Heterogeneous disease progression and treatment response in a C3HeB/FeJ mouse model of tuberculosis.
Heterogeneous disease progression and treatment response in a C3HeB/FeJ mouse model of tuberculosis.
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DOI：
10.1242/dmm.019513
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发表时间：
2015-06
影响因子：
4.3
通讯作者：
Nuermberger EL
中科院分区：
文献类型：
--
作者：
Lanoix JP;Lenaerts AJ;Nuermberger EL
小鼠是非临床评价抗结核药物疗效最常用的物种。与常用的菌株不同，C3HeB/FEJ小鼠在肺中出现干酪样坏死，这可能会以一种更像人类结核病的方式改变药物疗效的表现。由于这种病理的发展需要时间，我们研究了感染潜伏期对C3HeB/FEJ和BALB/c小鼠体内六种药物活性的影响。小鼠气雾化感染6、10或14 后，分别给予利福平、利福喷丁、吡嗪酰胺、利奈唑胺、舒替唑胺或甲硝唑治疗4~8 周。结果包括病理评估、液化干酪的pH值测量和肺培养的集落形成单位(CFU)计数的评估。在C3HeB/FEJ小鼠中观察到疾病进展的时间和程度的显著异质性，在很大程度上与潜伏期无关。同样，C3HeB/FEJ小鼠的药物疗效不受潜伏期的影响。然而，对于PZA、LZD和PNU，观察到与有或没有大的干酪性病变相关的二分治疗效果。在PZA的情况下，其在C3HeB/FEJ小鼠大干酪皮损亚群中的活性较低，可能是由于液化干酪中测得的pH值为7.36±0.09。这项研究突出了C3HeB/FEJ小鼠在非临床疗效测试方面的潜在价值，特别是在研究病变病理和药物效应的相互作用方面。谨慎使用这一模式可以加强非临床结果与临床结果之间的联系。摘要：C3HeB/FEJ小鼠发展出广泛的病变类型，这些病变类型以一种可能更好地指导结核病药物开发的方式改变药物反应。
Mice are the most commonly used species for non-clinical evaluations of drug efficacy against tuberculosis (TB). Unlike commonly used strains, C3HeB/FeJ mice develop caseous necrosis in the lung, which might alter the representation of drug efficacy in a way that is more like human TB. Because the development of such pathology requires time, we investigated the effect of infection incubation period on the activity of six drugs in C3HeB/FeJ and BALB/c mice. Mice were aerosol infected and held for 6, 10 or 14 weeks before receiving therapy with rifampin (RIF), rifapentine (RPT), pyrazinamide (PZA), linezolid (LZD), sutezolid (PNU) or metronidazole (MTZ) for 4-8 weeks. Outcomes included pathological assessments, pH measurements of liquefied caseum and assessment of colony-forming unit (CFU) counts from lung cultures. Remarkable heterogeneity in the timing and extent of disease progression was observed in C3HeB/FeJ mice, largely independent of incubation period. Likewise, drug efficacy in C3HeB/FeJ mice was not affected by incubation period. However, for PZA, LZD and PNU, dichotomous treatment effects correlating with the presence or absence of large caseous lesions were observed. In the case of PZA, its poor activity in the subset of C3HeB/FeJ mice with large caseous lesions might be explained by the pH of 7.36±0.09 measured in liquefied caseum. This study highlights the potential value of C3HeB/FeJ mice for non-clinical efficacy testing, especially for investigating the interaction of lesion pathology and drug effect. Careful use of this model could enhance the bridging of non-clinical results with clinical outcomes. Summary: C3HeB/FeJ mice develop a wide range of lesion types that alter drug response in a way that might better inform tuberculosis drug development.
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影响因子：
3.7
作者：
Wallis RS;Dawson R;Friedrich SO;Venter A;Paige D;Zhu T;Silvia A;Gobey J;Ellery C;Zhang Y;Eisenach K;Miller P;Diacon AH
通讯作者：
Diacon AH
影响因子：
3.1
作者：
Burian, A.;Erdogan, Z.;Zeitlinger, M.
通讯作者：
Zeitlinger, M.
DOI：
10.1164/rccm.200806-892oc
发表时间：
2008-12-01
影响因子：
24.7
作者：
Dietze, Reynaldo;Hadad, David Jamil;Johnson, John L.
通讯作者：
Johnson, John L.
影响因子：
6.4
作者：
Harper, Jamie;Skerry, Ciaran;Jain, Sanjay K.
通讯作者：
Jain, Sanjay K.
影响因子：
4.9
作者：
MOR, N;SIMON, B;HEIFETS, L
通讯作者：
HEIFETS, L