Department of Viroscience, Erasmus MC, Rotterdam, the Netherlands.
Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Virol. 2024 Mar 19;98(3):e0185023. doi: 10.1128/jvi.01850-23. Epub 2024 Feb 28.
Morbilliviruses are members of the family Paramyxoviridae and are known for their ability to cause systemic disease in a variety of mammalian hosts. The prototypic morbillivirus, measles virus (MeV), infects humans and still causes morbidity and mortality in unvaccinated children and young adults. Experimental infection studies in non-human primates have contributed to the understanding of measles pathogenesis. However, ethical restrictions call for the development of new animal models. Canine distemper virus (CDV) infects a wide range of animals, including ferrets, and its pathogenesis shares many features with measles. However, wild-type CDV infection is almost always lethal, while MeV infection is usually self-limiting. Here, we made five recombinant CDVs, predicted to be attenuated, and compared their pathogenesis to the non-attenuated recombinant CDV in a ferret model. Three viruses were insufficiently attenuated based on clinical signs, fatality, and systemic infection, while one virus was too attenuated. The last candidate virus caused a self-limiting infection associated with transient viremia and viral dissemination to all lymphoid tissues, was shed transiently from the upper respiratory tract, and did not result in acute neurological signs. Additionally, an in-depth phenotyping of the infected white blood cells showed lower infection percentages in all lymphocyte subsets when compared to the non-attenuated CDV. In conclusion, infection models using this candidate virus mimic measles and can be used to study pathogenesis-related questions and to test interventions for morbilliviruses in a natural host species.IMPORTANCEMorbilliviruses are transmitted via the respiratory route but cause systemic disease. The viruses use two cellular receptors to infect myeloid, lymphoid, and epithelial cells. Measles virus (MeV) remains an important cause of morbidity and mortality in humans, requiring animal models to study pathogenesis or intervention strategies. Experimental MeV infections in non-human primates are restricted by ethical and practical constraints, and animal morbillivirus infections in natural host species have been considered as alternatives. Inoculation of ferrets with wild-type canine distemper virus (CDV) has been used for this purpose, but in most cases, the virus overwhelms the immune system and causes highly lethal disease. Introduction of an additional transcription unit and an additional attenuating point mutation in the polymerase yielded a candidate virus that caused self-limiting disease with transient viremia and virus shedding. This rationally attenuated CDV strain can be used for experimental morbillivirus infections in ferrets that reflect measles in humans.
副黏液病毒属于副黏液病毒科，其特征是能够引起多种哺乳动物宿主的全身性疾病。麻疹病毒（Measles virus，MeV）是典型的副黏液病毒，感染人类，在未接种疫苗的儿童和年轻人中仍会导致发病和死亡。在非人类灵长类动物中的实验感染研究有助于了解麻疹的发病机制。然而，出于伦理限制，需要开发新的动物模型。犬瘟热病毒（Canine distemper virus，CDV）感染范围广泛，包括雪貂，其发病机制与麻疹有许多共同特征。然而，野生型 CDV 感染几乎总是致命的，而 MeV 感染通常是自限性的。在这里，我们构建了五个预测为减毒的重组 CDV，并在雪貂模型中比较了它们与非减毒重组 CDV 的发病机制。基于临床症状、死亡率和全身感染，三种病毒的减毒程度不足，而一种病毒的减毒程度过高。最后一种候选病毒引起的是自限性感染，伴有短暂的病毒血症和病毒向所有淋巴组织的传播，从呼吸道短暂排出，不会导致急性神经症状。此外，对受感染白细胞的深入表型分析表明，与非减毒 CDV 相比，所有淋巴细胞亚群的感染百分比都较低。总之，使用该候选病毒的感染模型模拟麻疹，可以用于研究发病机制相关问题，并在天然宿主物种中测试针对副黏液病毒的干预措施。
