CN113058029A - 胶原凝集素-11在制备防治泌尿系统感染的药物中的应用 - Google Patents
胶原凝集素-11在制备防治泌尿系统感染的药物中的应用 Download PDFInfo
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Abstract
本发明公开了胶原凝集素‑11在制备防治泌尿系统感染的药物中的应用,本发明通过实验首次揭示了CL‑11在致病性大肠杆菌引起的急性泌尿系统感染中是重要的宿主防御机制,并在动物模型中给予重组CL‑11,发现外源性CL‑11可以有效减轻小鼠急性肾盂肾炎症状。本申请通过在动物模型中证实CL‑11在泌尿系统感染中发挥保护作用并发现其作用机制,因此为泌尿系统感染过程中的宿主防御机制提供新的见解,本发明能够提供治疗新策略以改善当前治疗方案,并有助于应对抗生素耐药。
Description
技术领域
本发明属于生物医药领域,涉及胶原凝集素-11在制备防治泌尿系统感染的药物中的应用。
背景技术
泌尿系统感染是最常见的感染性疾病之一,全球每年新增病例有1.5至2.5亿例。泌尿系统感染多见于妇女、儿童和老人,也是长期困扰糖尿病、肾移植以及导尿管留置患者的临床问题。尽管抗生素可用于治疗,但在临床上还有不少亟待解决的问题,如感染的反复发作、顽固性感染以及抗生素耐药风险不断增高等。抗生素耐药是人类目前以及未来几十年所面临的最大的健康威胁之一。在全球范围内,多药耐药泌尿致病性大肠杆菌的患病率不断上升,并对抗生素耐药的整体发生率升高有重要影响。因此,非常有必要进一步认识泌尿系统感染的病理机制,积极探寻宿主内源性防御机制,找出治疗新策略以改善当前治疗方案。
胶原凝集素(Collectins)是一组可溶性的C型凝集素,已知的成员包括甘露糖结合凝集素(MBL),肺表面活性蛋白分子SP-A,SP-D以及新发现的胶原凝集素10,11,12(CL-10,CL-11,CL-12)。作为可溶性模式识别受体,胶原凝集素家族成员们是固有免疫系统网络调控的重要组成部分,它们可结合病原菌或宿主细胞表面糖类分子或特定受体,介导一系列的生物学效应,如调理吞噬,调控炎症反应,中和病原菌以及引发补体系统激活,从而在宿主防御、清除凋亡细胞以及在疾病发病机制中扮演重要角色。
胶原凝集素-11(CL-11,也称作Collectin kidney 1,CL-K1)是最近发现的凝集素家族新成员,与其它家族成员结构类似,CL-11由三条多肽链组成同源三聚体结构(100kDa),每条肽链包括头部糖类识别区域(carbohydrate recognition domain,CRD)、颈部区域(neck region)、胶原样区域(collagen-like region,CLR)以及N末端区域。其头部CRD区域可以识别并结合细菌或者细胞表面的岩藻糖或者甘露糖糖基(N-聚糖),或作为配体被免疫细胞表面的特异性受体(如SIRPα)识别;而尾部CLR区域则可识别免疫细胞的钙网蛋白/CD91共受体(Calreticulin/CD91)促进调理吞噬作用。与其他胶原凝集素相比,CL-11具有其独特之处,如:CL-11具有广泛的组织表达分布(高表达于肾脏,肝以及肾上腺),但其血清浓度相对较低(约为300ng/ml),能够与更为广泛的配体相结合。因此,CL-11可能参与更为广泛的细胞生物学功能;组织器官局部生成的CL-11可能在病原菌入侵处发挥重要的宿主防御作用。
尽管最近有报道发现CL-11在由肺炎链球菌引起的肺部感染中发挥重要保护作用,但CL-11在泌尿系统感染过程中所起的作用尚未见任何报道。
发明内容
为了克服上述现有技术的缺点,本发明的目的在于提供胶原凝集素-11在制备防治泌尿系统感染的药物中的应用。
为了达到上述目的,本发明采用以下技术方案予以实现:
本发明公开了胶原凝集素-11在制备预防和/或治疗泌尿系统感染的药物中的应用。
优选地,所述的药物为促进细菌凝集的药物。
优选地,所述的药物为减少细菌在膀胱和肾脏定量增殖的药物。
优选地,所述的药物为降低肾脏组织促炎症细胞因子水平的药物。
进一步优选地,所述促炎症细胞因子包括TNF-a,IL-6,CXCL-1,IL-17A和IL-10。
优选地,所述的药物为减轻急性肾盂肾炎症状的药物。
进一步优选地,所述的药物为减少肾脏组织中细菌负荷量、组织损伤及炎症程度的药物。
本发明还公开了一种重组Collectin-11蛋白在制备预防和/或治疗泌尿系统感染的药物中的应用,所述重组Collectin-11蛋白的氨基酸序列如SEQ.ID.NO.1所示。
优选地,所述重组Collectin-11蛋白能够与细菌结合并促进细菌凝集。
本发明还公开了一种表达载体在制备预防和/或治疗泌尿系统感染的药物中的应用,所述表达载体能够促进Collectin-11基因表达上调。
与现有技术相比,本发明具有以下有益效果:
本发明通过实验首次揭示了CL-11在致病性大肠杆菌引起的急性泌尿系统感染中是重要的宿主防御机制,并在动物模型中给予重组Collectin-11蛋白(重组CL-11),发现外源性CL-11可以有效减轻小鼠急性肾盂肾炎症状。本申请通过在动物模型中证实CL-11在泌尿系统感染中发挥保护作用并发现其作用机制,因此为泌尿系统感染过程中的宿主防御机制提供新的见解,本发明能够提供治疗新策略以改善当前治疗方案,并有助于应对抗生素耐药。
附图说明
图1为构建的pcDNA3.1(-)-CL-11表达质粒结构示意图;
图2为在HEK293细胞中转染及表达结果图;
图3为螯合SFF(Ni)柱纯化蛋白结果图;
图4为验证纯化蛋白产物的western blot结果图;
图5为WT和CL11KO小鼠膀胱感染情况;其中,(a)为感染3小时后两组小鼠膀胱内细菌负荷量计数(CFU)结果;(b)为感染6小时后两组小鼠膀胱内细菌负荷量计数(CFU)结果;(c)为感染24小时后两组小鼠膀胱内细菌负荷量计数(CFU)结果;
图6为WT和CL11KO小鼠肾脏感染情况;其中,(a)为感染6小时后两组小鼠肾脏内细菌负荷量计数(CFU)结果;(b)为感染24小时后两组小鼠肾脏内细菌负荷量计数(CFU)结果;(c)为感染48小时后两组小鼠肾脏内细菌负荷量计数(CFU)结果;
图7为感染48小时后两组小鼠肾脏病理损伤结果;其中,(a)为WT组PAS染色切片结果;(b)为CL-11敲除小鼠组PAS染色切片结果;(c)为两组小鼠肾脏组织病理学评分结果;
图8为两组小鼠感染48小时后肾脏组织表达炎症因子变化结果(RT-PCR);其中,(a)为TNF-α水平;(b)为IL-6水平;(c)为KC水平;(d)为MCP-1水平;(e)为IL-17A水平;(f)为IL-10水平;
图9为感染48小时后,两组小鼠肾脏组织中炎症细胞浸润结果;其中,(a)为WT组CD45阳性白细胞免疫组化染色切片结果;(b)为CL-11敲除小鼠组CD45+白细胞免疫组化染色切片结果;(c)为两组小鼠CD45阳性白细胞数目统计结果;(d)为WT组Ly6G阳性中性粒细胞免疫组化染色切片结果;(e)为CL-11敲除小鼠组Ly6G阳性中性粒细胞免疫组化染色切片结果;(f)为两组小鼠肾脏组织中Ly6G阳性中性粒细胞数目统计结果;
图10为不同浓度CL-11与细菌共孵育后引起细菌凝集的结果;其中,(a)为流式结果图;(b)为统计结果图;(c)为对照组免疫荧光染色结果;(d)为CL-11给药组细菌凝集免疫荧光染色结果;
图11为CL11可以抑制细菌运动性结果展示;其中,(a)为不同浓度CL11对细菌运动性影响作用;(b)为不同时间点24h,48h,96h,CL11对细菌运动性的影响作用;(c)为BSA对照细菌在培养基运动性情况;(d)为CL11对照细菌在培养基运动性情况;
图12为CL11治疗小鼠膀胱和肾脏感染情况;其中,(a)为对照组和CL-11给药组小鼠膀胱细菌CFU计数结果;(b)为对照组和CL-11给药组小鼠肾脏细菌CFU计数结果;
图13为CL11能够减少早期细菌在膀胱和肾脏的粘附;其中,(a)为感染3小时细菌粘附对照组小鼠膀胱免疫荧光结果;(b)为感染3小时后CL-11给药组细菌粘附小鼠膀胱免疫荧光结果;(c)为感染3小时后两组小鼠膀胱荧光细菌计数统计结果;(d)为感染6小时后细菌粘附对照组小鼠肾脏免疫荧光结果;(e)为感染6小时后CL-11给药组细菌粘附小鼠肾脏免疫荧光结果;(f)为感染6小时后细菌粘附两组小鼠肾脏细菌计数统计结果;
图14为感染24小时后两组小鼠肾脏病理损伤结果;其中,(a)为对照组PAS染色切片结果;(b)为CL-11给药组PAS染色切片结果;(c)为两组小鼠肾脏组织病理学评分结果;
图15为感染24小时后对照组和CL-11给药组小鼠肾脏组织表达炎症因子变化结果(RT-PCR);其中,(a)为TNF-α水平;(b)为IL-6水平;(c)为CXCL-1水平;(d)为IL-17A水平;(e)为IL-10水平;
图16为全身给药后,重组Collectin-11在小鼠脾脏、淋巴结和肾脏组织中的分布。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分的实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都应当属于本发明保护的范围。
需要说明的是,本发明的说明书和权利要求书及上述附图中的术语“第一”、“第二”等是用于区别类似的对象,而不必用于描述特定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换,以便这里描述的本发明的实施例能够以除了在这里图示或描述的那些以外的顺序实施。此外,术语“包括”和“具有”以及他们的任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
下面结合附图对本发明做进一步详细描述:
1、重组Collectin-11蛋白(以下简称重组CL-11)的制备过程
包括以下步骤:
1)构建pcDNA3.1(-)-CL-11表达质粒,该质粒是在哺乳动物表达载体pcDNA3.1(-)插入CL-11基因,启动子为CMV,其载体抗性为氨苄青霉素(Amp),筛选标记为Neo,CL-11基因插入酶切位点为EcoRI和HindIII,结果参见图1;
2)在HEK293细胞中进行表达实验,收集培养5天的HEK293细胞,检测重组CL-11的分泌型表达,结果参见图2;
3)使用镍螯合琼脂糖快速流动层析柱(chelating SFF[Ni])纯化重组CL-11蛋白,结果参见图3,其中I道显示的纯化蛋白是符合条件的终产物。
4)Western Blot方法验证纯化蛋白产物,结果参见图4,结果显示纯化蛋白为符合条件的重组CL-11。
重组Collectin-11蛋白(重组CL-11)的氨基酸序列为:MMMRDLALAGMLISLAFLSLLPSGCPQQTTEDACSVQILVPGLKGDAGEKGDKGAPGRPGRVGPTGEKGDMGDKGQKGTVGRHGKIGPIGAKGEKGDSGDIGPPGPSGEPGIPCECSQLRKAIGEMDNQVTQLTTELKFIKNAVAGLRETESKIYLLVKEEKRYADAQLSCQARGGTLSMPKDEAANGLMASYLAQAGLARVFIGINDLEKEGAFVYSDRSPMQTFNKWRSGEPNNAYDEEDCVEMVASGGWNDVACHITMYFMCEFDKENL。
2、WT和CL11KO小鼠膀胱和肾脏感染情况
在CL-11基因敲除小鼠(CL-11-/-,以下简称CL11KO)及同窝野生型雌性小鼠(以下简称WT,B6背景)中建立急性尿路感染,具体实验操作如下:
选取8周以上雌性小鼠(每组6-8只)麻醉下经尿道插管(内径0.3mm,MarathonLabs)无阻力缓慢推注50μl大肠杆菌混悬液(J96或CFT073,cfu 1×108)。在不同时间点(3,6,24小时)处死实验小鼠,采集血,尿液,膀胱,肾脏。取半侧膀胱及肾脏作病理包埋,或即刻行OCT封固液氮冻存;无菌操作下用组织研磨器将另一侧肾脏或膀胱磨碎,将组织匀浆均匀涂在CLED选择性培养基上(OXOID),37℃隔夜培养,计数菌落数。
在感染3h,6h和24h评估感染后膀胱细菌负荷量情况,WT和CL11KO小鼠膀胱感染实验结果参见图5,感染6h,24h和48h评估感染后肾脏细菌负荷量情况参见图6,结果显示出3h膀胱细菌负荷量两者无差异,其余时间点,WT小鼠细菌负荷量均比CL-11-/-小鼠细菌负荷量较低。
3、感染后肾脏病理损伤、组织表达炎症因子变化及肾脏组织中炎症细胞浸润实验
1)肾脏病理损伤实验
实验过程:采用PAS染色评估肾组织炎症损伤程度及评分,对右侧肾脏纵剖后取一半经4%甲醛固定,行石蜡包埋,2-3μm切片,进行PAS染色,经玻片扫描仪(Zeiss,Axio ScanZ1)扫描,由两名有经验人员双盲观察组织损伤情况:检测肾小管损伤、炎症细胞浸润以及菌斑形成,并进行病理学评分。感染48小时后两组小鼠肾脏病理损伤结果参见图7,可以看出,CL-11-/-小鼠病理损伤程度较WT高。
2)肾脏组织表达炎症因子变化实验
通过检测肾脏组织炎性细胞因子生成来评估组织炎症反应情况。通过RT-PCR检测组织匀浆中炎症因子mRNA水平,具体操作如下:将组织采用Trizol法提取组织RNA(Invitrogen),5μg总RNA以M-MLV逆转录为cDNA(Promega),反应体积为50μl。以SYBR Green(ABI)染料行实时定量PCR,采用相对定量△△Ct法计算。将检测促炎性细胞因子;检测抗炎性细胞因子水平、引物序列请参见课题组已发表的相关论文(C3a-C3aR axis-mediatedanti-inflammatory activity protects against uropathogenic E coli-inducedkidney injury in mice[J].Kidney International,2019,96:612-627.)。此外,还将根据实时定量PCR的结果选取变化较大的细胞因子,检测其蛋白水平。
实验结果参见图8,可以看出,CL-11-/-小鼠肾脏组织促炎症细胞因子水平较WT高(TNF-a,IL-6,KC,MCP-1,IL-17A,IL-10),而抑炎因子较WT水平低。
3)肾脏组织中炎症细胞浸润实验
采用免疫组化染色评估感染后肾脏组织白细胞和中性粒细胞分布及表达情况,具体采用冰冻切片染色:肾脏组织经OCT固封,液氮冻存行冰冻切片(4μm),冰丙酮固定、封闭后分别行CD45,Ly6G和F4/80抗体染色,在200倍视野下分别统计10-15个视野内的浸润白细胞总数、中性粒细胞及巨噬细胞数目。
感染48小时后,两组小鼠肾脏组织中炎症细胞浸润结果参见图9,可以看出,CL-11-/-小鼠肾脏组织白细胞(CD45)和中性粒细胞(Ly6G)较WT高。
4、不同浓度CL-11与细菌共孵育后引起细菌凝集实验
采用流式细胞技术和免疫荧光技术检测重组CL-11与细菌结合,促进细菌凝集。将不同浓度重组人CL-11(0,600,1200ng/ml)与大肠杆菌在含有Ca2+(2mM)的溶液里37℃孵育1小时,充分清,洗并离心细菌后,将加入抗CL-11抗体(荧光或生物素标记)。
结果参见图10,为不同浓度CL-11与细菌共孵育后引起细菌凝集的检测结果,可以看出,CL-11能与大肠杆菌结合,并能促进细菌凝集。
5、重组人CL-11对细菌运动性影响实验
采用琼脂平板法检测重组人CL-11对细菌运动性影响。具体操作如下,以BSA为对照,将两种浓度CL-11(600,1200ng/ml)与细菌在37℃培养箱孵育30分钟,用接种针将细菌穿刺在软培养基中,观察不同时间点(24h,48h,96h)细菌菌斑直径,
结果参见图11,结果表明重组人CL-11能够促进细菌运动性。
6、重组CL-11治疗膀胱和肾脏感染情况实验
在重组CL-11治疗实验中,将细菌(CFT073,cfu 1×108)与CL-11(1-2μg/小鼠)混悬液或等量对照剂经尿道插管注射,不同时间点(3h,6h,24h)处死小鼠收取组织。免疫荧光方法检测早期细菌在膀胱和肾脏的定殖情况,结果参见图12和图13,发现经CL-11处理后细菌在膀胱和肾脏定殖减少。采用PAS染色评估肾组织炎症损伤程度及评分,结果参见图14,结果显示CL-11处理后细菌的肾脏组织病理损伤程度减轻。通过RT-PCR检测组织匀浆中炎症因子mRNA水平,CL-11处理后细菌的肾脏组织促炎症细胞因子水平降低(TNF-a,IL-6,CXCL-1,IL-17A,IL-10),而抑炎因子较WT水平升高,结果参见图15。
7、治疗给药实验
在重组CL-11治疗实验中,全身给药后重组CL-11在小鼠脾脏、淋巴结和肾脏组织中的分布:尾静脉外源注射生物素标记的重组CL11(Bio-CL11)600ng/只小鼠,24h收取小鼠脾脏、淋巴结和肾脏组织,免疫荧光方法检测发现,在脾脏、淋巴结和肾脏组织均发现有CL-11分布,结果参考图16。
以上内容仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明权利要求书的保护范围之内。
序列表
<110> 西安交通大学
<120> 胶原凝集素-11在制备防治泌尿系统感染的药物中的应用
<160> 1
<170> SIPOSequenceListing 1.0
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Glu Lys Gly Asp Lys Gly Ala Pro Gly Arg Pro Gly Arg Val Gly Pro
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Thr Gly Glu Lys Gly Asp Met Gly Asp Lys Gly Gln Lys Gly Thr Val
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Gly Arg His Gly Lys Ile Gly Pro Ile Gly Ala Lys Gly Glu Lys Gly
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Asp Ser Gly Asp Ile Gly Pro Pro Gly Pro Ser Gly Glu Pro Gly Ile
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Pro Cys Glu Cys Ser Gln Leu Arg Lys Ala Ile Gly Glu Met Asp Asn
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Gln Val Thr Gln Leu Thr Thr Glu Leu Lys Phe Ile Lys Asn Ala Val
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Ala Gly Leu Arg Glu Thr Glu Ser Lys Ile Tyr Leu Leu Val Lys Glu
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Glu Lys Arg Tyr Ala Asp Ala Gln Leu Ser Cys Gln Ala Arg Gly Gly
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Thr Leu Ser Met Pro Lys Asp Glu Ala Ala Asn Gly Leu Met Ala Ser
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Tyr Leu Ala Gln Ala Gly Leu Ala Arg Val Phe Ile Gly Ile Asn Asp
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Leu Glu Lys Glu Gly Ala Phe Val Tyr Ser Asp Arg Ser Pro Met Gln
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Thr Phe Asn Lys Trp Arg Ser Gly Glu Pro Asn Asn Ala Tyr Asp Glu
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Glu Asp Cys Val Glu Met Val Ala Ser Gly Gly Trp Asn Asp Val Ala
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Cys His Ile Thr Met Tyr Phe Met Cys Glu Phe Asp Lys Glu Asn Leu
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Claims (10)
1.胶原凝集素-11在制备预防和/或治疗泌尿系统感染的药物中的应用。
2.如权利要求1所述的应用,其特征在于,所述的药物为促进细菌凝集的药物。
3.如权利要求1所述的应用,其特征在于,所述的药物为减少细菌在膀胱和肾脏定量增殖的药物。
4.如权利要求1所述的应用,其特征在于,所述的药物为降低肾脏组织促炎症细胞因子水平的药物。
5.如权利要求4所述的应用,其特征在于,所述促炎症细胞因子包括TNF-a,IL-6,CXCL-1,IL-17A和IL-10。
6.如权利要求1所述的应用,其特征在于,所述的药物为减轻急性肾盂肾炎症状的药物。
7.如权利要求6所述的应用,其特征在于,所述的药物为减少肾脏组织中细菌负荷量、组织损伤及炎症程度的药物。
8.一种重组Collectin-11蛋白在制备预防和/或治疗泌尿系统感染的药物中的应用,其特征在于,所述重组Collectin-11蛋白的氨基酸序列如SEQ.ID.NO.1所示。
9.如权利要求8所述的应用,其特征在于,所述重组Collectin-11蛋白能够与细菌结合并促进细菌凝集。
10.一种表达载体在制备预防和/或治疗泌尿系统感染的药物中的应用,其特征在于,所述表达载体能够促进Collectin-11基因表达上调。
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