CN112336745A - 含铁物质在制备抑制登革热病毒传播的产品中的应用 - Google Patents
含铁物质在制备抑制登革热病毒传播的产品中的应用 Download PDFInfo
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- CN112336745A CN112336745A CN201910737794.2A CN201910737794A CN112336745A CN 112336745 A CN112336745 A CN 112336745A CN 201910737794 A CN201910737794 A CN 201910737794A CN 112336745 A CN112336745 A CN 112336745A
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- iron
- aedes aegypti
- virus
- dengue virus
- dengue
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Abstract
本发明公开了一种含铁物质在制备抑制登革热病毒传播的产品中的应用。本发明首先公开了含铁物质在制备抑制登革热病毒传播和/或抑制蚊虫对登革热病毒的易感性的产品中的应用。本发明进一步公开了一种抑制登革热病毒传播和/或抑制蚊虫对登革热病毒的易感性的方法。本发明通过实验证明,埃及伊蚊叮咬不同铁状态的被登革热病毒感染的宿主出现显著差异的病毒感染率,埃及伊蚊对登革热病毒的易感性与宿主血液的铁状态呈显著负相关性。进一步,对缺铁小鼠模型进行补铁可有效降低埃及伊蚊引发登革热病毒的易感性,表明含铁物质可降低埃及伊蚊携带病毒的能力和阻断病毒的自然界中的传播。
Description
技术领域
本发明涉及含铁物质在制备抑制登革热病毒传播的产品中的应用。
背景技术
埃及伊蚊是一类以吸血获取和传播病毒的昆虫,是引发“登革热”的祸首。“登革热”是热带和亚热带地区流行的以蚊虫为媒介的急性传染病,具有传播快、发病率高等特点,由蚊虫所传播的病毒会表现出脑炎、脑膜炎、出血热等临床症状,每年导致上亿人次的感染以及数十万的死亡病例,对世界公共卫生造成严重的危害。
补铁是一种对缺铁、低铁人群普遍适用的医学方法,但目前为止还没有关于补铁能有效降低埃及伊蚊对登革热病毒的易感性的相关报道。
发明内容
本发明所要解决的技术问题为如何抑制登革热病毒的传播。
为解决上述技术问题,本发明首先公开了含铁物质在制备抑制登革热病毒传播的产品中的应用。
本发明进一步公开了含铁物质在制备抑制蚊虫对登革热病毒的易感性的产品中的应用。
本发明还提供了一种抑制登革热病毒传播的方法。
本发明抑制登革热病毒传播的方法,包括给被登革热病毒感染的宿主施用上述含铁物质,从而抑制登革热病毒的传播。
本发明进一步还提供了一种抑制蚊虫对登革热病毒的易感性的方法,包括给被登革热病毒感染的宿主施用上述含铁物质,从而抑制蚊虫对登革热病毒的易感性。
上文中,所述含铁物质的活性成分为含铁化合物;所述含铁物质可以为纯净物或混合物;具体的,所述含铁物质可以为补铁剂。
上文中,所述含铁物质的活性成分可为柠檬酸铁铵。
上文中,所述产品可为食品、药品或保健品等等。
所述产品除含有含铁化合物外,还可含有适宜的载体或赋形剂。这里的载体材料包括但不限于水溶性载体材料(如聚乙二醇、聚乙烯吡咯烷酮、有机酸等)、难溶性载体材料(如乙基纤维素、胆固醇硬脂酸酯等)、肠溶性载体材料(如醋酸纤维素酞酸酯和羧甲乙纤维素等)。其中优选的是水溶性载体材料。使用这些材料可以制成多种剂型,包括但不限于片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、脂质体、透皮剂、口含片、栓剂、冻干粉针剂等。可以是普通制剂、缓释制剂、控释制剂及各种微粒给药系统。为了将单位给药剂型制成片剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等;湿润剂与粘合剂,如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等;崩解剂,例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯、山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等;崩解抑制剂,例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等;吸收促进剂,例如季铵盐、十二烷基硫酸钠等;润滑剂,例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。为了将单位给药剂型制成丸剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如稀释剂与吸收剂,如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等;粘合剂如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等;崩解剂,如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。为了将单位给药剂型制成栓剂,可以广泛使用本领域公知的各种载体。关于载体的例子是,例如聚乙二醇、卵磷脂、可可脂、高级醇、高级醇的酯、明胶、半合成甘油酯等。为了将单位给药剂型制成注射用制剂,如溶液剂、乳剂、冻干粉针剂和混悬剂,可以使用本领域常用的所有稀释剂,例如,水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外,为了制备等渗注射液,可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油,此外,还可以添加常规的助溶剂、缓冲剂、pH调节剂等。此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。使用上述剂型可以经注射给药,包括皮下注射、静脉注射、肌肉注射和腔内注射等;腔道给药,如经直肠和阴道;呼吸道给药,如经鼻腔;粘膜给药。
上文中,所述蚊虫为埃及伊蚊或其他具有传播病毒能力的蚊虫。
上文中,所述登革热病毒为登革热2型病毒(dengue virus type-2,DENV-2)。
上文中,所述被登革热病毒感染的宿主可为缺铁或低铁动物,可为哺乳动物,如人和鼠。
本发明通过实验证明,埃及伊蚊叮咬不同铁状态的登革热病毒感染宿主出现显著差异的病毒感染率,埃及伊蚊对登革热病毒的易感性与宿主血液的铁状态呈显著负相关性,即埃及伊蚊叮咬低铁状态的感染宿主更易感染病毒。通过建立缺铁小鼠模型证实,对缺铁小鼠模型进行补铁(柠檬酸铁铵)可有效降低埃及伊蚊引发登革热病毒的易感性,因此,含铁物质(柠檬酸铁铵)可降低埃及伊蚊携带病毒的能力和阻断病毒的自然界中的传播。
附图说明
图1为柠檬酸铁铵对登革热病毒在埃及伊蚊体内的感染率的影响;每个空心圆点代表一只埃及伊蚊。
图2为缺铁小鼠对登革热病毒在埃及伊蚊体内的感染率的影响;每个空心圆点代表一只埃及伊蚊。
图3为缺铁小鼠与正常小鼠的血清铁测定,每个空心圆代表一只小鼠。
图4为缺铁小鼠补铁对埃及伊蚊肠组织的登革热病毒感染率的影响;每个空心圆点代表一只埃及伊蚊。
图5为缺铁小鼠补铁对埃及伊蚊唾液腺的登革热病毒感染率的影响;每个空心圆点代表一只埃及伊蚊。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中所使用的实验方法如无特殊说明,均为常规方法。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
下述实施例中埃及伊蚊(Aedes aegypti)在文献“Colpitts TM etal.Alterations in the Aedes aegypti Transcriptome during Infection with WestNile,Dengue and Yellow Fever Viruses.2011,PloSPathog 7(9):e1002189.”中公开过,公众可从清华大学医学院获得。
下述实施例中登革热2型病毒(dengue virus type-2,DENV-2)的New Guinea C株在文献“Liu et al.Flavivirus NS1 protein in infected host sera enhances viralacquisition by mosquitoes.2016,Nat Microbiol 1(9):16087.”中公开过,公众可从清华大学医学院获得。
下述实施例中柠檬酸铁铵购买于Sigma公司,产品目录号为F5879。
下述实施例中正常饲料购买于南通特洛菲饲料科技有限公司,货号:TP0306C。
下述实施例中缺铁饲料购买于南通特洛菲饲料科技有限公司,货号:TP0306。
实施例1、体外膜饲喂系统饲喂柠檬酸铁铵抑制登革热病毒在埃及伊蚊体内的易感性
体外膜饲喂系统饲喂柠檬酸铁铵可以降低埃及伊蚊对登革热病毒的感染率,具体试验如下:
1、将埃及伊蚊分成4组,即Mock组、25μM FAC组、50μM FAC组和150μM FAC组,分别进行如下处理:
Mock组:每只埃及伊蚊通过体外膜饲喂系统饲喂人抗凝全血样本和登革热2型病毒(DENV-2)上清(1∶1体积比)的混合液;
25μM FAC组:每只埃及伊蚊通过体外膜饲喂系统饲喂含有柠檬酸铁铵(FAC)的人抗凝全血样本和登革热2型病毒(DENV-2)上清(1∶1体积比)的混合液,所述柠檬酸铁铵在所述混合液中的浓度为25μM。
50μM FAC组:每只埃及伊蚊通过体外膜饲喂系统饲喂含有柠檬酸铁铵(FAC)的人抗凝全血样本和登革热2型病毒(DENV-2)上清(1∶1体积比)的混合液,所述柠檬酸铁铵在所述混合液中的浓度为50μM。
150μM FAC组:每只埃及伊蚊通过体外膜饲喂系统饲喂含有柠檬酸铁铵(FAC)的人抗凝全血样本和登革热2型病毒(DENV-2)上清(1∶1体积比)的混合液,所述柠檬酸铁铵在所述混合液中的浓度为150μM。
2、饲喂八天后,提取埃及伊蚊的总RNA,反转录为cDNA,利用SYBR RT-PCR试剂盒以埃及伊蚊的Actin作为基因内参检测埃及伊蚊体内的登革热2型病毒基因的相对表达量。根据不同组别中埃及伊蚊体内的登革热2型病毒基因的相对表达量判断埃及伊蚊是否感染登革热病毒。以登革热病毒表达量/Actin的表达量的比值(即相对表达量)≥0.001作为是否感染的临界值,即登革热病毒表达量/Actin的表达量的比值(即相对表达量)≥0.001表示埃及伊蚊成功感染登革热病毒。
其中,用于检测登革热2型病毒的引物如下:
上游引物:5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’(序列1);
下游引物:5’-CAGATCTCTGATGAATAACCAACG-3’(序列2)。
所用Actin基因的引物如下:
上游引物:5’-GAACACCCAGTCCTGCTGACA-3’(序列3);
下游引物:5’-TGCGTCATCTTCTCACGGTTAG-3’(序列4)。
Mock组(图中以“Mock”表示)、25μM FAC组(图中以“25μM FAC”表示)、50μM FAC组(图中以“50μM FAC”表示)和150μM FAC组(图中以“150μM FAC”表示)的埃及伊蚊体内的登革热2型病毒的感染情况如图1所示。结果显示:随着蚊虫饲喂柠檬酸铁铵的浓度逐渐上升,埃及伊蚊体内的登革热2型病毒感染率出现显著下降,表明埃及伊蚊饲喂柠檬酸铁铵可以降低登革热2型病毒在埃及伊蚊体内的病毒感染效率。
实施例2、缺铁小鼠模型显著提高登革热病毒在埃及伊蚊体内的易感性
在埃及伊蚊吸血过程中宿主体内的病毒颗粒和大量血液进入埃及伊蚊体内,因此,本发明采用如下方法进行缺铁小鼠模型对登革热病毒在埃及伊蚊体内的感染率试验:
一、制备正常对照小鼠和缺铁AG6小鼠
将四周龄AG6小鼠,体重是15g,随机分成2组,即Mock组和Iron-deficient mice组,每组4只,分别进行如下处理:
Mock组:四周龄AG6小鼠饲喂正常饲料五周;
Iron-deficient mice组:四周龄AG6小鼠饲喂将缺铁饲料五周。
二、两组小鼠饲喂五周之后,第0天通过小鼠足垫注射感染登革热2型病毒,从第一天到第五天每天由干净的埃及伊蚊(无感染登革热2型病毒的干净埃及伊蚊)对小鼠进行叮咬吸血,收集吸血完毕的埃及伊蚊进行培养,Mock组和Iron-deficient mice组均得到五组埃及伊蚊,即1d.p.i.组、2d.p.i.组、3d.p.i.组、4d.p.i.组和5d.p.i.组。
三、埃及伊蚊叮咬小鼠八天后,提取埃及伊蚊的总RNA,反转录为cDNA,利用SYBRRT-PCR试剂盒以埃及伊蚊的Actin作为基因内参检测埃及伊蚊体内的登革热2型病毒基因的相对表达量。根据不同组别中埃及伊蚊体内的登革热2型病毒基因的相对表达量判断埃及伊蚊是否感染登革热病毒。以登革热病毒表达量/Actin的表达量的比值(即相对表达量)≥0.001作为是否感染的临界值,即登革热病毒表达量/Actin的表达量的比值(即相对表达量)≥0.001表示埃及伊蚊成功感染登革热病毒。
其中,用于检测登革热2型病毒的引物如下:
上游引物:5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’;
下游引物:5’-CAGATCTCTGATGAATAACCAACG-3’。
所用Actin基因的引物如下:
上游引物:5’-GAACACCCAGTCCTGCTGACA-3’;
下游引物:5’-TGCGTCATCTTCTCACGGTTAG-3’。
Mock组和Iron-deficient mice组对应的五组埃及伊蚊的登革热病毒感染率如表1和图2所示,结果显示:Iron-deficient mice组(图中以“Iron-deficient mice”表示)中五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)的登革热病毒感染率均高于Mock组(图中以“Mock”表示)中对应的五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)的登革热病毒感染率,其中,三组埃及伊蚊(图中分别以“2d.p.i.”“3d.p.i.”“4d.p.i.”表示)达到了显著性的水平,表明宿主的铁含量对埃及伊蚊对登革热病毒的易感性造成显著影响,低铁或缺铁宿主可提高埃及伊蚊对登革热病毒的易感性。
表1缺铁小鼠模型对登革热病毒在埃及伊蚊的感染率情况
注:N表示埃及伊蚊总数,n表示被登革热病毒感染的埃及伊蚊数,W表示感染率
实施例3、对感染宿主进行补铁可显著抑制登革热病毒在埃及伊蚊体内的易感性
在埃及伊蚊吸血过程中宿主体内的病毒颗粒和大量血液进入埃及伊蚊体内,因此,本发明采用如下方法进行对感染宿主补铁后对登革热病毒在埃及伊蚊体内的感染率试验:
一、制备缺铁AG6小鼠
将四周龄AG6小鼠饲喂缺铁饲料五周,得到九周龄缺铁AG6小鼠,对饲喂第三周、第四周和第五周的小鼠的血清铁进行测定,结果如图3所示,与正常小鼠(图中以“Mock”表示)相比,饲喂缺铁饲料五周后小鼠血清铁浓度明显降低,说明构建了缺铁AG6小鼠(图中以“Iron-deficient mice”表示)。
二、对步骤一的九周龄缺铁AG6小鼠每只足垫注射感染登革热2型病毒,随后将感染登革热病毒的九周龄缺铁AG6小鼠,体重是25g,随机分成2组,即Mock组和Ironsupplementation组,每组4只,分别进行如下注射处理:
Mock组:每只九周龄AG6小鼠通过尾静脉注射质量百分含量为0.01%生理盐水,每只小鼠50μL。
Iron supplementation组:每只九周龄AG6小鼠通过尾静脉注射含量为60μg/mL柠檬酸铁铵溶液,每只小鼠50μL。
将经过上述注射处理的Mock组和Iron supplementation组小鼠,从第一天到第五天每天由干净的埃及伊蚊(无感染登革热2型病毒的干净埃及伊蚊)对小鼠进行叮咬吸血(第一天尾静脉注射15分钟之后,埃及伊蚊对小鼠进行叮咬),收集吸血完毕的埃及伊蚊进行培养,Mock组和Iron supplementation组分别得到五组埃及伊蚊,即1d.p.i.组、2d.p.i.组、3d.p.i.组、4d.p.i.组和5d.p.i.组,每组分为两小组(第一小组和第二小组)。
三、第一小组埃及伊蚊叮咬小鼠八天后,分离埃及伊蚊的中肠组织,提取肠的总RNA,反转录为cDNA,利用SYBR RT-PCR试剂盒以埃及伊蚊的Actin作为基因内参检测埃及伊蚊体内的登革热2型病毒E基因的相对表达量。根据不同组别中埃及伊蚊体内的登革热2型病毒E基因的相对表达量判断埃及伊蚊是否感染登革热病毒。以登革热病毒表达量/Actin的表达量的比值(即相对表达量)≥0.001作为是否感染的临界值,即登革热病毒表达量/Actin的表达量的比值(即相对表达量)≥0.001表示埃及伊蚊成功感染登革热病毒。
其中,用于检测登革热2型病毒的引物如下:
上游引物:5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’;
下游引物:5’-CAGATCTCTGATGAATAACCAACG-3’。
所用Actin基因的引物如下:
上游引物:5’-GAACACCCAGTCCTGCTGACA-3’;
下游引物:5’-TGCGTCATCTTCTCACGGTTAG-3’。
Mock组和Iron supplementation组对应的五组埃及伊蚊的登革热病毒感染率如表2和图4所示,结果显示:Iron supplementation组(图中以“Iron supplementation”表示)中五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)中肠的登革热病毒感染率均低于Mock组(图中以“Mock”表示)对应的五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)的登革热病毒感染率,其中,三组埃及伊蚊(图中分别以“2d.p.i.”“3d.p.i.”“4d.p.i.”表示)达到了显著性的水平,表明对感染宿主进行补铁可显著抑制埃及伊蚊对登革热病毒的易感性,从而达到防控登革热病毒传播的目的。
表2感染宿主补铁后对登革热病毒在埃及伊蚊肠细织的感染率情况
注:N表示埃及伊蚊总数,n表示被登革热病毒感染的埃及伊蚊数,W表示感染率
四、第二小组埃及伊蚊叮咬小鼠十四天后,分离埃及伊蚊的唾液腺,提取唾液腺的总RNA,反转录为cDNA,利用SYBR RT-PCR试剂盒以埃及伊蚊的Actin作为基因内参检测埃及伊蚊体内的登革热2型病毒基因的相对表达量。根据不同组别中埃及伊蚊体内的登革热2型病毒基因的相对表达量判断埃及伊蚊是否感染登革热病毒。以登革热病毒表达量/Actin的表达量的比值(即相对表达量)≥0.001作为是否感染的临界值,即登革热病毒表达量/Actin的表达量的比值(即相对表达量)≥0.001表示埃及伊蚊成功感染登革热病毒。
其中,用于检测登革热2型病毒的引物如下:
上游引物:5’-CATTCCAAGTGAGAATCTCTTTGTCA-3’;
下游引物:5’-CAGATCTCTGATGAATAACCAACG-3’。
所用Actin基因的引物如下:
上游引物:5’-GAACACCCAGTCCTGCTGACA-3’;
下游引物:5’-TGCGTCATCTTCTCACGGTTAG-3’。
Mock组和Iron-deficient mice组对应的五组埃及伊蚊的唾液登革热病毒感染率如表3和图5所示,每个空心圆点代表一只埃及伊蚊唾液腺。结果显示缺铁小鼠(图中以“Iron-deficient mice”表示)中五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)唾液腺的登革热病毒感染率均显著低于Mock组(图中以“Mock”表示)对应的五组埃及伊蚊(图中分别以“1d.p.i.”“2d.p.i.”“3d.p.i.”“4d.p.i.”“5d.p.i.”表示)的登革热病毒感染率,其中,三组埃及伊蚊(图中分别以“2d.p.i.”“3d.p.i.”“4d.p.i.”表示)达到了显著性的水平,表明对感染宿主进行补铁可显著抑制埃及伊蚊对登革热病毒的传播能力。
表3感染宿主补铁后对登革热病毒在埃及伊蚊唾液腺的感染率情况
注:N表示埃及伊蚊总数,n表示被登革热病毒感染的埃及伊蚊数,W表示感染率
以上结果表明,对被登革热病毒感染的宿主进行补铁能有效抑制蚊虫对登革热病毒传播能力和蚊虫对登革热病毒的易感性。
以上对本发明进行了详述。对于本领域技术人员来说,在不脱离本发明的宗旨和范围,以及无需进行不必要的实验情况下,可在等同参数、浓度和条件下,在较宽范围内实施本发明。虽然本发明给出了特殊的实施例,应该理解为,可以对本发明作进一步的改进。总之,按本发明的原理,本申请欲包括任何变更、用途或对本发明的改进,包括脱离了本申请中已公开范围,而用本领域已知的常规技术进行的改变。按以下附带的权利要求的范围,可以进行一些基本特征的应用。
SEQUENCE LISTING
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<120> 含铁物质在制备抑制登革热病毒传播的产品中的应用
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Claims (10)
1.含铁物质在制备抑制登革热病毒传播的产品中的应用。
2.含铁物质在制备抑制蚊虫对登革热病毒的易感性的产品中的应用。
3.根据权利要求1或2所述的应用,特征在于:所述含铁物质的活性成分为含铁化合物。
4.根据权利要求1-3任一所述的应用,其特征在于:所述含铁物质为补铁剂。
5.根据权利要求1-4任一所述的应用,特征在于:所述含铁物质的活性成分为柠檬酸铁铵。
6.根据权利要求1-5任一所述的应用,特征在于:所述产品为药品、食品或保健品。
7.根据权利要求2所述的应用,特征在于:所述蚊虫为埃及伊蚊或其他具有传播病毒能力的蚊虫。
8.一种抑制登革热病毒传播的方法,特征在于:所述方法包括给被登革热病毒感染的宿主施用权利要求1-5中任一所述的含铁物质,从而抑制登革热病毒的传播。
9.一种抑制蚊虫对登革热病毒的易感性的方法,特征在于:所述方法包括给被登革热病毒感染的宿主施用权利要求1-5中任一所述的含铁物质,从而抑制蚊虫对登革热病毒的易感性。
10.根据权利要求8或9所述的方法,其特征在于:所述被登革热病毒感染的宿主为缺铁或低铁动物。
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