载脂蛋白E及其模拟肽对细菌感染性疾病诊断和治疗作用及机制研究
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摘要
研究目的
1.研究血清及脑脊液(CSF)载脂蛋白E(ApoE)浓度测定对细菌性脓毒血症和细菌性脑膜炎的诊断价值。
2.通过体外细胞培养和动物实验,研究自主设计的ApoE模拟肽(ApoE23)的抗菌作用及其机制,为其作为新型抗菌药物和免疫调节剂的潜在临床应用提供实验依据。
研究方法
1.将临床已明确诊断的细菌性脑膜炎、病毒性脑膜炎、细菌性脓毒症患儿纳入研究,以非感染患儿为对照。除常规实验室检验指标(外周血白细胞计数、CRP、CSF常规及生化。CSF及血液细菌培养鉴定、CSF肺炎链球菌抗原检测和革兰染色、CSF肠道病毒RNA定量PCR检测)外,采用透射免疫比浊法测定研究对象的CSF及血清ApoE浓度,采用ROC曲线分析确定诊断界值(CUT-OFF),评价ApoE浓度测定对儿童侵袭性细菌感染的诊断价值。
2.自主设计ApoE模拟肽ApoE23序列,采用固相合成法合成,高效液相色谱法(HPLC)纯化,质谱及电喷雾质谱对合成肽纯度、氨基酸残基组成及分子量进行测定,圆二色谱技术结合K3D3软件进行合成肽二级结构分析。通过α螺旋轮法检测其亲水氨基酸残基及疏水氨基酸残基分布特点。
3. ApoE23抗菌活性采用体外杀菌试验。
4.采用体外细胞培养技术、酶联免疫吸附法(ELISA)、及定量PCR法检测ApoE23对LPS诱导的THP-1细胞(人单核细胞株)及人外周血单个核细胞(PBMC)的TNF-a、IL-6、IL-10表达的调节作用。
5.采用B组鼠伤寒沙门菌脓毒血症小鼠模型研究ApoE23静脉注射治疗对脓毒血症小鼠死亡率影响,通过对脓毒血症小鼠脾脏细菌负荷测定、血浆LPS、TNF-a、IL-6测定及对脾脏、肺脏、肝脏及小肠形态或病理切片分析了解ApoE23抗脓毒血症机理。
研究结果
1、共有185例患儿入组,其中细菌性脑膜炎患者26例,病毒性脑膜炎患儿32例,细菌性脓毒血症36例,对照组91例,年龄范围为1月～13岁。细菌性脑膜炎患儿脑脊液ApoE浓度与对照组相比明显增高,而病毒性脑膜炎、脓毒血症患儿脑脊液ApoE仅轻微升高。当脑脊液ApoE浓度cut-off值为1.7>mg/L,其诊断细菌性脑膜炎的敏感度、特异度、分别为0.85(95%CI,0.71-1)、1(95%CI,0.89-1),诊断价值高于脑脊液WBC计数、脑脊液总蛋白、葡萄糖及氯化物。当血清ApoE浓度cut-off值为42.0>mg/L,其诊断细菌性脓毒血症的敏感度、特异度分别为0.80(95%CI,0.64-0.89)、0.93(95%CI,0.88-0.97),诊断价值高于外周血CRP及WBC计数。
2、自主设计的ApoE23二级结构α螺旋比例为21.6%,且为两亲性螺旋,较国外同类肽具有更好的组织细胞穿透性。
3、ApoE23对革兰阴性杆菌有明显抗菌活性,其MIC50值为1～1.25μmol/L,低于国外同类肽(ApoEdp),对泛耐药鲍曼不动杆菌仍具有明显杀菌活性。ApoE23对革兰阳性葡萄球菌的杀菌活性低于革兰阴性杆菌,对肠球菌及对白色念珠无抗菌活性。
4. ApoE23具有显著下调LPS诱导的人PBMC及THP-1细胞TNF-a、IL-6mRNA及蛋白表达作用,下调THP-1IL-10mRNA及蛋白表达作用、下调人PBMCIL-10蛋白表达。
5、106CFU剂量B鼠伤寒沙门菌腹腔注射后24小时内,生理盐水治疗组小鼠死亡率为60%,ApoE23治疗组死亡率为0。ApoE治疗组小鼠体内细菌负荷、血浆TNF-a、1L-6、LPS浓度均低于生理盐水治疗组。ApoE23治疗组小鼠脾脏、肺脏、肝脏及小肠的炎性改变程度明显低于生理盐水治疗组。
结论
1、CSF和血清ApoE浓度测定可作为儿童侵袭性细菌感染的快速诊断指标,具有良好的特异性和敏感性。
2、自主设计的ApoE23抗菌谱窄,可抗胞内寄生菌及泛耐药菌,MIC50低,抗菌活性和组织穿透性优于国外同类肽,具有优质抗菌药物特性。
3、ApoE23对LPS诱导的体外培养免疫细胞的应答反应具有调节作用。
4、ApoE23具有的抗菌及免疫调节双重功能,可显著降低脓毒血症小鼠死亡率,是潜在的脓毒血症治疗药物。
Objective
1. To evaluate the potential diagnostic value of apolipoprotein E (Apo E) measurements in pediatric patients with invasive bacterial infections.
2. In the second part, we analyze the biological actions of antimicrobial and immunomodulatory activity of a new ApoE-dervied pepetide (ApoE23), and evaluated the therapeutic approach of ApoE23against the spesis in mice model.
Methods
1. The patients with confirmable infections, including bacterial meningitis, virus meningitis, and sepsis associated with bacterial infection, were enrolled in this study, and the subjects who were without confirmable infections were included as control.The investigative data collected from a series of laboratroy tests included the C-reactive protein levels in the peripheral blood, the peripheralblood white blood cell counts, the CSF routine tests and the CSF biochemical profiles, the microbiological results collected from bacterial cultivation in blood and CSF samples, the Streptococcus pneumonia antigens measurment and Gram strain in the CSF samples, and enterovirus RNA detection in the CSF samples. ApoE levels in serum and in CSF were measured by immunoturbidimetry. The diagnostic values of ApoE and the cut-off value of prediction for bacterial infections were established by the receiver operating curve (ROC) method.
2. The ApoE mimetic peptide, named ApoE23, was designed by ourself. ApoE23and control peptides (ApoEdp, ApoEll) were synthesized using solid phase synthesis and were purified by high performance liquid chromatography (HPLC).The mass spectrum and electrospray ionization mass spectrum (ESI-MS) were employed to check the produces. The secondary structures of the ApoE23and the control peptides were analyzed by circular dichroism spectra technique aided by K3D3software. The distribution patterns of hydrophobic amino acid residues and hydrophilic amino acid residues of the peptides were analyzed by a-helical wheel picture.
3. The antimicriobial activity of peptides were detected by bactericidal method in vitro.
4. Cell culture in vitro, Enzyme-Linked Immunosorbent Assay (ELISA)and quantified PCR were employed to measure the TNF-a, IL-6, and IL-10expressions in THP-1cells and human peripheral blood mononuclear cell (PBMC)induced by lipopolysaccharide (LPS)with or without ApoE23intervention.
5. The sepsis C57BL mice was established by peritoneal cavity injection of Salmonella typhimurium group B. After tail vein injection of ApoE23, the therapeutic effect were evaluated by calculation the mortality of the septic mice. The bacterial load test in the spleen tissue samples and the LPS, TNF-a, IL-6levels measurement in the plasma samples were carried out to investigate the anti-sepsis mechanisms of ApoE23.
Results
1. A total number of185pediatric patients aged from1month to13years old were enrolled. Among them,26patients with bacterial meningitis,32patients with virus meningitit,36patients with bacterial sepsis, and91patients without infections were enrolled in the control group. ApoE levels in CSF significantly increased in patients with bacterial meningitis, and serum ApoE markedly elevated in patients with sepsis or with bacterial meningitis compared with patients with other infections and uninfected children (control group). The optimal ApoE cutoff value for CSF was>1.7mg/L with85%(95%confidence interval,0.71-1) sensitivity and100%specificity (95%CI,0.89-1) and was>42mg/L in serum with80%(95%CI,0.64-0.89) sensitivity and93%(95%CI,0.88-0.97) specificity. The CSF ApoE level measurements by immunoturbidimetry showed higher diagnostic values than the CSF WBC count, CSF proteintest, and CSF glucose test. The diagnostic value of the serum ApoE measurement as an indicator of sepsis was higher than that of the CRP test and WBC count of whole blood.
2. The a-helical proportion in the secondary constrcture of ApoE23were21.6%,which appeared amphipathic properties and better penetrability than the other ApoE mimetic peptides designed by foreign.
3. ApoE23has higher bactericid activity against gram negtive bacterial than that against the gram positive germs. The same bactericid activities of ApoE23against resistant bacterial such as Acinetobacter baumannii were detected. The minimal inhibitory concentrations of inhibition by50%(MIC50) of ApoE23was in the range of1-1.25μmol/L, which is lower than the MIC50of the ApoEdp reported by now. However, no antimicrobial activities against enterococcus and Candida albicans were detected.
4. ApoE23down-regulated the mRNA and protein expression levels of TNF-a and IL-6induced by LPS in THP-1cells and human PBMC. ApoE23also down regulated the expression of IL-10in mRNA and protein levels in THP-1cells. But, in the human PBMC only IL-10protein was reduced.
5. Twenty-four hours after the live Salmonella typhimurium groups B (106CFU/mouse)were inculated by peritoneal cavity injection in the C57BL mice, the mortality of mice accepted physiological saline therapy was60%. No mouse died in the group with ApoE23treatment. Moreover, our results showed that the load of bacteria in the spleen tissue and the concentrations of plasma LPS, TNF-a, IL-6in the mice with ApoE23therapy were lower than that in the mice with physiological saline treatment. The morphological and pathological changes in the spleen, lung, liver and small intestine were slighter in the mice with ApoE23treatment than that in mice with physiological saline treatment.
Conclutions
1. CSF and serum ApoE detection provided with a good specificity and sensibility marker for prediction the invasive bacterial infections in pediatric patients.
2. ApoE23has good antibacterial characteristics including narrow antibacterial spectrum, low MIC50, showing antibacterial activity against intracellular growth of bacteria and the resistant bacteria.
3. ApoE23can regulate the response reaction induced by LPS in the immune cells cultured in vitro.
4. ApoE23has both of antibacterial effect and immunomodulatory effect, which can significantly reduce the mortality of the sepsis mice. ApoE23is a potential anti-sepsis drug.
1.研究血清及脑脊液(CSF)载脂蛋白E(ApoE)浓度测定对细菌性脓毒血症和细菌性脑膜炎的诊断价值。
2.通过体外细胞培养和动物实验,研究自主设计的ApoE模拟肽(ApoE23)的抗菌作用及其机制,为其作为新型抗菌药物和免疫调节剂的潜在临床应用提供实验依据。
研究方法
1.将临床已明确诊断的细菌性脑膜炎、病毒性脑膜炎、细菌性脓毒症患儿纳入研究,以非感染患儿为对照。除常规实验室检验指标(外周血白细胞计数、CRP、CSF常规及生化。CSF及血液细菌培养鉴定、CSF肺炎链球菌抗原检测和革兰染色、CSF肠道病毒RNA定量PCR检测)外,采用透射免疫比浊法测定研究对象的CSF及血清ApoE浓度,采用ROC曲线分析确定诊断界值(CUT-OFF),评价ApoE浓度测定对儿童侵袭性细菌感染的诊断价值。
2.自主设计ApoE模拟肽ApoE23序列,采用固相合成法合成,高效液相色谱法(HPLC)纯化,质谱及电喷雾质谱对合成肽纯度、氨基酸残基组成及分子量进行测定,圆二色谱技术结合K3D3软件进行合成肽二级结构分析。通过α螺旋轮法检测其亲水氨基酸残基及疏水氨基酸残基分布特点。
3. ApoE23抗菌活性采用体外杀菌试验。
4.采用体外细胞培养技术、酶联免疫吸附法(ELISA)、及定量PCR法检测ApoE23对LPS诱导的THP-1细胞(人单核细胞株)及人外周血单个核细胞(PBMC)的TNF-a、IL-6、IL-10表达的调节作用。
5.采用B组鼠伤寒沙门菌脓毒血症小鼠模型研究ApoE23静脉注射治疗对脓毒血症小鼠死亡率影响,通过对脓毒血症小鼠脾脏细菌负荷测定、血浆LPS、TNF-a、IL-6测定及对脾脏、肺脏、肝脏及小肠形态或病理切片分析了解ApoE23抗脓毒血症机理。
研究结果
1、共有185例患儿入组,其中细菌性脑膜炎患者26例,病毒性脑膜炎患儿32例,细菌性脓毒血症36例,对照组91例,年龄范围为1月～13岁。细菌性脑膜炎患儿脑脊液ApoE浓度与对照组相比明显增高,而病毒性脑膜炎、脓毒血症患儿脑脊液ApoE仅轻微升高。当脑脊液ApoE浓度cut-off值为1.7>mg/L,其诊断细菌性脑膜炎的敏感度、特异度、分别为0.85(95%CI,0.71-1)、1(95%CI,0.89-1),诊断价值高于脑脊液WBC计数、脑脊液总蛋白、葡萄糖及氯化物。当血清ApoE浓度cut-off值为42.0>mg/L,其诊断细菌性脓毒血症的敏感度、特异度分别为0.80(95%CI,0.64-0.89)、0.93(95%CI,0.88-0.97),诊断价值高于外周血CRP及WBC计数。
2、自主设计的ApoE23二级结构α螺旋比例为21.6%,且为两亲性螺旋,较国外同类肽具有更好的组织细胞穿透性。
3、ApoE23对革兰阴性杆菌有明显抗菌活性,其MIC50值为1～1.25μmol/L,低于国外同类肽(ApoEdp),对泛耐药鲍曼不动杆菌仍具有明显杀菌活性。ApoE23对革兰阳性葡萄球菌的杀菌活性低于革兰阴性杆菌,对肠球菌及对白色念珠无抗菌活性。
4. ApoE23具有显著下调LPS诱导的人PBMC及THP-1细胞TNF-a、IL-6mRNA及蛋白表达作用,下调THP-1IL-10mRNA及蛋白表达作用、下调人PBMCIL-10蛋白表达。
5、106CFU剂量B鼠伤寒沙门菌腹腔注射后24小时内,生理盐水治疗组小鼠死亡率为60%,ApoE23治疗组死亡率为0。ApoE治疗组小鼠体内细菌负荷、血浆TNF-a、1L-6、LPS浓度均低于生理盐水治疗组。ApoE23治疗组小鼠脾脏、肺脏、肝脏及小肠的炎性改变程度明显低于生理盐水治疗组。
结论
1、CSF和血清ApoE浓度测定可作为儿童侵袭性细菌感染的快速诊断指标,具有良好的特异性和敏感性。
2、自主设计的ApoE23抗菌谱窄,可抗胞内寄生菌及泛耐药菌,MIC50低,抗菌活性和组织穿透性优于国外同类肽,具有优质抗菌药物特性。
3、ApoE23对LPS诱导的体外培养免疫细胞的应答反应具有调节作用。
4、ApoE23具有的抗菌及免疫调节双重功能,可显著降低脓毒血症小鼠死亡率,是潜在的脓毒血症治疗药物。
Objective
1. To evaluate the potential diagnostic value of apolipoprotein E (Apo E) measurements in pediatric patients with invasive bacterial infections.
2. In the second part, we analyze the biological actions of antimicrobial and immunomodulatory activity of a new ApoE-dervied pepetide (ApoE23), and evaluated the therapeutic approach of ApoE23against the spesis in mice model.
Methods
1. The patients with confirmable infections, including bacterial meningitis, virus meningitis, and sepsis associated with bacterial infection, were enrolled in this study, and the subjects who were without confirmable infections were included as control.The investigative data collected from a series of laboratroy tests included the C-reactive protein levels in the peripheral blood, the peripheralblood white blood cell counts, the CSF routine tests and the CSF biochemical profiles, the microbiological results collected from bacterial cultivation in blood and CSF samples, the Streptococcus pneumonia antigens measurment and Gram strain in the CSF samples, and enterovirus RNA detection in the CSF samples. ApoE levels in serum and in CSF were measured by immunoturbidimetry. The diagnostic values of ApoE and the cut-off value of prediction for bacterial infections were established by the receiver operating curve (ROC) method.
2. The ApoE mimetic peptide, named ApoE23, was designed by ourself. ApoE23and control peptides (ApoEdp, ApoEll) were synthesized using solid phase synthesis and were purified by high performance liquid chromatography (HPLC).The mass spectrum and electrospray ionization mass spectrum (ESI-MS) were employed to check the produces. The secondary structures of the ApoE23and the control peptides were analyzed by circular dichroism spectra technique aided by K3D3software. The distribution patterns of hydrophobic amino acid residues and hydrophilic amino acid residues of the peptides were analyzed by a-helical wheel picture.
3. The antimicriobial activity of peptides were detected by bactericidal method in vitro.
4. Cell culture in vitro, Enzyme-Linked Immunosorbent Assay (ELISA)and quantified PCR were employed to measure the TNF-a, IL-6, and IL-10expressions in THP-1cells and human peripheral blood mononuclear cell (PBMC)induced by lipopolysaccharide (LPS)with or without ApoE23intervention.
5. The sepsis C57BL mice was established by peritoneal cavity injection of Salmonella typhimurium group B. After tail vein injection of ApoE23, the therapeutic effect were evaluated by calculation the mortality of the septic mice. The bacterial load test in the spleen tissue samples and the LPS, TNF-a, IL-6levels measurement in the plasma samples were carried out to investigate the anti-sepsis mechanisms of ApoE23.
Results
1. A total number of185pediatric patients aged from1month to13years old were enrolled. Among them,26patients with bacterial meningitis,32patients with virus meningitit,36patients with bacterial sepsis, and91patients without infections were enrolled in the control group. ApoE levels in CSF significantly increased in patients with bacterial meningitis, and serum ApoE markedly elevated in patients with sepsis or with bacterial meningitis compared with patients with other infections and uninfected children (control group). The optimal ApoE cutoff value for CSF was>1.7mg/L with85%(95%confidence interval,0.71-1) sensitivity and100%specificity (95%CI,0.89-1) and was>42mg/L in serum with80%(95%CI,0.64-0.89) sensitivity and93%(95%CI,0.88-0.97) specificity. The CSF ApoE level measurements by immunoturbidimetry showed higher diagnostic values than the CSF WBC count, CSF proteintest, and CSF glucose test. The diagnostic value of the serum ApoE measurement as an indicator of sepsis was higher than that of the CRP test and WBC count of whole blood.
2. The a-helical proportion in the secondary constrcture of ApoE23were21.6%,which appeared amphipathic properties and better penetrability than the other ApoE mimetic peptides designed by foreign.
3. ApoE23has higher bactericid activity against gram negtive bacterial than that against the gram positive germs. The same bactericid activities of ApoE23against resistant bacterial such as Acinetobacter baumannii were detected. The minimal inhibitory concentrations of inhibition by50%(MIC50) of ApoE23was in the range of1-1.25μmol/L, which is lower than the MIC50of the ApoEdp reported by now. However, no antimicrobial activities against enterococcus and Candida albicans were detected.
4. ApoE23down-regulated the mRNA and protein expression levels of TNF-a and IL-6induced by LPS in THP-1cells and human PBMC. ApoE23also down regulated the expression of IL-10in mRNA and protein levels in THP-1cells. But, in the human PBMC only IL-10protein was reduced.
5. Twenty-four hours after the live Salmonella typhimurium groups B (106CFU/mouse)were inculated by peritoneal cavity injection in the C57BL mice, the mortality of mice accepted physiological saline therapy was60%. No mouse died in the group with ApoE23treatment. Moreover, our results showed that the load of bacteria in the spleen tissue and the concentrations of plasma LPS, TNF-a, IL-6in the mice with ApoE23therapy were lower than that in the mice with physiological saline treatment. The morphological and pathological changes in the spleen, lung, liver and small intestine were slighter in the mice with ApoE23treatment than that in mice with physiological saline treatment.
Conclutions
1. CSF and serum ApoE detection provided with a good specificity and sensibility marker for prediction the invasive bacterial infections in pediatric patients.
2. ApoE23has good antibacterial characteristics including narrow antibacterial spectrum, low MIC50, showing antibacterial activity against intracellular growth of bacteria and the resistant bacteria.
3. ApoE23can regulate the response reaction induced by LPS in the immune cells cultured in vitro.
4. ApoE23has both of antibacterial effect and immunomodulatory effect, which can significantly reduce the mortality of the sepsis mice. ApoE23is a potential anti-sepsis drug.
引文
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