摘要
副猪嗜血杆菌(Haemophilus parasuis, HPS)属于革兰氏阴性多形短小杆菌,是猪Glasser氏病的致病菌,临床上典型症状为纤维素性多发性浆膜炎、多发性关节炎和脑膜炎。副猪嗜血杆菌感染已成为目前养猪生产中的严重威胁之一,造成了很大的经济损失。尽管商业化疫苗已经被开发出来,可是由于该细菌存在众多的血清型,市售疫苗往往难以起到全面的保护作用,这些局限也与目前人们对该细菌感染的分子机理缺乏深入的认识密切相关。从长远的角度考虑,在猪群中培育具有HPS抗性的新品系(品种)是解决感染的最佳途径,代表了未来养猪业可持续发展的方向。而无论是深入了解致病机理还是培育抗性品种都离不开对宿主候选基因的研究,也许,距离真正培育出抗性品种还比较遥远,但那仅仅是时间问题。基于这些科学疑问,本论文：
1.利用高通量基因芯片技术(Affymetrix Porcine GeneChip(?))首次对副猪嗜血杆菌感染后宿主的转录组变化(脾脏中,感染后6天检测)进行了分析。多种组织的切片结果显示：HPS感染在肺部、肝脏、脾脏中可导致明显的病理变化/较为强烈的免疫应答；以脾脏组织为主要研究对象的芯片原始数据先后经过GCRMA法标准化处理、SAM法显著性分析和基因注释之后共发现有286个基因存在显著差异表达,倍数变化(Fold Change, FC)>2,假阳性率(False Discovery Rate, FDR)<10%,其中157个基因上调表达,129个基因下调表达；定量PCR结果证明：这些差异表达基因真实可靠地反映出了组织本身在感染状态的转录组变化,排除了不确定因素的干扰；此外,还采用定量PCR (Quantitative real-time PCR, qRT-PCR)对芯片差异表达基因进行了进一步的验证。
2.利用Ingenuity(?)技术对HPS感染导致的差异表达基因所代表的生物学意义进行了全面地解析。分子水平上,HPS感染整体引起了机体一系列的功能性改变；先天免疫如炎症反应、免疫细胞迁移,后天免疫如细胞介导的免疫应答、体液介导的免疫应答,以及宿主抗微生物应答等均受到明显地影响；HPS入侵还导致宿主发生
一系列感染性疾病,特别明显的是呼吸系统疾病；其他重要的变化还包括多种组织器官的功能性障碍、物质代谢等,从分子水平上显示出宿主免疫应答与机体生长发育之间的内在联系。
3.重点对HPS感染过程中宿主的免疫应答进行了分析。结果表明：宿主免疫启动以MYD88 (myeloid differentiation primary response gene 88)依赖的TLR2 (Toll-like receptor 2)信号通路为主,该信号通路以核转录因子CEBPB (Ccaat/enhancer binding protein beta)为中心与感染过程中的炎症反应和急性期应答等重要免疫反应形成完整的信号转导级联；在差异表达基因的基础上揭示出了与呼吸系统疾病、遗传紊乱、关节炎等密切相关的分子网络；对差异显著的经典信号通路分析表明：HPS通过下调CCL5 (chemokine (C-C motif) ligand 5).PRKCH(protein kinase C, eta).ACTA1 (actin,alpha 1, smooth muscle, aorta)、ACTC1 (actin, alpha, cardiac muscle 1)、ACTG2 (actin, gamma 2, smooth muscle, enteric)、TRD@ (T cell receptor delta locus)以及CD3系列基因阻止先天免疫应答中吞噬细胞的募集、细胞内完整吞噬体的形成、先天免疫和后天免疫应答之间的信号交流并抑制淋巴细胞活化,这代表了HPS最主要的免疫逃避机制；
4.对HPS感染引起的猪钙粒蛋白基因S100A8 (S100 calcium binding protein A8)、S100A9 (S100 calcium binding protein A9)、S100A12 (S100 calcium binding protein A12)首次进行了基因克隆并分析了它们的基本分子特征。结果表明：猪钙粒蛋白基因组结构均由3个外显子和2个内含子组成,基因组全长分别为1000 bp、2817 bp、1440 bp;猪体细胞杂种板和辐射杂种板的基因定位结果显示它们均位于猪4号染色体q21-q23区段,与SW512紧密连锁；这3个基因主要在猪免疫器官或与免疫应答密切相关的器官如骨髓、淋巴节、肺脏、肝脏等组织中高表达,LPS和Poly (I:C)在猪PK-15细胞以及体外全血培养系统中的免疫刺激显著上调它们的表达,结果初步证明了它们在猪免疫应答中的重要作用。
5.结合生物信息学预测、启动子区系列删除实验和基因芯片结果初步表明：猪钙粒蛋白在HPS感染过程中的上调表达需要核转录因子CEBPB,基因转录与p38MAPK信号密切有关并极有可能依赖IL10；分子结构特征分析显示猪S100A8、S100A12、S100A9含有一些宿主保护性免疫应答中非常重要的氨基酸位点如Met(S100A8 Met42)位点和Zn2+结合位点等；提出了“猪钙粒蛋白主要通过调节炎症反应信号实现对宿主的免疫保护作用”这一假设。
6.通过对影响猪免疫力(Immune Capacity)的数量性状位点(QTLs)和HPS感染的差异表达基因进行联合分析,积极探索了特异性免疫应答对免疫力的影响,可能代表了今后数据联合分析的新方向。
总之,本论文内容填补了HPS感染过程中宿主应答方面的研究空白,鉴定出许多与感染密切相关的宿主基因,初步揭示了宿主免疫应答的分子信号通路和基因网络,这为深入了解HPS感染的致病机理、治疗、宿主抗性基因的筛选奠定了一定的基础,也为我们研究猪免疫应答提供了新的参考。
Haemophilus parasuis (HPS) is a small, pleomorphic, Gram-negative bacillus that causes Glasser's disease, which is characterized by fibrinous polyserositis, meningitis and arthritis. It has become an increasing threat in pig herds worldwide and causes devastating losses to the pig industry. Commercial vaccines against HPS have been developed, but none of them offer effective protection against all heterologous strains. One of the most important reasons is that little is known about the pathogenesis, especially, the host immune responses (IR) to the infection. In the long run, it will be the best to shift our focus in breeding for resistance to Glasser's disease. Research on host genes is not only helpful for our understanding of the pathogenesis but also very useful to enhance porcine genetic abilities to combat HPS. May be, there is still a long way to go, but much progress will be achived sooner or later. Because of these, in this article:
1. For the first time, we analyzed the global change following HPS infection in porcine spleen (6 days post infection) based on the Affmetrix Porcine GeneChip(?) technology. Histology detections of porcine main organs show that HPS infection result in significant responses in spleen, lung, and liver; Raw data of the GeneChip(?) was normalized by GCRMA method, following significant analysis using SAM. After gene annotations, a total of 286 genes (Fold change>2, False discovery rate<10%) are differentially expressed, in which 157 and 129 genes are up-regulated and down-regulated, respectively. No evidence was obtained that expression levels had changed as a result of significant migration of cells, which could result in masking of the gene expression levels (Quantitative real-time PCR results).10 genes were selectively validated using Quantitative real-time PCR (qRT-PCR)
2. Ingenuity(?) Pathway Analysis (IPA) of the microarray result show that HPS infection result in a serial significant changes of host biology functions, including those involved in innate IR, e.g., Inflammatory Response, Immune Cell Trafficking, and adaptive IR, e.g., Humoral Immune Response, Cell-mediated Immune Response, and Antimicrobial Response; Infection also result in several kinds of infectious diseases such as respiratory disease; Additionally, tissue or organ abnormals and metabolisms such as those in lipids, amino acids, vitamins, and minerals are significantly affected too. These data indicate a molecular connection between IRs and organismal development.
3. Host IRs are the main issue during HPS infection. Our results indicate that the MYD88 (myeloid differentiation primary response gene 88) dependent TLR2 (Toll-like Receptor 2) signaling plays a crucial role in initiating host IRs following HPS infection. CEBPB (Ccaat/enhancer binding protein beta) is the core transcription factor in this signaling that connect to a wide range of cascades like inflammatory responses and acute phase reactions. Gene networks on respiratory disease, genetic disorder, arthritis, etc., are identified too; Canonical pathway analysis indicate that HPS employes several strategies for immune evasion, including inhibiting leukocyte migrations, phagocytosis, and communations between immune cells in innate IR and activation of T/B lymphocytes in adaptive IR and so on. Key down-regulated genes in these dead pathways are CCL5 (chemokine (C-C motif) ligand 5), PRKCH(protein kinase C, eta), ACTA1 (actin, alpha 1, smooth muscle, aorta), ACTC1 (actin, alpha, cardiac muscle 1), ACTG2 (actin, gamma 2, smooth muscle, enteric), TRD@ (T cell receptor delta locus), and CD3.
4. All of the three genes encoding porcine calgranulins:S100A8 (S100 calcium binding protein A8), S100A9 (S100 calcium binding protein A9), and S100A12 (S100 calcium binding protein A12), which are closely related to HPS infection are cloned. Our results show that they share the same gene structures with human/mouse homologs. The genome (1000 bp、2817 bp、1440 bp in order) comprises 3 exons dividing by 2 introns; Gene mapping using SCHP (Somatic Cell Hybrid Panel) and IMpRH (INRA-UMN porcine Radiation Hybrid panel) show that they are located on SSC4 q21-q23 and closely linked with SW512; Under normal condition, most abundant mRNA levels are seen in the organs of the immune system, e.g., bone marrow, spleen, and lymph nodes, and other organs that have important functions during IR such as lung and liver; Immunostimulations in PK-15 (porcine kidney-15) cells and porcine whole blood cultures mimicking bacterial or viral infections using LPS and Poly (I:C) significantly enhanced their mRNA levels. These results further confirmed their immunological characterizations.
5. Promoter analysis of porcine S100A8, S100A9, and S100A12 were performed by bioinformatics predictions in combine with promoter serial deletion experiments. We show that CEBPB is required for their up-regulations during HPS infection. The up-regulation is also closely related to p38 MAPK pathway and maybe IL10 dependent. Importantly, there are many key amino acid sites in these molecues such as Met42 in porcine S100A8 and Zn2+-binding sites that have been proven to play key antimicrobial roles in human and/or mouse. All together, we herein presume that porcine calgranulins might protect host from HPS infection (or many other kinds of pathogens in pig) through regulating inflammations.
6. At last but not least, we show a meta-analysis between differentially expressed genes during HPS infection and the up-to-date pig QTLs (quantitative trait locus) of Immune Capacity. Many interesting candiadate genes are identified, indicating that important relationships exist between these genes and the pig general resistance. The method we use provide a new way for high-throughout data analysis and may have a "bright" usage in the future for a deep understanding of candidate genes in pig breeding. In conclusion, we herein fill the "blank" on host responses to HPS infection. Genes, pathways, and gene networks underlying the infection are identified. These results will lead to therapies for HPS and candidate genes for HPS resistance as well as provide fundamental information regarding porcine immune response mechanisms.
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