Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies.
Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies.
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人类结核病病理的小鼠模型：在坏死分析和宿主定向疗法的发展中的作用。
DOI：
10.1007/s00281-015-0538-9
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发表时间：
2016-03
影响因子：
9
通讯作者：
Beamer G
中科院分区：
文献类型：
--
作者：
Kramnik I;Beamer G
结核发病机制维持结核分枝杆菌在人群中的一个关键方面是在肺病变中引起坏死的能力。由于共同进化塑造了结核分枝杆菌和人类的反应，因此任何动物模型都无法完全再现完整的结核病概况和病变表现。然而，动物模型对于理解强毒性结核分枝杆菌感染如何产生病原体传播和进化成功所必需的结果至关重要。在人类中，根据临床和流行病学数据，已认识到结核病的广泛结局。在小鼠中，易感性有明确的遗传基础。尽管人类结核病和小鼠结核病的光谱并不完全重叠，但将人类结核病与小鼠病变在不同遗传菌株中的比较牢固地建立了趋同点。通过接受小鼠种群的遗传异质性，我们在寻找合适的体内模型方面获得了巨大的优势。下面，我们回顾了遗传定义的小鼠模型，这些模型概括了结核分枝杆菌发病的关键因素-诱导肺部坏死结核病变-并讨论了这些模型如何反映人类结核的分层和发病机制。该方法确保小鼠模型在基础和转化结核研究中发挥的作用将继续增加，使研究人员能够利用这一定义明确、可重复且具有成本效益的系统解决结核病发病机制和体内细菌生理学的基本问题。将新一代小鼠模型与先进的成像技术相结合，还可以在大型动物试验和临床试验之前对实验性疫苗和疗法进行快速和廉价的评估。
A key aspect of TB pathogenesis that maintains Mycobacterium tuberculosis in the human population is the ability to cause necrosis in pulmonary lesions. As co-evolution shaped M. tuberculosis (M.tb) and human responses, the complete TB disease profile and lesion manifestation are not fully reproduced by any animal model. However, animal models are absolutely critical to understand how infection with virulent M.tb generates outcomes necessary for the pathogen transmission and evolutionary success. In humans, a wide spectrum of TB outcomes has been recognized based on clinical and epidemiological data. In mice, there is clear genetic basis for susceptibility. Although the spectra of human and mouse TB do not completely overlap, comparison of human TB with mouse lesions across genetically diverse strains firmly establishes points of convergence. By embracing the genetic heterogeneity of the mouse population, we gain tremendous advantage in the quest for suitable in vivo models. Below, we review genetically defined mouse models that recapitulate a key element of M.tb pathogenesis—induction of necrotic TB lesions in the lungs—and discuss how these models may reflect TB stratification and pathogenesis in humans. The approach ensures that roles that mouse models play in basic and translational TB research will continue to increase allowing researchers to address fundamental questions of TB pathogenesis and bacterial physiology in vivo using this well-defined, reproducible, and cost-efficient system. Combination of the new generation mouse models with advanced imaging technologies will also allow rapid and inexpensive assessment of experimental vaccines and therapies prior to testing in larger animals and clinical trials.