中和抗体结合MCP-1对狂犬病暴露后预防研究及嵌合糖蛋白重组狂犬病病毒的构建
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摘要
狂犬病是一种致死性的中枢神经嗜性的人兽共患传染病，病原是狂犬病病毒，能感染人和所有温血动物。据世界卫生组织（WHO）报道，每年造成全世界大约26,000~55,000人的死亡，其中绝大多数发生于非洲和亚洲的发展中国家，对人类的公共卫生一直存在着威胁。在亚洲、非洲和拉丁美洲，犬源的狂犬病毒是人类感染狂犬病的主要来源。在美国，犬源的狂犬病通过宠物免疫计划得到控制，而来源于蝙蝠等野生动物感染是引起人狂犬病的主要原因。目前暴露后预防（PEP）主要包括接种疫苗和抗狂犬病免疫球蛋白等措施，尽管许多报道表明一旦出现神经症状，狂犬病是没有办法治疗的。但是如果在暴露后能够及时采取PEP措施，使外周免疫效应因子和抗体进入中枢神经，动物感染病毒后即使到达了脑部，还是可以有效阻止狂犬病的发生。尽管有通过昏迷疗法（Milwaukee Protocol）及其衍生法治疗狂犬病的案例，但该方法的有效性一直存在质疑。
我们以前的研究表明，表达GM-CSF等免疫刺激因子的重组狂犬病毒（rRABVs）可通过激活、聚集树突状细胞（Dendritic cells，DCs），在中枢神经系统（CNS）诱导表达高水平的趋化因子及细胞因子，增强血脑屏障（BBB）通透性，提高中和抗体（VNA）水平，进而消除CNS中的病毒，致使避免街毒株狂犬病感染的发生；同时MCP-1增强BBB通透性后提高了灭活重组病毒对街毒感染的治疗效果，因此中和抗体与BBB通透性的增强是狂犬病暴露后有效预防的主要因素。为了研究狂犬病病毒中和抗体结合MCP-1对小鼠暴露狂犬病街毒后的预防效果，在ICR小鼠肌肉感染10IMLD50狂犬病街毒株DRV后不同时间点，以静脉注射（i.v.）中和抗体和（或）脑内接种（i.c.）单核细胞趋化蛋白1（MCP-1）进行处理。结果发现，在感染街毒后3d和5d开始处理，中和抗体结合MCP-1的方法均具有显著的保护作用。通过病毒滴定、组织切片、免疫组化等方法检测存活和死亡小鼠脑内的病毒含量，发现存活小鼠中检测不到病毒，死亡小鼠脑内检测到较高的病毒滴度；通过中和实验与ELISA方法检测抗体水平发现，存活小鼠脑内检测到显著升高的中和抗体与IgG水平，死亡小鼠脑内检测不到中和抗体与检测到较低的IgG水平。数据说明，中和抗体结合MCP-1的方法能成功地清除小鼠CNS中的病毒，从而阻止狂犬病感染的发生。
由于存活的ICR小鼠脑内检测到较高水平的κ轻链mRNA水平（代表B细胞数量），为了研究B细胞在小鼠狂犬病暴露后预防中的作用，我们选取B细胞敲除的C57BL/6J小鼠复制ICR小鼠的实验。在B细胞缺失小鼠肌肉感染DRV后，用中和抗体和MCP-1进行处理。结果发现，小鼠感染后5d开始处理的存活率只有25%，而在5d和7d重复注射MCP-1后的存活率上升到75%。在存活小鼠中检测到显著升高的中和抗体与较高的IgG水平，而检测不到狂犬病病毒；相反在死亡小鼠脑内检测到较高的病毒滴度，而检测不到中和抗体。在存活B细胞敲除小鼠脑内检测不到κ轻链mRNA水平，说明即使在没有分泌抗体B细胞的情况下，只要BBB通透性持续增强，足够的中和抗体进入CNS，中和抗体结合MCP-1的方法就能成功地清除B细胞缺失小鼠CNS中的病毒，从而阻止小鼠感染狂犬病。
为了研究中和抗体结合MCP-1对狂犬病暴露后预防的保护机制，我们分成未感染与感染DRV两种情况进行探讨。在未感染DRV情况下，中和抗体与MCP-1同时处理后ICR小鼠脑内检测到显著升高的中和抗体，单独处理中和抗体组小鼠脑内检测不到中和抗体水平，说明MCP-1使BBB通透性增高，外周的VNA进入脑组织中，使脑内的中和抗体显著升高；在感染DRV情况下，发现MCP-1处理后脑内BBB通透性在12h后开始上升，36h时达到峰值，处理48h后开始下降，逐渐恢复正常水平，与之前的报道保持一致的趋势。而紧密连接分子（Occludin、Claudin-5和ZO-1）表达量随着NaF吸收量的增加而下调，脑内中和抗体水平随着BBB通透性的升高而增高，病毒含量随着中和抗体水平的升高而降低。这些结果说明，中和抗体结合MCP-1的方法利用MCP-1增强BBB通透性的功能，允许外周的中和抗体进入CNS中，从而达到清除病毒，阻止狂犬病发生的目的，再一次证实了中和抗体与BBB通透性对清除CNS中病毒的必要性。
研究表明，狂犬病病毒的G蛋白表达量与致病性呈负相关，而强弱毒株（B2C和DRV）G蛋白的表达量存在差异。为了研究G蛋白的跨膜区、膜内区与G蛋白表达量及病毒致病力的相关性，我们利用实验室构建的B2C反向遗传系统，将DRV G蛋白跨膜区（TM）和膜内区（CT）替换B2C G蛋白的相对应区域，成功拯救嵌合病毒并命名为rB2C-(DRV-TM+CT)、rB2C-(DRV-CT)和rB2C-(DRV-TM)，构建的嵌合病毒与母本病毒具有相似的复制和增殖水平，关于嵌合病毒G蛋白的表达量及其与病毒致病性的相关性还有待进一步的研究。
综上所述，只要BBB的通透性持续增高，中和抗体结合MCP-1的方法能够有效的阻止免疫系统完善或B细胞缺陷的小鼠暴露狂犬病后疾病的发生。
Rabies, which is caused by rabies virus, has been known as a deadly neurological zoonosis of bothhumans and other warm-blooded animals and remains a major threat to public health. According to thereport from WHO, rabies causes about26,000to55,000deaths worldwide each year, most of whichoccur in Asia and Africa. Canine rabies is responsible for more than90%of the human cases in Asia,Africa and Latin America. In the United States, dog rabies has been largely brought under controlthrough pet vaccination programs. Most of the human cases in the USA have been associated withrabies virus (RABV) found in wildlife, especially bats. The postexposure prophylaxis (PEP) of rabiesmainly includes vaccination and administration of anti-rabies immunoglobulin. Although it is widelyaccepted that there is no effective treatment and rabies is almost always fatal once neurologicalsymptoms develop, PEP is very effective if it is initiated promptly after exposure, because it permitsimmune effectors and antibodies to enter the central nervous system (CNS) tissues and clear virus fromCNS and prevent the development of rabies even if virus exist in the brain. Although human survivorshave been reported recently after treatment with the Milwaukee Protocol or a modification thereof, theeffectiveness of the method has been questioned.
Our previous studies revealed that intracerebral administration of rRABV-GMCSF or a combinationof inactivated rRABV and monocyte chemotactic protein-1(MCP-1) can prevent mice from developingrabies by activating and recruiting dentritic cells, stimulating the production of virus neutralizingantibody (VNA), enhancing the BBB permeability, and clearing RABV from the CNS. To investigate ifintravenous administration of VNA together with (MCP-1) can protect mice from RABV infection, ICRmice were infected intramuscularly with10IMLD50(50%mouse intramuscular lethal dose) of a streetRABV (DRV-Mexico) then treated with VNA(i.v.) and (or) MCP-1(i.c.) at different time points afterinfection. It was found that significantly more mice treated with VNA and MCP-1at days3and5afterinfection with DRV were protected from developing rabies than sham-treated mice. No virus could bedetected in the brains of surviving mice, in contrast, high titers of virus were measured in the brains ofdead mice, by virus titration, pathology and immunopathochemestry. On the other hand, no antibodiescould be detected in the brains of dead mice, whereas high titers of VNA and Ig G were measured in thebrains of surviving animals, using FAVN and ELISA testes. The data showed that administration ofVNA and MCP-1can effectively clear virus from the CNS and prevent mice from developing rabies.
Since high level of κ light chain mRNA was measured in the brains of surviving ICR mice, in orderto exclude the possibility that B cells entering into the CNS are absolutely required to clear RABV fromthe CNS, the experiment as summarized in ICR mice was repeated in B-cell deficient mice. The resultsshowed that only25%B cells k.o. mice survived when treated with MCP-1once at5d.p.i, however, thesurvivorship was significantly enhanced (up to75%) as long as MCP-1was repeatedly treated at day5and7post infection. Similarly, no virus and high level of neutralizing antibodies could be detected inthe brains of surviving mice, whereas no antibodies and high titers of virus was measured in the brains of dead mice. The data showed that administration of VNA and MCP-1can effectively clear virus fromthe CNS and prevent developing rabies in B cells k.o. mice once the blood-brain barrier (BBB)permeability is enhanced, even absence of VNA-producing plasma cells.
To investigate the protection mechanism of administration of VNA and MCP-1for PEP of rabies,answers can be searched in possible two situations: with infection and without infection of rabies virus.In the case without DRV infection, the significant high neutralizing antibody was detected in the brainsof mice treated with VNA and MCP-1, while no VNA was measured in the VNA only-treated group.The result indicated that MCP-1enhanced the BBB permeability, which allows VNA entering the CNSand increases the level of VNA in the brains. In the case of DRV infection, results demonstrated thatBBB permeability started to increase at12h after MCP-1treatment and peeked at36h, then declined tonormal at48h. The expression of tight junction proteins (Occludin, Claudin-5and ZO-1) was reducedas the level of NaF in the brains increased. On the other hand，increasing BBB permeability enhancedthe level of VNA, and which reduced the titers of virus in the brains. In summary, MCP-1enhanced theBBB permeability, permitted VNA enter the CNS and cleared RABV from the CNS, then prevented thedevelopment of rabies. It is confirmed that it is needed for both VNA and enhanced BBB permeabilityin clearing virus from the CNS.
Previous studies showed that pathogenicity of rabies virus variants inversely correlates withglycoprotein expression levels. There is an obvious difference in G protein expression levels betweenB2C (low virulent) and DRV (highly virulent) virus strains. To investigate the correlation oftransmembrane anchor (TM) and cytoplasmic domain (CT) of G protein invovled in the glycoproteinexpression levels and pathogenicity of rabies virus, we construct B2C recombinant virus with chimericDRV G protein (TM and CT) using the B2C reverse genetics system. The chimeric viruses wererescued and designated as rB2C-(DRV-TM+CT), rB2C-(DRV-CT) and rB2C-(DRV-TM). It was foundthat no significant difference of virus growth kinetics between the chimeric viruses and parental virus.Further studies need to be conducted to address the virus glycoprotein expression and its correlationwith the viral pathogenicity.
In conclusion, intravenous administration of virus neutralizing antibodies can clear rabies virus fromthe CNS in both immunocompetent and immunocompromised mice as long as the blood-brain barrierpermeability is enhanced.
我们以前的研究表明，表达GM-CSF等免疫刺激因子的重组狂犬病毒（rRABVs）可通过激活、聚集树突状细胞（Dendritic cells，DCs），在中枢神经系统（CNS）诱导表达高水平的趋化因子及细胞因子，增强血脑屏障（BBB）通透性，提高中和抗体（VNA）水平，进而消除CNS中的病毒，致使避免街毒株狂犬病感染的发生；同时MCP-1增强BBB通透性后提高了灭活重组病毒对街毒感染的治疗效果，因此中和抗体与BBB通透性的增强是狂犬病暴露后有效预防的主要因素。为了研究狂犬病病毒中和抗体结合MCP-1对小鼠暴露狂犬病街毒后的预防效果，在ICR小鼠肌肉感染10IMLD50狂犬病街毒株DRV后不同时间点，以静脉注射（i.v.）中和抗体和（或）脑内接种（i.c.）单核细胞趋化蛋白1（MCP-1）进行处理。结果发现，在感染街毒后3d和5d开始处理，中和抗体结合MCP-1的方法均具有显著的保护作用。通过病毒滴定、组织切片、免疫组化等方法检测存活和死亡小鼠脑内的病毒含量，发现存活小鼠中检测不到病毒，死亡小鼠脑内检测到较高的病毒滴度；通过中和实验与ELISA方法检测抗体水平发现，存活小鼠脑内检测到显著升高的中和抗体与IgG水平，死亡小鼠脑内检测不到中和抗体与检测到较低的IgG水平。数据说明，中和抗体结合MCP-1的方法能成功地清除小鼠CNS中的病毒，从而阻止狂犬病感染的发生。
由于存活的ICR小鼠脑内检测到较高水平的κ轻链mRNA水平（代表B细胞数量），为了研究B细胞在小鼠狂犬病暴露后预防中的作用，我们选取B细胞敲除的C57BL/6J小鼠复制ICR小鼠的实验。在B细胞缺失小鼠肌肉感染DRV后，用中和抗体和MCP-1进行处理。结果发现，小鼠感染后5d开始处理的存活率只有25%，而在5d和7d重复注射MCP-1后的存活率上升到75%。在存活小鼠中检测到显著升高的中和抗体与较高的IgG水平，而检测不到狂犬病病毒；相反在死亡小鼠脑内检测到较高的病毒滴度，而检测不到中和抗体。在存活B细胞敲除小鼠脑内检测不到κ轻链mRNA水平，说明即使在没有分泌抗体B细胞的情况下，只要BBB通透性持续增强，足够的中和抗体进入CNS，中和抗体结合MCP-1的方法就能成功地清除B细胞缺失小鼠CNS中的病毒，从而阻止小鼠感染狂犬病。
为了研究中和抗体结合MCP-1对狂犬病暴露后预防的保护机制，我们分成未感染与感染DRV两种情况进行探讨。在未感染DRV情况下，中和抗体与MCP-1同时处理后ICR小鼠脑内检测到显著升高的中和抗体，单独处理中和抗体组小鼠脑内检测不到中和抗体水平，说明MCP-1使BBB通透性增高，外周的VNA进入脑组织中，使脑内的中和抗体显著升高；在感染DRV情况下，发现MCP-1处理后脑内BBB通透性在12h后开始上升，36h时达到峰值，处理48h后开始下降，逐渐恢复正常水平，与之前的报道保持一致的趋势。而紧密连接分子（Occludin、Claudin-5和ZO-1）表达量随着NaF吸收量的增加而下调，脑内中和抗体水平随着BBB通透性的升高而增高，病毒含量随着中和抗体水平的升高而降低。这些结果说明，中和抗体结合MCP-1的方法利用MCP-1增强BBB通透性的功能，允许外周的中和抗体进入CNS中，从而达到清除病毒，阻止狂犬病发生的目的，再一次证实了中和抗体与BBB通透性对清除CNS中病毒的必要性。
研究表明，狂犬病病毒的G蛋白表达量与致病性呈负相关，而强弱毒株（B2C和DRV）G蛋白的表达量存在差异。为了研究G蛋白的跨膜区、膜内区与G蛋白表达量及病毒致病力的相关性，我们利用实验室构建的B2C反向遗传系统，将DRV G蛋白跨膜区（TM）和膜内区（CT）替换B2C G蛋白的相对应区域，成功拯救嵌合病毒并命名为rB2C-(DRV-TM+CT)、rB2C-(DRV-CT)和rB2C-(DRV-TM)，构建的嵌合病毒与母本病毒具有相似的复制和增殖水平，关于嵌合病毒G蛋白的表达量及其与病毒致病性的相关性还有待进一步的研究。
综上所述，只要BBB的通透性持续增高，中和抗体结合MCP-1的方法能够有效的阻止免疫系统完善或B细胞缺陷的小鼠暴露狂犬病后疾病的发生。
Rabies, which is caused by rabies virus, has been known as a deadly neurological zoonosis of bothhumans and other warm-blooded animals and remains a major threat to public health. According to thereport from WHO, rabies causes about26,000to55,000deaths worldwide each year, most of whichoccur in Asia and Africa. Canine rabies is responsible for more than90%of the human cases in Asia,Africa and Latin America. In the United States, dog rabies has been largely brought under controlthrough pet vaccination programs. Most of the human cases in the USA have been associated withrabies virus (RABV) found in wildlife, especially bats. The postexposure prophylaxis (PEP) of rabiesmainly includes vaccination and administration of anti-rabies immunoglobulin. Although it is widelyaccepted that there is no effective treatment and rabies is almost always fatal once neurologicalsymptoms develop, PEP is very effective if it is initiated promptly after exposure, because it permitsimmune effectors and antibodies to enter the central nervous system (CNS) tissues and clear virus fromCNS and prevent the development of rabies even if virus exist in the brain. Although human survivorshave been reported recently after treatment with the Milwaukee Protocol or a modification thereof, theeffectiveness of the method has been questioned.
Our previous studies revealed that intracerebral administration of rRABV-GMCSF or a combinationof inactivated rRABV and monocyte chemotactic protein-1(MCP-1) can prevent mice from developingrabies by activating and recruiting dentritic cells, stimulating the production of virus neutralizingantibody (VNA), enhancing the BBB permeability, and clearing RABV from the CNS. To investigate ifintravenous administration of VNA together with (MCP-1) can protect mice from RABV infection, ICRmice were infected intramuscularly with10IMLD50(50%mouse intramuscular lethal dose) of a streetRABV (DRV-Mexico) then treated with VNA(i.v.) and (or) MCP-1(i.c.) at different time points afterinfection. It was found that significantly more mice treated with VNA and MCP-1at days3and5afterinfection with DRV were protected from developing rabies than sham-treated mice. No virus could bedetected in the brains of surviving mice, in contrast, high titers of virus were measured in the brains ofdead mice, by virus titration, pathology and immunopathochemestry. On the other hand, no antibodiescould be detected in the brains of dead mice, whereas high titers of VNA and Ig G were measured in thebrains of surviving animals, using FAVN and ELISA testes. The data showed that administration ofVNA and MCP-1can effectively clear virus from the CNS and prevent mice from developing rabies.
Since high level of κ light chain mRNA was measured in the brains of surviving ICR mice, in orderto exclude the possibility that B cells entering into the CNS are absolutely required to clear RABV fromthe CNS, the experiment as summarized in ICR mice was repeated in B-cell deficient mice. The resultsshowed that only25%B cells k.o. mice survived when treated with MCP-1once at5d.p.i, however, thesurvivorship was significantly enhanced (up to75%) as long as MCP-1was repeatedly treated at day5and7post infection. Similarly, no virus and high level of neutralizing antibodies could be detected inthe brains of surviving mice, whereas no antibodies and high titers of virus was measured in the brains of dead mice. The data showed that administration of VNA and MCP-1can effectively clear virus fromthe CNS and prevent developing rabies in B cells k.o. mice once the blood-brain barrier (BBB)permeability is enhanced, even absence of VNA-producing plasma cells.
To investigate the protection mechanism of administration of VNA and MCP-1for PEP of rabies,answers can be searched in possible two situations: with infection and without infection of rabies virus.In the case without DRV infection, the significant high neutralizing antibody was detected in the brainsof mice treated with VNA and MCP-1, while no VNA was measured in the VNA only-treated group.The result indicated that MCP-1enhanced the BBB permeability, which allows VNA entering the CNSand increases the level of VNA in the brains. In the case of DRV infection, results demonstrated thatBBB permeability started to increase at12h after MCP-1treatment and peeked at36h, then declined tonormal at48h. The expression of tight junction proteins (Occludin, Claudin-5and ZO-1) was reducedas the level of NaF in the brains increased. On the other hand，increasing BBB permeability enhancedthe level of VNA, and which reduced the titers of virus in the brains. In summary, MCP-1enhanced theBBB permeability, permitted VNA enter the CNS and cleared RABV from the CNS, then prevented thedevelopment of rabies. It is confirmed that it is needed for both VNA and enhanced BBB permeabilityin clearing virus from the CNS.
Previous studies showed that pathogenicity of rabies virus variants inversely correlates withglycoprotein expression levels. There is an obvious difference in G protein expression levels betweenB2C (low virulent) and DRV (highly virulent) virus strains. To investigate the correlation oftransmembrane anchor (TM) and cytoplasmic domain (CT) of G protein invovled in the glycoproteinexpression levels and pathogenicity of rabies virus, we construct B2C recombinant virus with chimericDRV G protein (TM and CT) using the B2C reverse genetics system. The chimeric viruses wererescued and designated as rB2C-(DRV-TM+CT), rB2C-(DRV-CT) and rB2C-(DRV-TM). It was foundthat no significant difference of virus growth kinetics between the chimeric viruses and parental virus.Further studies need to be conducted to address the virus glycoprotein expression and its correlationwith the viral pathogenicity.
In conclusion, intravenous administration of virus neutralizing antibodies can clear rabies virus fromthe CNS in both immunocompetent and immunocompromised mice as long as the blood-brain barrierpermeability is enhanced.
引文
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