Persistent and Severe Viral Replication in PBMCs with Moderate Immunosuppression Served an Alternative Novel Pathogenic Mechanism for Canine Morbillivirus.
Persistent and Severe Viral Replication in PBMCs with Moderate Immunosuppression Served an Alternative Novel Pathogenic Mechanism for Canine Morbillivirus.
复制标题
中度免疫抑制下的 PBMC 中持续且严重的病毒复制为犬麻疹病毒提供了另一种新的致病机制
DOI：
10.1128/spectrum.04060-22
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发表时间：
2023-02-14
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管广泛的疫苗运动，家犬，犬瘟热仍然是一个重要的传染病，在接种疫苗的食肉动物和野生物种。近年来，区域性流行的CDV分离株强调了对全球濒危物种的保护威胁和潜在的灾难性流行。摘要麻疹病毒和犬瘟热病毒（CDV）在其各自的宿主中引起以严重免疫抑制为特征的致死性感染。为了进一步了解该地区流行的CDV分离株的减毒机制，并为设计新的疫苗和治疗药物提供新的视角，采用基于CDV野生型HBF-1株的感染性cDNA克隆的反向遗传学的疫苗血凝素（H）基因置换的重组CDV rHBF-vacH。有趣的是，与先前发表的报道不同，疫苗H蛋白完全改变了致病性野生型CDV变异体为无毒的，rHBF-vacH仅通过减轻病毒免疫抑制程度而部分减毒，并且在长期患病的雪貂中仍导致66.7%的致死率。进一步的致病机制的比较证明，较弱的，但必要的侵入外周血单核细胞（PBMC）的rHBF-vacH，随后持续的病毒复制在PBMC和多个器官，共同贡献了其66.7%的死亡率。此外，尽管rHBF-vacH的滴度明显高于亲本病毒，但它不适合作为活疫苗的候选者，因为它对来自16种受试宿主物种的PBMC具有很大的侵袭和感染潜力。总之，持续和严重的病毒复制在PBMC中，中度免疫抑制首次被证明是一种替代的新的致病机制，这可能有助于我们了解可能的原因，CDV致死性感染家犬和高度敏感的野生物种在自然传播。重要性尽管广泛开展了家犬疫苗接种运动，但犬瘟热病毒仍然是接种疫苗的食肉动物和野生物种的重要传染病。近年来，区域性流行的CDV分离株强调了对全球濒危物种的保护威胁和潜在的灾难性流行。然而，对于如何应对CDV变异株不断区域性流行却知之甚少。在这项研究中，我们采用了重组CDV rHBF-vacH与疫苗H基因替换在CDV野生型HBF-1的背景下，以减弱流行性CDV变异设计一种新的疫苗候选。有趣的是，rHBF-vacH通过减轻病毒免疫抑制的程度仅部分减弱，并且通过较弱但必要的侵入PBMC以及随后在PBMC中持续和严重的病毒复制，仍然在雪貂中引起66.7%的致死率。体外rHBF-vacH病毒滴度显著升高可能表明rHBF-vacH在体内的快速细胞间传播间接导致雪貂中rHBF-vacH的致命感染。
Despite widespread vaccine campaigns for domestic dogs, CDV remained an important infectious disease in vaccinated carnivores and wild species. In recent years, the regionally ongoing epidemic CDV isolates have emphasized conservation threats to, and potentially disastrous epidemics in, endangered species worldwide. ABSTRACT Measles virus and canine distemper virus (CDV) cause lethal infections in their respective hosts characterized by severe immunosuppression. To furtherly acknowledge the attenuated mechanisms of the regionally ongoing epidemic CDV isolates and provide novel perspectives for designing new vaccines and therapeutic drugs, a recombinant CDV rHBF-vacH was employed with a vaccine hemagglutinin (H) gene replacement by reverse genetics based on an infectious cDNA clone for the CDV wild-type HBF-1 strain. Interestingly, unlike previously published reports that a vaccine H protein completely changed a pathogenic wild-type CDV variant to be avirulent, rHBF-vacH was only partially attenuated by alleviating the degree of viral immunosuppression, and still caused 66.7% lethality in ferrets with a prolonged period of disease. Further comparisons of pathogenic mechanisms proved that the weaker but necessary invasions into peripheral blood mononuclear cells (PBMCs) of rHBF-vacH, and subsequently persistent viral replications in PBMCs and multiple organs, together contributed to its 66.7% mortality. In addition, despite significantly higher titers than the parent viruses, rHBF-vacH would not be a suitable candidate for a live vaccine, with great invasion and infection potentials of PBMCs from 16 tested kinds of host species. Altogether, sustained and severe viral replication in PBMCs with moderate immunosuppression was first proven to be an alternative novel pathogenic mechanism for CDV, which might help us to understand possible reasons for CDV fatal infections among domestic dogs and the highly susceptible wild species during natural transmission. IMPORTANCE Despite widespread vaccine campaigns for domestic dogs, CDV remained an important infectious disease in vaccinated carnivores and wild species. In recent years, the regionally ongoing epidemic CDV isolates have emphasized conservation threats to, and potentially disastrous epidemics in, endangered species worldwide. However, little is known about how to deal with the CDV variants constantly regional epidemic. In this study, we employed a recombinant CDV rHBF-vacH with a vaccine H gene replacement in a CDV wild-type HBF-1 context to attenuate the epidemic CDV variant to design a new vaccine candidate. Interestingly, rHBF-vacH was only partially attenuated by alleviating the degree of viral immunosuppression, and still caused 66.7% lethality in ferrets by weaker but necessary invasions into PBMCs, and subsequently persistent and severe viral replications in PBMCs. Significantly higher virus titers of rHBF-vacH in vitro might indicate the rapid cell-to-cell spreads in vivo that indirectly contribute to fatal infections of rHBF-vacH in ferrets.
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影响因子：
5.4
作者：
Ludlow, M.;Nguyen, D. T.;Duprex, W. P.
通讯作者：
Duprex, W. P.
影响因子：
5.4
作者：
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影响因子：
11.8
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Gordon CH;Banyard AC;Hussein A;Laurenson MK;Malcolm JR;Marino J;Regassa F;Stewart AM;Fooks AR;Sillero-Zubiri C
通讯作者：
Sillero-Zubiri C
影响因子：
2.7
作者：
King, Andrew M. Q.;Lefkowitz, Elliot J.;Davison, Andrew J.
通讯作者：
Davison, Andrew J.
影响因子：
6.4
作者：
Seimon TA;Miquelle DG;Chang TY;Newton AL;Korotkova I;Ivanchuk G;Lyubchenko E;Tupikov A;Slabe E;McAloose D
通讯作者：
McAloose D