和损伤作用。用灭活的鳗弧菌对亲贝进行免疫刺激后，除CfLGBP外，其它免疫分子的蛋白表达在扇贝子代卵细胞、胚胎或幼虫中均明显升高，且在卵细胞、4细胞和担轮幼虫期，母源免疫刺激组的抗菌活力和Cu/Zn-SOD活力显著高于相应对照组。鳗弧菌感染试验发现在担轮幼虫和D形幼虫期，母源免疫刺激组扇贝子代的死亡率均显著低于对照组。以上结果表明栉孔扇贝中存在母源免疫分子的传递及传代免疫效应，且它们在扇贝发育早期对病原入侵的免疫防御中发挥重要作用。
综上所述，在个体发生过程中，栉孔扇贝经历两次造血过程，免疫系统在担轮幼虫期开始出现，至面盘幼虫早期发育较为成熟。在免疫系统发育成熟前，母源免疫在免疫防御中发挥重要作用。该研究结果为进一步阐明贝类免疫系统发生的调控机制提供线索，同时也为创新贝类苗种养殖方式提供了理论依据。
The scallop Chlamys farreri is one of the important economic mollusc speciescultured widely in China. However, the frequently occurrence of infectious disease inscallop aquaculture, especially during the larviculture stage has been threatening thesustainable development of the industry seriously. A better understanding of theontogenesis of immune system in scallop C. farreri and the maternal immunity atearly life stage is not only enriching the knowledge of mollusc developmentalimmunology, but also helping us to find available way for disease management duringlarviculture. In the present study, using molecular biological and immunologicalmethods, hematopoietic transcription factors were identified and functional analyzed,and the expression pattern of these transcription factors and immune factor duringscallop ontogenesis was examined to explore the ontogeny of immune system.Moreover, the maternal immunity of scallop and its trans-generational effect wasinvestigated to explore their protective role at early life stage.
1. Identification and functional analysis of hematopoietic transcription factorsin scallop
Three hematopoietic transcription factor genes CfRunt, CfCBFβ and CfGATAwere cloned from scallop C. farreri, which contains conserved runt homology domain,core binding factor beta domain and zinc finger GATA domain respectively,belonging to the runx, CBFβ and GATA123family. The recombinant protein ofCfRunt and CfGATA could bind to the DNA motif specifically, while CfCBFβ couldsignificantly increase the DNA binding activity of CfRunt. After Vibrio anguillarumstimulation, the number of circulating hemocytes was significant decreased to thelowest level at6h, and has no significant difference with that of control until48h,whereas the mRNA expression of CfRunt and CfCBFβ was significantly up-regulatedat6-48h or6-96h respectively, and the expression of CfGATA was dramaticallydown-regulated between6-12h. In vivo RNA interference of CfRunt and CfGATAcould induce the remarkable decreases of hemocytes renew rate and circulatinghemocytes number in scallop. Moreover, after the RNA interference of CfRunt, thecontinual LPS stimulation could up-regulate the expression of CfRunt, and induce the increases of hemocytes renew rate and circulating hemocytes number. In contrast,LPS stimulation in CfGATA interference group could not induce significant changesof CfGATA expression, as well as hemocytes renew rate and circulating hemocytesnumber. The results indicated that hematopoietic transcription factor CfRunt, CfCBFβand CfGATA play essential role in regulating hemocyte production.
2. The expression of hematopoietic transcription factors during ontogenesis ofscallop and its response to bacterial challenge
During the early developmental stages of scallop, both mRNA expression levelsof CfRunt and CfCBFβ increased significantly at32-cell stage and D-hinged larvaestage, also at late veliger larval stage for CfCBFβ, while CfGATA expression wasreached to the highest level at gastrula. Further whole mount embryoimmunofluorescence assay showed that CfRunt protein was first expressed in thewhole embryo at32-cell stage, then its distribution was specialized with development,locating mainly in the vegetal pole cells of morula, mesoderm of gastrula and ventralprototroch of trochophore subsequently. At early trochophore stage, CfRunt, CfCBFβand CfGATA were all appeared symmetrically on the basal side of ventral prototrochof larvae as the bilateral cells. Since the bilateral cells of CfRunt and CfGATA wereshifted to the basal side of larvae velum at D-hinged larval stage, the expression ofCfCBFβ on velum was disappeared; however a new saccular area appeared in thedorsal posterior of larvae with strong expression of the three hematopoietictranscription factors. Subsequently, in mid-veliger larvae, the expression of CfRuntand CfGATA on velum was also disappeared, and all of the hematopoietictranscription factors were expressed remarkably in the saccular area. In addition, themRNA expression of CfRunt and CfGATA at late trochophore, D-hinged and veligerlarval stages was significantly up-regulated at6,12or24h after V. anguillarumstimulation respectively, while the expression of CfCBFβ was significantly down-regulated and up-regulated at D-hinged and veliger larval stages after12h V.anguillarum stimulation. The results indicated that the scallop might experience twowaves of hematopoiesis during ontogenesis, which occurred at ventral prototroch oftrochophore as the bilateral cells and the saccular area in the dorsal posterior ofveliger larvae resceptively.
3. The expression of immune factors during ontogenesis of scallop and itsresponse to bacterial challenge
The mRNA expression of PRR (CfPGRP-S1, CfLGBP, CfLec-1and CfLec-3)and immune effectors (CfLYZ and CfLBP/BPI) was dramatically increased attrochophore or D-hinged larvae respectively, and then kept at a high expression level,whereas the mRNA expression of CfCu/Zn-SOD and CfCAT was significantlyincreased until early veliger larval stage. Consistently, the whole mount embryoimmunofluorescence assay showed that all of the PRR and immune effectors was firstappeared symmetrically in the bilateral cells of prototroch in trochophore or the velumin D-hinged larvae. However, the distribution of these immune factors was differentafter early veliger larvae. PRR and CfLBP/BPI was mainly located in the velum,mouth, esophagus or stomach region of early and mid-veliger larvae, while CfLYZ,CfCAT and CfCu/Zn-SOD mainly located in the digestive gland, stomach or velumregion. After V. anguillarum stimulation, the mRNA expression of immune effectorswas significantly up-regulated at6or12h in trochophore respectively. In D-hingedlarvae, the mRNA expression of immune factors was significantly up-regulated ordown-regulated after stimulation except CfCAT, while all expression of the immunefactors was up-regulated at6or12h at late veliger larval stage. The results suggestedthat the immune system might firstly formed in the bilateral cells of ventral prototrochof trochophore, developed gradually at D-hinged larvae, and then matured at earlyveliger larvae when it possessed functional immune response.
4.Maternal transfer of immune factors and its trans-generational effect inscallop
In the eggs of scallop, the mRNA transcript of CfCu/Zn-SOD was higher thanother immune factors, such as CfLBP/BPI, CfLGBP, CfLec-3and CfLYZ, which wasextremely lower in eggs. In contrast, the protein level of those immune factors wasdectected highly except CfLec-3, while the protein level of CfCu/Zn-SOD was alsothe highest. The protein extract of scallop eggs exhibited remarkable agglutinationactivity and bactericidal effect against gram-negative bacteria Escherichia coli and V.anguillarum, and fungi P. pastoris, but gram-positive bacteria Staphyloccocus aureus.Furthermore, the protein contents of LBP/BPI, LYZ and Cu/Zn-SOD increasedsignificantly in the offspring when female scallop was stimulated with heat-killed V.anguillarum, also a significant enhancement of the Cu/Zn-SOD and antibacterialactivity was observed in the offspring from maternal immune stimulated mother scallops at eggs,4-cell and trochophore stages. Moreover, the mortality of offspringfrom the maternal immune stimulated mother scallops was significantly lower thanthat of control in trochophore and D-hinged larvae after bacterial challenge. Theresults suggested that the maternal factors could be transferred to offspring in scallop,and the maternal immunity have the trans-generational effect which played importantrole in protecting the offspring against pathogens.
In summary, it could be considered that with two waves of hematopoiesis, theimmune system of scallop was formed firstly at trochophore stage, and functionalmatured after early veliger larval stage. Maternal immunity was available to protectthe offspring from invading pathogens before the maturation of immune system.These data provided useful evidences for the further study on the regulationmechanism of immune system ontogenesis, as well as enriched our knowledge todevelop new strategy for scallop aquaculture.
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