Jahrling Peter B, Fritz Elizabeth A, Hensley Lisa E
National Institute of Allergy and Infectious Diseases, National Institutes of Health, 6700-B Rockledge Drive, Bethesda, MD 20892-7609, USA.
Curr Mol Med. 2005 Dec;5(8):817-26. doi: 10.2174/156652405774962326.
Variola, the agent of smallpox, is a bioterrorist threat, as is monkeypox virus, which also occurs naturally in Africa. Development of countermeasures, in the form of improved vaccines, antiviral drugs, and other therapeutic strategies are a high priority. Recent advances in molecular biology and in animal model development have provided fresh insight into the virulence determinants for smallpox and the pathophysiology of disease. The complex replication cycle for orthopoxviruses, and the pivotal role for viral-specific immunomodulatory proteins which contribute to escape from immunologic surveillance, provide many unique targets for therapeutic intervention. The "toxemia" of smallpox has been elucidated in part by variola-infected primate studies which revealed the central role of apoptosis and the evolution of a cytokine storm leading to hemorrhagic diathesis, resembling fulminent "black" smallpox. This suggests a potential role for therapeutic strategies developed for septic shock, in treatment of smallpox. Drugs licensed for other viruses which share molecular targets with orthopoxviruses (e.g. Cidofovir) or cancer drugs (e.g. Gleevec and other tyrosine kinase inhibitors) have immediate application for treatment of smallpox and monkeypox and provide leads for second generation drugs with higher therapeutic indices. Recent advances in identification of virulence determinants and immune evasion genes facilitate the design of alternative vaccines to replace live vaccinia strains that are unsuitable for a large proportion of individuals in a mass immunization campaign.
天花病毒是天花的病原体，是一种生物恐怖主义威胁，猴痘病毒也是如此，它在非洲也有自然发生。以改进疫苗、抗病毒药物和其他治疗策略的形式开发应对措施是当务之急。分子生物学和动物模型开发的最新进展为天花的毒力决定因素和疾病的病理生理学提供了新的见解。正痘病毒复杂的复制周期，以及病毒特异性免疫调节蛋白在逃避免疫监视中所起的关键作用，为治疗干预提供了许多独特的靶点。天花的“毒血症”部分已通过感染天花病毒的灵长类动物研究得以阐明，这些研究揭示了细胞凋亡的核心作用以及导致出血素质的细胞因子风暴的演变，类似于暴发性“黑”天花。这表明为感染性休克开发的治疗策略在天花治疗中可能发挥作用。已获许可用于与正痘病毒有共同分子靶点的其他病毒的药物（如西多福韦）或癌症药物（如格列卫和其他酪氨酸激酶抑制剂）可立即用于治疗天花和猴痘，并为具有更高治疗指数的第二代药物提供了线索。毒力决定因素和免疫逃逸基因鉴定的最新进展有助于设计替代疫苗，以取代在大规模免疫接种运动中不适用于很大一部分人群的活牛痘菌株。
