CN115916982A - 表达血管活性肠肽的微生物及其用途 - Google Patents
表达血管活性肠肽的微生物及其用途 Download PDFInfo
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- CN115916982A CN115916982A CN202180029642.2A CN202180029642A CN115916982A CN 115916982 A CN115916982 A CN 115916982A CN 202180029642 A CN202180029642 A CN 202180029642A CN 115916982 A CN115916982 A CN 115916982A
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Abstract
提供了一种表达VIP基因的重组微生物以及包括其的组合物,该组合物用于预防或治疗引起胃肠道损伤的疾病。
Description
技术领域
本公开涉及一种表达血管活性肠肽(vasoactive intestinal peptide:VIP)的微生物以及包括其的组合物,该组合物用于预防或治疗引起胃肠道(gastrointestinaltract)损伤的疾病。
背景技术
血管活性肠肽(vasoactive intestinal peptide:VIP)是在肠道中具有血管活性的肽激素。VIP是一种具有28个氨基酸残基的肽,其属于胰高血糖素/促胰液素(Secretin)超家族、II类G蛋白偶联受体的配体。
韩国公开专利第2014-0000620号公开了在肠神经***(enteric nervoussystem)中提高VIP水平的乳杆菌及其治疗肠易激综合征(IBD;Inflammatoryboweldisease)的用途。其并非重组微生物,而是从自然界中筛选出来的菌株。
中国公开专利第108753670号公开了一种重组微生物乳酸乳球菌(Lactococcuslactis)NZ9000,其表达VIP并且细胞中的硒纳米颗粒(SeNP)丰富。该公开专利描述称,由于硒以纳米颗粒形式存在于该重组微生物的细胞中,因而当该重组微生物用作硒添加剂时,能够解决硒所具有的毒性强、生物利用度低、环境污染可能性高以及生产成本高等问题,同时由于该重组微生物分泌作为抗菌肽的VIP,因而能够解决抗生素残留问题。另外,为了VIP分泌表达,使用了乳酸乳球菌表达***的pNZ8148质粒。
目前尚未公开将表达外源VIP的乳杆菌属重组微生物、在组成型启动子下表达外源VIP的重组乳酸菌以及这些微生物用于预防或治疗在人中引起胃肠道损伤的疾病诸如IBD。
发明内容
技术问题
本公开的目的在于提供一种乳杆菌(Lactobacillus)属重组微生物,该微生物表达外源VIP(vasoactive intestinal peptide:VIP)。
另一目的在于提供一种重组乳酸菌,该乳酸菌在组成型启动子下表达外源VIP。
另一目的在于提供一种包括所述微生物的组合物,该组合物用于预防或治疗在人中引起胃肠道损伤的疾病。
技术方案
本公开一方面提供一种重组微生物,其为乳杆菌属,其中引入启动子和编码血管活性肠肽(vasoactive intestinal peptide:VIP)的外源基因并且蛋白酶失活,所述血管活性肠肽与所述启动子可操作地连接。
本公开另一方面提供一种重组微生物,其为乳酸菌,其中引入组成型启动子(constitutive promoter)和编码血管活性肠肽(VIP)的外源基因并且蛋白酶失活,所述血管活性肠肽与所述启动子可操作地连接。
本公开另一方面提供一种组合物,其用于预防或治疗在人中引起胃肠道损伤的疾病,其包括重组微生物,所述重组微生物为乳酸菌,并且其中引入启动子和编码血管活性肠肽(VIP)的外源基因且蛋白酶失活,所述血管活性肠肽与所述启动子可操作地连接。
以下进行详细描述。
在本说明书中,术语“VIP”或“VIP蛋白”或“VIP多肽”意指具有至少一种本说明书中描述的生物活性的生物活性多肽。
以人类为例,人类基因组中6号染色体的q25区域编码长度为170个氨基酸的促胰液素家族成员。长度为170个氨基酸的所述成员在翻译后被截断以形成血管活性肠肽(VIP)。VIP多肽的活性形式具有以下功能,降低血压、增强血管壁的血管舒张(vasodilation)、放松呼吸道和胃肠道组织的平滑肌、降低Th1反应的同时通过促进Th2降低免疫反应、调节先天性免疫反应和获得性免疫反应、或促进肠内电解质分泌。另外,已发现作为神经递质的VIP在中枢神经***和淋巴细胞之间的连通中具有活性。VIP的生物活性通过VIP1R、VIP2R以及PAC1R三种已知受体传递。已知这些受体会引起细胞内的钙生成以及cAMP的富集。与VIP一样,这些受体对促胰液素(Secretin)的亲和力取决于亚型和配体的氨基酸序列。人类天然VIP的半衰期较短,在血液中的半衰期约为2分钟。
本说明书中提及的VIP包括模仿天然VIP功能的变体。所述变体包括具有相比于天然VIP增加的半衰期和与天然VIP相比的相等水平或更高生物活性的变体。
在本说明书中,VIP包括但不限于人VIP、重组人VIP、鼠VIP和/或重组小鼠VIP。与SEQ ID NO:1的氨基酸序列相比,所述VIP可以具有大于或等于50%、大于或等于60%、大于或等于70%、大于或等于85%、大于或等于90%、大于或等于95%、大于或等于98%、大于或等于99%,或者大于或等于100%的序列同一性。所述VIP可以分别具有SEQ ID NO:1、2、3、4、5、6、7、8和9的氨基酸序列。SEQ ID NO:1的VIP是人源天然VIP。具有SEQ ID NO:2、3、4、5、6、7、8以及9的氨基酸序列的VIP是人源天然VIP变体VIP1、VIP2、VIP3、VIP4、VIP5、VIP6、VIP7以及VIP8。
本说明书中的所述VIP多肽可以通过从人体组织或其它供应源等各种供应源分离或重组或合成的方法来制备。
术语“VIP多肽”还包括VIP多肽的变体。在本说明书中,VIP可以通过形成嵌合体分子的方式来被修饰,所述嵌合体分子包括异种多肽或融合至其它氨基酸序列的VIP。
在本说明书中,“蛋白酶”是分解蛋白质的酶的总称,其可以包括本领域已知的任意类型而无特别限制。
在本说明书中,“营养缺陷株(auxotroph)”是指不能在仅由无机盐和碳源组成的合成培养基中增殖,因而需要补充一种或多种营养素才能生长的菌株,其可以包括本领域已知的任意类型而无特别限制。
根据本公开一方面的微生物为乳杆菌属重组微生物,所述重组微生物中引入启动子和编码血管活性肠肽(VIP)的外源基因且蛋白酶失活,所述血管活性肠肽与所述启动子可操作地连接。
根据本公开另一方面的微生物为重组微生物且为乳酸菌,所述重组微生物中引入组成型启动子和编码血管活性肠肽(VIP)的外源基因且蛋白酶失活,所述血管活性肠肽与所述启动子可操作地连接。
所述乳酸菌可以是乳杆菌属(Lactobacillus)、乳球菌(Lactococcus)属、比菲德氏菌(Bifidobacteria)属、链球菌(Streptococcus)属、明串珠菌(Leuconostoc)属、魏斯氏菌(Weissella)属、片球菌(Pediococcus)属,或肠球菌(Enterococcus)属,特别地,可以是乳杆菌属(Lactobacillus)、乳球菌(Lactococcus)属,例如,可以是副干酪乳杆菌(Lactobacillus paracasei)、短乳杆菌(Lactobacillus brevis)、植物乳杆菌(Lactobacillus plantarum)或乳酸乳球菌(Lactococcus lactis)。
所述乳杆菌属微生物可以是副干酪乳杆菌(Lactobacillus paracasei)、短乳杆菌(Lactobacillus brevis)或植物乳杆菌(Lactobacillus plantarum)。例如,可以是植物乳杆菌LMT1-9(KCTC 13421BP)、副干酪乳杆菌LMT1-21(KCTC 13422BP)或短乳杆菌LMT1-46(KCTC 13423BP)。
所述启动子可以是组成型启动子。所述启动子在乳酸菌中的转录起始效率与现有启动子(例如,P11启动子)相同或更高。所述启动子还可以是诱导型启动子(induciblepromoter)。所述诱导型启动子可以是例如,乳链菌肽诱导型启动子(Nisin induciblepromoter)。所述启动子可以是来源于副干酪乳杆菌(Lactobacillus paracasei)的PR4,所述副干酪乳杆菌包括SEQ ID NO:10的多核苷酸。PR4可由SEQ ID NO:11的核苷酸序列组成。
根据本公开的微生物的特征在于其中引入编码VIP的外源基因。所述引入可以通过转化、转导、转染或电穿孔来实现。引入的所述外源基因可以合并(integrated)到宿主细胞的基因组中,或者以未合并状态存在。例如,所述外源基因可以合并到宿主细胞的基因组中。
另外,根据本公开的微生物的特征在于蛋白酶失活。根据一具体实施例,编码蛋白酶的基因可以缺失(deleted)。“缺失”包括基因的至少一部分(例如,全部或部分)的缺失。
根据一具体实施例,通过编码蛋白酶的基因被编码血管活性肠肽(VIP)的外源基因所取代(replaced),可以同时实现外源VIP基因的引入和蛋白酶基因的缺失,所述血管活性肠肽与启动子可操作地连接。“取代”包括基因的至少一部分(例如,全部或部分)被取代。
在本说明书中,“蛋白酶”可以包括本领域已知的任意类型而无特别限制。例如,可以是选自由HtrA(高温热应激需求蛋白A,high temperature requirement A)、PepN(氨肽酶N,Aminopeptidase N)、ClpP(酪蛋白分解蛋白酶P,Caseinolytic pretease P)以及Lon(Lon蛋白酶,Lon protease)所组成的组中的至少一种,例如,HtrA和/或PepN,例如,HtrA。htrA基因可以是短乳杆菌htrA基因,特别地,可以是SEQ ID NO:14的基因。pepN基因可以是短乳杆菌pepN基因,特别地,可以是SEQ ID NO:15的基因。clpP基因可以是短乳杆菌clpP基因,特别地,可以是SEQ ID NO:16的基因。lon基因可以是短乳杆菌lon基因,特别地,可以是SEQ ID NO:17的基因。由于蛋白酶在这种微生物中不表达,能够防止外源VIP蛋白的分解,因此可以提高VIP蛋白的收率或生产性。根据一具体实施例,当HtrA不表达时可以大幅提高VIP蛋白的生产性。
所述重组微生物可以另外包括可操作地连接在所述启动子和所述外源基因之间的信号序列。当所述信号序列与外源蛋白基因框内连接时,分泌到细胞外的能力可以高于现有信号序列,例如,USP45信号序列。所述信号序列可以编码来源于副干酪乳杆菌的SP4(SEQ ID NO:12)。例如,SP4可以具有SEQ ID NO:13的核苷酸序列。所述微生物可以将VIP分泌到细胞外。
在一具体实施例中,所述重组微生物可以是营养缺陷株(auxotroph)。营养缺陷株可以是选自由,例如,核黄素生物合成蛋白基因(ribB:Riboflavin biosynthesis proteingene)、胸苷酸合成酶基因(thyA:Thymidylate synthase gene)以及谷氨酰胺-果糖-6-磷酸氨基转移酶基因(glmS:Glutamine--fructose-6-phosphate aminotransferase gene)所组成的组中的至少一种基因缺失,例如,可以是ribB和/或thyA缺失,例如,ribB缺失,但无特别限制。ribB可以是短乳杆菌ribB,特别地,可以是SEQ ID NO:18的基因。thyA可以是短乳杆菌thyA,特别地,可以是SEQ ID NO:19的基因。glmS可以是短乳杆菌glmS,特别地,可以是SEQ ID NO:20的基因。在此情况下,可以通过控制重组微生物的生长和存活来提高环境安全性。“缺失”包括基因的至少一部分(例如,全部或部分)的缺失。
本公开另一方面提供一种组合物,所述组合物用于预防或治疗引起胃肠道损伤的疾病,所述组合物包括上述微生物。
所述疾病可能引起胃肠道的炎症。所述疾病可以是选自由炎症性肠病(IBD:Inflammatory bowel disease)和结肠炎(colitis)所组成的组中的至少一种。所述炎症性肠病可以是溃疡性结肠炎(ulcerative colitis)或克罗恩氏病(Crohn's disease)。
所述组合物可以包括药学上或食品学上可接受的载体、赋形剂或稀释剂。所述药学上或食品学上可接受的载体可以是指任意一种标准药物或食品载体,例如,磷酸缓冲生理盐水(phosphate buffered saline solution)、5%右旋糖水溶液以及乳液(例如,油/水或者水/油乳液)。赋形剂的非限制性实例包括辅助剂、粘合剂、填充剂、稀释剂、崩解剂、乳化剂、润湿剂、润滑剂、助流剂、甜味剂、香料以及着色剂。优选的药物或食品载体取决于活性剂的预期施用方式。典型的施用方式包括肠内(例如,口服)施用。所述组合物可以是单位剂施用剂型(unit dosage form)。所述组合物可以具有口服施用剂型。所述组合物可以是食品或药物组合物。所述组合物可以包括所述微生物的干燥产物。所述组合物可以包括所述微生物的培养基。
在本说明书中,“药学上或食品学上可接受的”是指,当施用于个体时实际不引起副作用的物质。所述副作用可以是毒性、过敏或免疫反应。
另一方面提供一种试剂盒,所述试剂盒用于预防或治疗引起胃肠道损伤的疾病,所述试剂盒包括上述重组微生物和用于治疗胃肠道损伤疾病的其它药物。所述重组微生物如上所述。所述重组微生物可具有上述组合物的形式。所述试剂盒可以包括说明书,所述说明书指示将重组微生物和治疗胃肠道损伤疾病的其它药物用于预防或治疗引起胃肠道损伤的疾病。
所述治疗胃肠道损伤疾病的其它药物包括任意一种治疗胃肠道损伤疾病的药物,例如,炎症性肠病。治疗胃肠道损伤疾病的药物可包括下列药物:
(i)甾体类抗炎药
***(dexamethasone)、己烷雌酚(hexestrol)、甲巯咪唑(methimazole)、倍他米松(betamethasone)、曲安奈德(triamcinolone)、醋酸曲安奈德(triamcinoloneacetonide)、氟轻松(fluocinonide)、醋酸氟轻松(fluocinolone acetonide)、***龙(predonisolone)、甲泼尼龙(methylpredonisolone)、可的松乙酸酯(cortisoneacetate)、氢化可的松(hydrocortisone)、氟米龙(fluorometholone)、丙酸倍氯米松(beclomethasone dipropionate)、雌三醇(estriol)、醋酸对氟米松(paramethasoneacetate)、氟化可的松乙酸酯(fludrocortisone acetate)、丙酸氯氟美松(clobetasolpropionate)、乙酸二氟拉松(diflorasone acetate)、丙酸***(dexamethasonepropionate)、二氟泼尼酯(difluprednate)、二丙酸倍他米松(betamethasonedipropionate)、布***(budesonide)、双氟皮甾松戊酸酯(diflucortolone valerate)、安西奈德(amcinonide)、哈西奈德(halcinonide)、糠酸莫米松(mometasone furoate)、丁酸丙酸氢可的松(hydrocortisone butyrate propionate)、特戊酸氟米松(flumetasonepivalate)、丁氯倍他松(clobetasone butyrate)、乙酸***(dexametasone acetate)等。
(ⅱ)5-氨基水杨酸
柳氮磺吡啶(sulfasalazine)、美沙拉嗪(mesalazine)、奥沙拉嗪(olsalazine)、巴柳氮(balsalazide)等。
(ⅲ)免疫调节剂或免疫抑制剂
甲胺噪呤(methotrexate)、环磷酰胺(cyclophosphamide)、MX-68、二盐酸阿替莫德(atiprimod dihydrochloride)、BMS-188667、CKD-461、双甲丙酰龙(rimexolone)、环孢灵(cyclosporine)、他克莫司(tacrolimus)、胍立莫司(gusperimus)、硫唑嘌呤(azathiopurine)、抗淋巴细胞血清(antilymphocyte serum)、冷冻干燥的磺化的正常免疫球蛋白(freeze-dried sulfonated normal immunoglobulin)、红细胞生成素(erythropoietin)、菌落刺激因子(colony stimulating factor)、白介素(interleukin)、干扰素(interferon)等。
(iv)JAK抑制剂
托法替尼(tofacitinib)、芦可替尼(ruxolitinib)等。
(ⅴ)TNF抑制剂
重组TNF-α受体IgG-Fc融合蛋白(etanercept)、英夫利西单抗(infliximab)、阿达木单抗(adalimumab)、培塞利珠单抗(certolizumab pegol)、戈利木单抗(golimumab)、PASSTNF-α、可溶性TNF-α受体、TNF-α结合蛋白、抗TNF-α抗体、CDP571等。
(ⅵ)整合素抑制剂
那他珠单抗(natalizumab)、维得利珠单抗(vedolizumab)、AJM300、TRK-170、E-6007等。
(ⅶ)白介素-12/23抑制剂
乌司奴单抗(ustekinumab)、布雷奴单抗(briakinumab、抗白介素12/23抗体)等。
(ⅷ)非甾体抗炎药(NSAIDs)
(a)传统非甾体抗炎药
阿氯芬酸(alcofenac)、醋氯芬酸(aceclofenac)、舒林酸(sulindac)、甲苯酰吡酸(tolmetin)、依托度酸(etodolac)、非诺洛芬(fenoprofen)、噻洛芬酸(thiaprofenicacid)、甲氯灭酸(meclofenamic acid)、美洛昔康(meloxicam)、替诺昔康(tenoxicam)、氯诺昔康(lornoxicam)、萘普酮(nabumeton)、醋氨酚(acetaminophen)、非那西汀(phenacetin)、乙水杨胺(ethenzamide)、安乃近(sulpyrine)、安替比林(antipyrine)、米格来宁(migrenin)、阿司匹林、甲芬那酸(mefenamic acid)、氟芬那酸(flufenamic acid)、双氯芬酸钠(diclofenac sodium)、酮基保泰松(ketophenylbutazone)、环氧洛芬钠(loxoprofen sodium)、苯丁唑酮(phenylbutazone)、消炎痛(indomethacin)、布洛芬(ibuprofen)、酮洛芬(ketoprofen)、萘普生(naproxen)、奥沙普秦(oxaprozin)、氟比洛芬(flurbiprofen)、芬布芬(fenbufen)、普拉洛芬(pranoprofen)、夫洛非宁(floctafenine)、吡罗昔康(piroxicam)、替诺昔康(tenoxicam)、依匹唑(epirizole)、盐酸噻拉米特(tiaramide hydrochloride)、扎托洛芬(zaltoprofen)、甲磺酸加贝酯(gabexatemesylate)、甲磺酸卡莫司他(camostat mesylat)、乌司他丁(ulinastatin)、秋水仙碱(colchicine)、丙磺舒(probenecid)、苯磺唑酮(sulfinpyrazone)、布可隆(bucolome)、苯溴马隆(benzbromarone)、别嘌醇(allopurinol)、金硫丁二钠(sodium aurothiomalate)、透明质酸钠(hyaluronate sodium)、水杨酸钠(sodium salicylate)、水杨酸(salicylicacid)、阿托品(atropine)、东莨菪碱(scopolamine)、左啡诺(levorphanol)、羟***酮(oxymorphone)或其盐等。
(b)环加氧酶抑制剂(COX-1选择性抑制剂、COX-2选择性抑制剂等)
水杨酸衍生物(例如,塞来昔布、阿司匹林)、依托考昔(etoricoxib)、伐地考昔(valdecoxib)、双氯芬酸钠(diclofenac sodium)、消炎痛、洛索洛芬(loxoprofen)等。
(c)释放一氧化氮的非甾体抗炎药(nitric oxide-releasing NSAID)
对所述微生物的描述可适用于所述组合物。
另一方面提供一种预防或治疗引起胃肠道损伤疾病的方法,所述方法包括将有效量的所述微生物施用于个体,所述有效量是指有效预防或治疗引起胃肠道损伤疾病的量。
所述方法可以进一步包括将有效量的TNF-α阻断剂施用于个体,所述有效量是指有效预防或治疗引起胃肠道损伤疾病的量。所述将TNF-α阻断剂施用于个体的步骤可以与所述将微生物施用于个体的步骤同时、之前或之后进行。所述TNF-α阻断剂可以通过与所述微生物的施用途径相同或不同的途径施用。例如,所述TNF-α阻断剂可以通过口服或肠胃外施用。所述肠胃外可以是注射,例如,血管注射、腹腔注射或皮下注射。例如,所述TNF-α阻断剂可以腹腔内施用,所述微生物可以口服施用。所述TNF-α阻断剂可以在所述微生物经口服施用后通过腹腔内施用。所述TNF-α阻断剂的施用量可以是每次施用5mg至100mg、5mg至50mg、5mg至40mg、10mg至50mg或20mg至50mg。
在所述方法中,所述疾病可能引起胃肠道的炎症。所述疾病可以是选自由炎症性肠道病(inflammatory intestinal disease)、自身免疫性疾病(autoimmune disease)、放射线引起的胃肠道损伤或移植物抗宿主病(GVHD)、炎症性肠病(IBD)以及包括慢性结肠炎在内的结肠炎(colitis)所组成的组中的至少一种。所述炎症性肠病可以是溃疡性结肠炎(ulcerative colitis)或克罗恩氏病(Crohn's disease)。
在本说明书中,所述“施用(administering或administration)”是指向生理***(个体或体内、体外、或离体细胞、组织和器官)给予所述微生物、包括所述微生物的组合物或治疗性处理(therapeutic treatment)的行为。因此,在所述方法中,所述微生物可以是上述组合物的形式。对人体施用时可接受的途径可以是口部或粘膜(例如,肠粘膜、口腔粘膜或口腔)。所述施用可以与另外的治疗剂(therapeutic agent)组合施用。所述组合施用包括同时施用或连续施用中的任意顺序。
在本说明书中,术语“治疗”是指预防性治疗或治疗性治疗。在特定实施方案中,“治疗”是指出于治疗或预防的目的将微生物或组合物施用于个体。
“治疗性(therapeutic)”治疗是指,对表现出病理学体征(signs)或症状(symptoms)的个体进行施用,以降低或消除体征或症状的治疗。体征或症状可以是生化性、细胞性、组织学性、功能性或物理性、主观性或客观性的。
“预防性(prophylactic)”治疗是指,对未表现出体征或仅表现出疾病早起体征的个体进行施用,以降低发生病理(pathology)问题的风险。本说明书中的微生物或组合物能够以预防性治疗提供,以降低发生病理问题的可能性(likelihood),或在发生病理问题后最小化所述病理问题的严重性。
在本说明书中,“治疗有效量(therapeutically effective amount)”是指足以实现文中提及的目的的量。有效量可通过实验来决定。例如,有效量可根据所述微生物将VIP分泌到细胞外的程度来决定。例如,可以是针对体重为60kg的人,一天能够分泌0.01mg至300mg或0.5mg至100mg VIP的所述微生物的数量。例如,针对每个个体每次施用1×105cfu至1×1013cfu、1×106cfu至1×1013cfu、1×107cfu至1×1013cfu、1×107cfu至1×1012cfu、1×107cfu至1×1011cfu、1×107cfu至1×1010cfu、1×108cfu至1×1011cfu、1×108cfu至1×1010cfu、2.5×108cfu至7.5×109cfu、5.0×108cfu至5.0×109cfu、7.5×108cfu至2.5×109cfu,或约1×109cfu。
在所述方法中,所述个体可以是哺乳动物。所述哺乳动物可以是人、马、猪、牛、狗、猫、猴子、黑猩猩、羊或山羊。
对所述微生物和/或组合物的描述也可适用于所述方法。
有益效果
根据本公开的重组微生物不仅能够以更高的生产性生产和分泌VIP,而且表现出较高的环境安全性,因此可以更有效地预防或治疗引起胃肠道损伤的疾病。
<110> 丽必微股份有限公司
<120> 表达血管活性肠肽的微生物及其用途
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Phe Thr Ala Asn Tyr Thr Arg Leu Arg Arg Gln Leu Ala Val Arg Arg
1 5 10 15
Tyr Leu Ala Ala Ile Leu Gly Arg Arg
20 25
<210> 5
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> VIP变体4
<400> 5
His Ser Asp Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln
1 5 10 15
Met Ala Val Lys Lys Tyr Leu Ala Ala Val Leu Asn
20 25
<210> 6
<211> 28
<212> PRT
<213> 人工序列
<220>
<223> VIP变体5
<400> 6
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Ala Arg Leu Arg Lys Gln
1 5 10 15
Met Ala Val Lys Lys Ala Leu Asn Ser Ile Leu Ala
20 25
<210> 7
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> VIP变体6
<400> 7
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gln
1 5 10 15
Val Ala Ala Lys Lys Tyr Leu Gln Ser Ile Lys Asn Lys Arg Tyr
20 25 30
<210> 8
<211> 31
<212> PRT
<213> 人工序列
<220>
<223> VIP变体7
<400> 8
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Arg Gln
1 5 10 15
Leu Ala Val Arg Arg Tyr Leu Asn Ser Ile Leu Asn Gly Arg Arg
20 25 30
<210> 9
<211> 23
<212> PRT
<213> 人工序列
<220>
<223> VIP变体8
<400> 9
His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Arg Gln
1 5 10 15
Leu Ala Val Arg Arg Tyr Leu
20
<210> 10
<211> 31
<212> DNA
<213> 副干酪乳杆菌
<400> 10
tcgtcacggc gctgcttttt tcatacaaaa t
31
<210> 11
<211> 500
<212> DNA
<213> 副干酪乳杆菌
<400> 11
tccacaatca aggtgcttgg ctttttcgat cgcgaggtca ccatgtacat cagtcgtgag
60
agcattgtgt tgacagtgat cggcatcgtg ttcggctatc tgctcggcaa tttgctgaca
120
gcctacattt tgtatcaagc cgaaactgag gccgtggttt ttccactcac gatcagcatt
180
gtcggctacc tcacggccac gttactcatg ttggccttca ccggcgtcgt cacctggctc
240
acgcatcgtc gactccaacg ggtggacatg gtcgaagccc tgaaatcaaa cgaataacct
300
acaattttgt caggcagcgt cgtcacggcg ctgctttttt catacaaaat tcatcaaaaa
360
ttgggattaa aaacgttcat gatcgcaatt ttgaagcgca aatgaagatt gagaccaact
420
cctaacagtc ctgtaacgct gacgtaacat tgacacagta aagtagcctt tagttaatca
480
aattaagggt gaggtcaaaa
500
<210> 12
<211> 31
<212> PRT
<213> 副干酪乳杆菌
<400> 12
Met Lys Phe Asn Lys Val Met Ile Thr Leu Val Ala Ala Val Thr Leu
1 5 10 15
Ala Gly Ser Ala Ser Ala Val Thr Pro Val Phe Ala Asp Thr Ser
20 25 30
<210> 13
<211> 93
<212> DNA
<213> 副干酪乳杆菌
<400> 13
atgaaattca ataaagtcat gatcacgttg gttgctgcag ttaccttagc aggttctgct
60
agcgccgtaa caccagtttt cgctgataca agc
93
<210> 14
<211> 1347
<212> DNA
<213> 短乳杆菌
<400> 14
gtgatggata acaataataa tcaatttaat aaccaacaac atgatcataa tgaagaaacc
60
acaccaactc cggaaccacg gaaacggcgg ggtggcctga cactgacgaa agtggcagtg
120
acggctgcgg tcgctggact cttaggcggc ggggttgcgt acggcggtat caactacttt
180
aataatagtg ggatgaatga tacggcggtg ccagccggga gtaactcgac cgggaacacc
240
aagacctcta acgtcaacgt caatgtctcg agtcaatcaa ccaaggcctt taataaggtt
300
aaaggggcca tggtctcggt gattaattta cagaaggaaa atagtagtag cgggacgctt
360
ggccaattat tcggctcaag ctcgagctcc aattcatcga aatccaagtc agagctggaa
420
gaagcttccg aaggttctgg ggtgatttat aagaaggacg gtaacgtggc ttacatcgtg
480
acgaacaatc acgtggtttc cggctcttca gccttacgag tcgtgacgag ttccggtaaa
540
caactgcaag cgaagttggt tggtaaggat tccgttaccg acttggccgt cttaaaggtt
600
aacggctcgt cattaaagac cgtggcgtca tttggaaact cagataatat caaggttggg
660
gaaacggcct tggcaattgg ctcaccactg ggcagccaat acgcaacgtc attgacgcaa
720
gggatcatct ccgccaagaa gcggacgatt gaaacgacta attcttcggg aacgcaaacc
780
gggaatgcaa cggttattca gacggatgcg gcgattaacc ctgggaactc agggggggcc
840
ttgattaatg tcggtggcca agtggtcggc attacctcat cgaagatcgc cagtgatgcg
900
gaaggcacca gcgttgaagg gatgggcttt gccattccat ctaacgaagt ggtcaatatc
960
atcaatcaac tggtcaagaa cgggaaggtc gtgcggccag cgttagggat tacctacgtt
1020
gacttggcga acgtttctag tgcgcaacag aaatcgatcc tgaagttacc atctaatgtg
1080
gaaaacgggg tcgtggtgat gagtgcttcg gcgggctcac cagcgaagaa ggccggcttg
1140
agcaagtatg atgtgattac ggcgctgggc ggtcatcaga tttcagacca atccacgttg
1200
cgagatattt tgtacaagta taagctgaac gataaggtct cgatcactta ctatcacaat
1260
ggtaagaaga agaccagcac cattaaatta acggaaacat cttctcaatt aaagactagc
1320
tcgacgacgg caacgtcaga gagttag
1347
<210> 15
<211> 2535
<212> DNA
<213> 短乳杆菌
<400> 15
atgacagaat caacgcactt gtatgacctg ttccacccgg cacactacga tatttatctc
60
gatattaacc gcgaaacgaa gcaaattagc gggaagacga cgattactgg tgatgcctta
120
gccacgacga ttggcattca ccagaagttc ttaaagatcc aacaggtaac ggttgacggc
180
aaagccgtga cggttacgga tgatcctgcg gccgaagcca ttcggattcc ggtcccacag
240
acgggtaacg tgacgttagc cattgattac acggcgccat taactgatag catgatgggg
300
atttacccat cctactacga cgttaacggc gtacaaaagc aaatcattgg aacccagttt
360
gaaacgaccg ctgcgcgcca agctttccca agtatcgatg aaccggaggc caaagcaacc
420
tttgacctag cgattaagtt cgatgaacag cctggtgaaa cggttatcag taacatgcct
480
gagaccaagg tcgaagccgg cgtgcactac tttgacacca cggttaagat gtccacgtac
540
ctgattgcct ttgcctttgg tgatttgcaa agtaagatga cgactactaa gagtggggtt
600
caggttgggg tgtttgctac caaggcgcat caagccaatg aattggactt tgcgttagac
660
attgccaagc gctcaattga attttacgaa gacttctatc agacacctta tccactacca
720
cattcctggc agttagcttt acctgacttt tccgctggcg ccatggaaaa ctggggattg
780
gttacttacc gggaagctta cctcgtttta gaccccgaca atacgtcgtt tgaaacgaag
840
caacgggttg ccaccgtcat tgctcatgaa ctggcccacc aatggtttgg tgatttggtt
900
acgatgaagt ggtgggatga tctttggttg aacgaaagtt ttgccaacat gatggaatac
960
gttgctattg atgccatcga acctgactgg cacatttggg aagtcttcca aacaactgaa
1020
gccccgatgg ccttacaacg ggacgcaacg gacggtgtac aatctgtcca cgtgcaagta
1080
gaagatccag ctgaaattga tgcgctcttt gatagtgcca ttgtttacgc caagggtgcc
1140
cggatgttag tcatggtacg ggctttaatt ggcgatgatg ctctgcgaac gggcctgaag
1200
gcttacttcg acgcccataa gtttggtaat gcaactgggg ctgacttgtg gtctgcttta
1260
gggactgctg ccaatatgga tttgaagagc gtaatgaatt cgtggctgga acaacctggt
1320
tacccagtct taacggctgc ggtggtcgat ggtcagttga cagtgaccca gcaacaattc
1380
tttattggcg atggcacaga cgccaaacgt caatggcaag tgccattgag cagtaactat
1440
gctgaagtcc cagaattgtt gacggcgcca caagtgacgt taggaactta tgcggattta
1500
cggcaggcta atggacagcc gttccggcta aatgtcggca ataattcaca tgcgattgtg
1560
aagtacgatg ataccttact agcagatatt ttagatcaca tcactgagtt aacagcgatt
1620
gatcaactcc aattgctaca agatcaacga ctactggctg aagggcggca gatttcttat
1680
gcggatgtcg tcgccttgtt gccacgattt gcggctagtg aagctacggt ggttaacgat
1740
gcgttgtatc aggtcgctgg taacttgaag aagttcgtca cgccagattc tgatgccgaa
1800
aagcaactgc aacaattctt tgatcggtta agtgcggcac aagttgaccg gttggggtgg
1860
acccctaaag ctggcgaatc taatgatgac cagttaaccc ggccatatgt attaagcgcg
1920
gccctctatg ctaaaaatgc ccaatcagtc gccgctgcgc atgaactgtt cacagccaat
1980
cgcgacaatt tagcaggctt gccagctgca acgcgttact atgttttggc aaatgaagtc
2040
acgaacttca gtgacgcaac ggtctttgat cagttgctga cagattaccg gcaagcaacg
2100
gatgccagct acaaggccga tctgtgtgcc gcattgacga ccacaccaga tgccaagttg
2160
attgcgaagt taatcgcagt ctttgaaaac gcggccacgg ttaaaccaca ggacttacgg
2220
gcttggtacc gtggtgtctt ggccaatgcc aaggggcagc aggtggcttg ggactggatc
2280
cgtcaagatt gggattggtt ggaagcaact gtgggtggtg atatggaatt caccacattt
2340
attacggtaa ctgcggcgat cttccacaca cctgaacggt tagctgagtt caaggaattc
2400
tttgaaccaa agattccgac gcctggttta ggacgtgaaa tcaagatgga taccaaggtt
2460
atcgcaagtc gcgtggcctt agttgaagat gaaaaagccg cagtgaatgc tgcggtggca
2520
caagtcgtcc aataa
2535
<210> 16
<211> 597
<212> DNA
<213> 短乳杆菌
<400> 16
atgaatttag taccaacagt tattgaacaa tcatcccgtg gcgaacgggc ctatgatatt
60
tattcacgac tattaaaaga ccggattatc atgttatctg gtccaattga agatgacatg
120
gccaacgcca tcatcgcgca gttactcttc ttggatgccc aagactcaac caaggacatt
180
tcactctaca tcaactcacc tggtggtgtc gtttcttccg gcttggccat ctatgatacc
240
atgaacttca tccaatctga cgtgcaaacg atcacgttag ggatggcagc ttccatggca
300
agtgtcttgg cttcatctgg gactaagggc aagcgttttg ctttgcctca cgcccaagtg
360
atgattcacc aaccatctgg tggtgcccaa ggacaacaaa cggaaatcga aattgctgct
420
cgtgaaatct tgaagacccg tgaattgatc aacaagattt tagcagagaa ttccggtcaa
480
ccgattgaac gcctcaatca agatactgaa cgagacaact acttgagtgc tcaagaagcg
540
gttgattatg gattaattga ccacatcatg accaacagta gtgaacaaaa gaagtaa
597
<210> 17
<211> 1050
<212> DNA
<213> 短乳杆菌
<400> 17
gtgtggaatt taacgcgacg gcagtggcgg cagattctag taacggtgat attagcactt
60
gcagtgttgc tattttttct gtggccattg cccaagtata ttgagggtcc cggtgaggca
120
gacaatttga aatcatttgt cacagttgcc caacatcccg ataagcataa gggaaaatat
180
atgattacct cagttgcgtt ggcgcaagct cgtccagttt cctacctcta tgccaaattt
240
aatccctatt acagcattga gagtgtagcg tcagtgacgg gtggcgagag taatgcgacc
300
tatgataaag ttcagaactt ttatatgaaa agcgccatca atgagtcgat ttataccgca
360
tatcgggcgg cccataaaac ggtgaagcgt cattatttgg gaatttacgt tttgagtgtt
420
gatcgtcggt caccctttgc ccaagcgtta aaggtgggcg atacggtgac ggaggtaaat
480
ggtcatcatt tcaactctat gacggggtat caacgatata tccagcgaca aaaagtggga
540
caacggacga ccattacgta tcagcacaat ggtaaaacac accacgtaac tgccaaattg
600
atgcggttgc caacgaaaaa agcgggtatt gggattactt tgacggataa cgtcaaagtt
660
agtgctcggc ctaaagtgca ggtgaatccc ggcaacatcg gtggtccgtc aggtggttta
720
atgtttagct tacagattta tacgcaagtg acggggcagg acttacgtca cgggcgaaag
780
attgcaggaa ccggaacggt tgatggtgac ggcaacgttg gcgagattgg tggtattgat
840
aagaaaatta tcgctgctaa gcgcgcaggg gcgacggtct tctttgctcc ctacgtgaaa
900
ccgacaaaat tgttactgaa gtatgaagaa caacaccaaa cgaattatca attggctaag
960
gcaacagcga aaaagtatgc gccgaatatg aaagttgtgc cagtaaaatc gtttgacgat
1020
gcagttcatt acttaaggac acaccgttaa
1050
<210> 18
<211> 606
<212> DNA
<213> 短乳杆菌
<400> 18
atgttcacag gaataattac agatcaaggt tacattcgac aaataaataa aacagccacg
60
ggagcacagc tcgttattca aacgacacgg gctcatcaga cacgacacgt cggggacagc
120
atcgccgtga acgggatctg cctcacttta accgcagtga ctgacgaagc atttaccgtt
180
gttgcaatgg ctgaaacctt gcagcgtacg acactgggaa cttggcagac tggtatgcag
240
gtcaatctgg aagctgcttt acgagcagat caaggattgg atggacatat cgttcagggg
300
cacgttgaca ccacagcgac cttacgagca agtcataccg aaggggccgc agtccggttg
360
acctttgatg tatcagctga tcaagctcct tacttggttg aaaagggtgc tgtggccttg
420
gatggtgtta gtttaacggt cacggcagtt actcgtcaga cggttcaggt agcgctgatt
480
ccctatacgt tggcacatac gagtcttggt catctacagt gcggtgatca ggtgaatgta
540
gagacagata ttttggggaa gtacgtggtt cgtcagtacc agttaggggg gatgactgat
600
gactag
606
<210> 19
<211> 951
<212> DNA
<213> 短乳杆菌
<400> 19
gatttgccgg tgtccccgga attagcgacc aagtcccagt atagggcagt ggaattacag
60
tgagtagagt attagcttct atgagctgaa tagtcctaaa ttggtgttga caccgcgtcg
120
tacaccacag gcgcgatcga cccaaaacta aacgagttgc actaatgaca tttacacgcg
180
cagtgggtcg catacctgct ttagcgggtg gagattcggg tgaaggaatc gttagtcgct
240
acagttgtta cgcatcgacc gttataactt cccgtgtgga tccttctata gtcgtgaaga
300
gaccatttcg actgtcgaat taaacggtag taactgcatt ttaactttct cgcacaccgt
360
tccaccgttt cggtaactac cgtgtagtcg gcctaaggtg cgactttgct agtaggcggc
420
tctcagaccc acgcaggcgt tgcagagtta gtgtaaccgg tcaactagtt accaaagtgg
480
aactactgga acggttcggg cggtgactga tggtatttga tctgggttta gtggtttcac
540
cagtggtttt cgaactaggc aatgctaagc tagtgtttta cggaaaaaaa gacgaactat
600
aacgactaat ttcagacgta ggtggttcct tgccgctggt ttcagccagt atagaccggg
660
cactataagc cctgatagtt gcatcgcaac tttccgggtg agcagggttt ataccaacac
720
cacaacgtta tttttggctt ataatcatag gggtgcttcc ttggtgttct caagcctaaa
780
ttactctggt ttcccgtgga aaaatcatca gttatcaccc ttcgggagaa cgtttaattt
840
ggcgtaaacc atcggtttat tcgattagca aggccaaggg catgccaggc aaaaaagcac
900
tgggcagcag ttctgtcaga atcgatttag atttatacgg agaagattgt g
951
<210> 20
<211> 1818
<212> DNA
<213> 短乳杆菌
<400> 20
atgtgtggaa ttgttggagt gacgggtaac gataacgccg ttaaaatttt agttaatggg
60
ctacaaaagt tggaatatcg cggctatgat tcagccggaa tctatgttaa tgaccaaaaa
120
ggccaggatt atttggtaaa ggccaagggc cggatttccg aattaagtgc taagattacg
180
ccagaagttc acggatcaac tgggattggt catacgcgtt gggcaacgca tggggtggtt
240
agcgtggata atgcgcaccc acatttctcc aacgacgacc gcttttactt ggttcacaat
300
ggtgtgattg ataacttcca agaacttaag gcgcaatatt taagtgatgt acctttccgg
360
agccaaacgg atacagaagt tgtcgtacag ttgattgata agtttgcggt agaagatcac
420
ttagatgcta agcaggcttt cttgaagaca ctaggcctgc tgaagggttc ctcatatgcc
480
ttcttaatga tggatcggga acaaccagac acattatttg tggctaagaa caagagcccc
540
ttattaattg gtgtcggcga tggcttcaac gttgtctgct cagatgcctt ggccatgtta
600
cgggaaaccc acgatttctt ggaattaatg gatggtgaag ttgtaacgat cacgccagat
660
aaagtggcaa tcgaagacgc tgatggtcag actgttgagc ggaaaccttt ccacgttgac
720
atgaacgctg atgaagcaga caagggcact tatccattct acatgttaaa agaagttgat
780
gaacaaccta acgtgatgcg taaattagcc caaacatatc tgtcagaaca cggcgaacct
840
aacattgaca agcaattgct acaagcaatg gaagccgctg atcgattgta tatcattggc
900
gctgggacga gttaccacgc tgggctgatt ggtaagcgcc tctttgaaaa cttggctcac
960
attccaacgg aagttcatgt gtcatcagaa tttgcgtatg aacaaccgat gttatctgag
1020
aagccattct ttattttcct gacccaatct ggagaaacag ctgatagtcg tgaagttttg
1080
gttaacgtga acgatgcggg ttacccaagc ttgacaatca ccaatgtgca aaactccacg
1140
ttatcacgtg aagccactta caccttgttg ttacatgccg gtccagaaat tgcggtggct
1200
tcaaccaagg cgtacacggc ccaaattgct ttggaagcta tcttggccaa ggctttaggt
1260
gaattaactg gccagattat tgcgcagaat ttcaatattc ggcaacagtt gggactcgtc
1320
gcaactggga tgcaagccat tgtggatgaa aaggataagc tggaagaaat gtcttccaag
1380
tacttgttaa agactaaccg ggcgttttac attggccggg ggatcgacca cgccgtttcc
1440
ttagaagcag ctttgaaact gaaagagatt tcttatattc agtgtgaagg cttcgcgtct
1500
ggtgaattaa agcatggcac gattgcatta attgaggctg gaacaccagt tattgggttt
1560
attacgcagg cgaagacggc tggtttaacc cggagtaact tacaagaaac gatggcccgt
1620
ggtgcacaaa cattgacgat tgtccgggaa agtttagccg tagatggtga tgacttagtc
1680
ttaccggatg tcgatgagat gttaatgcca ctcttaagtg ttgtaccagc acaattgttg
1740
gcctactaca cgagtttaaa taagggctta gatgttgata agccacggaa cttggccaag
1800
agtgtgacag ttgaataa
1818
<210> 21
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 21
agcaaccttt gacctagc
18
<210> 22
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 22
aattccatat caccacccac
20
<210> 23
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 23
cccgatggcc ttacaac
17
<210> 24
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 24
ggaacggctg tccattag
18
<210> 25
<211> 20
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 25
ctaaatgagg agggttcgcg
20
<210> 26
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 26
aagctggcgc tttcattcc
19
<210> 27
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 27
acctctaacg tcaacgtc
18
<210> 28
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 28
agttcccagg gttaatcg
18
<210> 29
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 29
taaccgcagt gactgac
17
<210> 30
<211> 19
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 30
agctgataca tcaaaggtc
19
<210> 31
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 31
agcattgtgt tatcagc
17
<210> 32
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 32
gcagcattgg tagcaac
17
<210> 33
<211> 22
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 33
gtgtggcaag gtggcaaagc ca
22
<210> 34
<211> 25
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 34
ccgatctaca ggcccaactc gatga
25
附图说明
图1A和1B是示出根据一具体实施例的重组微生物基因编辑位点的示意性视图。
图2A和2B是确认根据一具体实施例的血管活性肠肽(VIP:vasoactiveintestinal peptide)生产性得到提高的重组微生物生成的图。
图3A和3B是示出根据一具体实施例的重组微生物的VIP生产性得到提高的图。
图4A和4B是确认根据一具体实施例的环境安全性得到提高的重组微生物生成的图。
图5A和5B是示出根据一具体实施例的重组微生物环境安全性得到提高的图。
图6是示出根据一实施方案的重组微生物在动物模型中显示出IBD治疗效果的图。
最佳模式
以下,通过实施例进一步详细描述。但是,这些实施例仅用于描述,本发明的范围并不受其限制。
实施例1:制备重组微生物
使用短乳杆菌LMT1-46(KCTC 13423BP)并根据乳酸菌中常用的同源重组基因工程方法(Zhang等人,D-Ala-D-Ala ligase as a broad host-range counterselectionmarker in vancomycin resistant lactic acid bacteria,J.Bacteriol.,2018)制备了表达外源VIP的重组微生物。
图1A和1B示意性示出根据本实施例的微生物基因编辑位点。图1A示出用血管活性肠肽(VIP:vasoactive intestinal peptide)基因取代蛋白酶基因(htrA或pepN),以提高VIP生产性的过程。在VIP基因之前和之后,将帮助VIP分泌的信号肽和用于检测的标签包括在一个盒中。蛋白酶基因是短乳杆菌htrA(SEQ ID NO:14)或短乳杆菌pepN(SEQ ID NO:15)。图1B示出形成营养缺陷株以提高环境安全性的过程,该过程利用去除靶基因部分区域的方法。靶基因为短乳杆菌ribB(SEQ ID NO:18)。在图1A和图1B中,每个缩略语的含义如下。P:启动子、SP:信号肽、UTR:非翻译区、VIP:血管活性肠肽、A:短乳杆菌ribB、B:短乳杆菌htrA或短乳杆菌pepN。
实施例2:确认重组微生物的生成
进行PCR以确认重组微生物是否如预期生成。使用在MRS板中以37℃静置培养16小时的乳酸菌菌落。挑取单个菌落悬浮在装有100μl蒸馏水的试管中。对其进行珠子撞击(bead-beating)后,在98℃下加热10分钟以用作DNA模板。混合1μlDNA模板、1μl正向引物、1μl反向引物以及25μlDNA聚合酶预混液,以制备用于聚合酶链式反应(PCR:Polymerasechain reaction)的混合液。PCR条件以每次循环下列步骤来实施,(a)变性步骤,98℃下10秒;(b)退火步骤,在55℃下15秒;以及(c)延伸步骤,由72℃下10秒构成的40次循环的扩增步骤以及由72℃下2分钟构成的最后延伸步骤。所使用的引物设计为待编辑基因区域的ORF外区域,其序列示于下表1。
[表1]
将其结果分别示于图2A和图2B。更具体地,图2A和图2B是示出蛋白酶基因htrA(图2A)和pepN(图2B)分别被VIP表达盒所取代的示意性视图(左侧),以及由此生成重组微生物从而使条带大小如预期发生变化的凝胶图(右侧)。如图2A和2B所示,证实蛋白酶基因htrA和pepN分别被VIP表达盒所取代的重组微生物生成。以htrA为例,野生型显示出的PCR产物的条带大小为1.5kb,当htrA区域被VIP表达盒所取代时,显示出的条带大小为920bp。以pepN为例,野生型显示出的PCR产物的条带大小为2kb,当pepN区域被VIP表达盒所取代时,显示出的条带大小为1.3kb。在图2A和图2B的示意性视图中,每个缩略语的定义与实施例1相同,凝胶图的WT意指野生型(wild type)。
实施例3:评估重组微生物的VIP生产性
为了确认重组微生物的VIP生产性是否提高,进行了评估以确认通过实施例1制备的菌株的VIP表达量。将制备的菌株的原液划线接种在MRS板中,并在37℃下静置培养3天。在此,挑选单个菌落后在MRS液体培养基中以37℃振荡培养24小时。将其接种到25ml的MRS中直至OD600为0.1,然后在37℃下振荡培养16小时。提取10ml菌株培养液,以4000rpm离心10分钟,仅提取上清液后添加1ml的TCA(Trichloroacetic acid),并在4℃下处理30分钟或更长时间。将其以10000rpm离心10分钟后去除上清液,使用1ml贮存在4℃的丙酮悬浮沉淀。将其以13000rpm离心10分钟后去除上清液,添加0.5ml的丙酮悬浮沉淀。将其再次以13000rpm离心10分钟,并在60℃下干燥5分钟。添加样品缓冲液(还原缓冲液)后充分混合沉淀,并在98℃下处理10分钟。利用其进行蛋白质印迹。基于蛋白质印迹结果,利用名为ImageJ的程序对按照相同大小的区域测量的条带强度进行量化。
将其结果分别示于图3A和图3B。更具体地,图3A是示出生成htrA和/或ribB缺失的重组菌株后由此表达的VIP的凝胶图(左侧)以及对VIP表达量进行量化的图表(右侧)。图3B是示出从pepN缺失的重组菌株表达的VIP表达量的图表。如图3A和图3B所示,当短乳杆菌的蛋白酶基因缺失时,作为有效物质的VIP表达量增加。特别地,当htrA缺失时,作为靶物质的VIP表达量为其它基因缺失时的3倍或更高。
实施例4:确认营养缺陷株的生成
进行PCR以确认营养缺陷株是否如预期生成。使用在MRS板中以37℃静置培养16小时的乳酸菌菌落。挑取单个菌落悬浮在装有100μl蒸馏水的试管中。对其进行珠子撞击(bead-beating)后,在98℃下加热10分钟以用作DNA模板。混合1μlDNA模板、1μl正向引物、1μl反向引物以及25μlDNA聚合酶预混液,以制备用于PCR的混合液。PCR条件以每次循环下列步骤来实施,(a)变性步骤,98℃下10秒;(b)退火步骤,在55℃下15秒;以及(c)延伸步骤,由72℃下10秒构成的40循环的扩增步骤以及由72℃下2分钟构成的最后延伸步骤。所使用的引物设计为待编辑基因位点的ORF内外区域,其序列示于下表2。
[表2]
将其结果分别示于图4A和图4B。更具体地,图4A和图4B是示出制备rib和thyA分别缺失的重组微生物的示意性视图(左侧),以及由此生成重组微生物从而使条带大小如预期发生变化的凝胶图(右侧)。在图4A和图4B中,每个缩略语的定义与实施例1相同,凝胶图的WT意指野生型(wild type)。如图4A和图4B所示,确认生成ribB和thyA分别缺失的重组微生物。以ribB为例,野生型显示出的PCR产物的条带大小为1.0kb,当ribB区域缺失时显示出的条带大小为500bp。当利用结合到ribB区域内部的引物进行PCR时,野生型显示为250bp,在ribB缺失的菌株中未观察到条带。以thyA为例,野生型显示出的PCR产物的条带大小为700bp,当部分thyA区域缺失时显示出的条带大小为500bp。
实施例5:评估营养缺陷株的环境安全性
为了了解通过实施例1制备的菌株的生长模式进行了生长实验。将制备的菌株的原液划线接种在MRS板中,并在37℃下静置培养3天。在此,挑选单个菌落后在MRS液体培养基中以37℃振荡培养24小时(230rpm)。提取1ml的培养液后,以13000rpm离心1分钟。用1ml的1x PBS溶液悬浮细胞沉淀后测量OD600,并将其接种到属于可抑制生长环境的SDM(Semi-defined media,其为乳酸菌最小培养基)25ml中直到OD600为0.0025。在37℃、振荡培养(230rpm)条件下培养40小时,并将接种15、17、20、22、24、40小时后检测的OD600值通过图表示出。
将其结果分别示于图5A和图5B。更具体地,图5A和图5B是示出ribB缺失的重组乳酸菌(图5A)以及thyA缺失的重组乳酸菌(图5B)生长模式的图表。在图5A和图5B中,WT意指野生型(wild type)。通过图5A和图5B,证实营养缺陷型乳酸菌在营养不足培养基条件下抑制生长。
实施例6:体内功效:IBD动物模型实验
为了评价转化菌株来源的VIP蛋白治疗功效,将转化菌株口服施用于通过硫酸葡聚糖钠盐(DSS:dextran sulfate sodium)诱导的小鼠肠道炎症模型后,确认存活率或疾病活动指数(DAI:disease activity index)分数。在5ml的MRS培养基中培养1天以进行第一次培养后,将培养的菌株接种到50ml的MRS培养基中直至OD600为0.1。在经过16小时至18小时后培养液的OD600为4至5时,按照施用的小鼠个体数量和施用次数回收菌株。以4000rpm离心10分钟去除上清液,回收的菌株悬浮于1x PBS中,以使能够对每只每次施用1×109cfu。每天一次共施用16天菌株。
将初始菌株施用日期设置为Day-9后进行治疗功效实验,从Day0到Day5,对除PBS组之外的所有组饮水处理2%DSS,并在Day8实施安乐死。处理DSS后每隔2天确认体重下降、毛发竖立、动物的活动程度以及是否出现腹泻,从而计算出DAI分数。
将其结果示于图6。如图6所示,证实提高生产性和环境安全性的菌株在IBD动物模型实验中显示出比对照组更优异的功效。
[保藏号]
保藏单位:韩国生命工学研究院
保藏编号:KCTC13421BP
保藏日期:20171212
保藏单位:韩国生命工学研究院
保藏编号:KCTC13422BP
保藏日期:20171212
保藏单位:韩国生命工学研究院
保藏编号:KCTC13423BP
保藏日期:20171212
Claims (15)
1.一种重组微生物,其为乳杆菌属,其中引入启动子和编码血管活性肠肽的外源基因并且蛋白酶失活,所述血管活性肠肽与所述启动子可操作地连接。
2.根据权利要求1所述的微生物,其中,其为副干酪乳杆菌、短乳杆菌或植物乳杆菌。
3.一种重组微生物,其为乳酸菌,其中引入组成型启动子和编码血管活性肠肽的外源基因并且蛋白酶失活,所述血管活性肠肽与所述启动子可操作地连接。
4.根据权利要求3所述的微生物,其中,所述乳酸菌为乳杆菌属或乳球菌属。
5.根据权利要求4所述的微生物,其中,所述乳酸菌为副干酪乳杆菌、短乳杆菌、植物乳杆菌或乳酸乳球菌。
6.根据权利要求1至5中任意一项所述的微生物,其进一步包括信号序列,所述信号序列可操作地连接在所述启动子和所述外源基因之间。
7.根据权利要求1至5中任意一项所述的微生物,其中,编码蛋白酶的基因缺失。
8.根据权利要求7所述的微生物,其中,编码蛋白酶的基因被编码血管活性肠肽的外源基因所取代,所述血管活性肠肽与启动子可操作地连接。
9.根据权利要求1至5中任意一项所述的微生物,其中,蛋白酶为选自由HtrA、PepN、ClpP以及Lon所组成的组中的至少一种。
10.根据权利要求1至5中任意一项所述的微生物,其为营养缺陷株。
11.根据权利要求10所述的微生物,其中,选自由ribB、thyA以及glmS所组成的组中的至少一种基因缺失。
12.一种组合物,其用于预防或治疗在人中引起胃肠道损伤的疾病,其包括重组微生物,
所述重组微生物为乳酸菌,其中引入启动子和编码血管活性肠肽的外源基因且蛋白酶失活,所述血管活性肠肽与所述启动子可操作地连接。
13.根据权利要求12所述的组合物,其中,所述疾病引起胃肠道的炎症。
14.根据权利要求13所述的组合物,其中,所述疾病是选自由炎症性肠病和结肠炎所组成的组中的至少一种。
15.根据权利要求14所述的组合物,其中,所述炎症性肠病是溃疡性结肠炎或克罗恩氏病。
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