Models to understand the population-level impact of mixed strain M. tuberculosis infections.
Models to understand the population-level impact of mixed strain M. tuberculosis infections.
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DOI：
10.1016/j.jtbi.2011.04.011
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发表时间：
2011-07-07
影响因子：
2
通讯作者：
Cohen, Ted
中科院分区：
文献类型：
--
作者：
Sergeev, Rinat;Colijn, Caroline;Cohen, Ted
在过去的十年中，许多研究已经确定了结核病患者中有一种以上的不同菌株的M。肺结核存在。虽然已经表明，这些混合菌株感染可以降低同时携带药物敏感和耐药菌株的个体的治疗成功概率，但尚不清楚这种现象是否以及如何影响社区内结核病的长期动态。菌株特异性的免疫原性差异和与耐药性的关联表明，更好地了解菌株如何在宿主内竞争，对于预测混合菌株感染对未来药物敏感和耐药结核病负担的影响是必要的。在本文中，我们开发了一个建模框架，使我们能够调查宿主内的应变竞争机制，并评估这种竞争对种群中应变生态的长期影响。这些模型使我们能够系统地评估未知参数的重要性，并为未来的实验研究提出优先领域。尽管目前缺乏数据来告知几个模型参数的值，但我们能够从这项工作中得出重要的定性结论。我们发现混合菌株感染可能通过两种方式促进药物敏感菌株和耐药菌株的共存。首先，混合菌株感染允许具有较低基本繁殖数的菌株在种群中持续存在，否则如果在共感染宿主中具有竞争优势，则会被竞争击败。其次，一些从药物敏感和耐药混合感染状态发展为表型药物敏感结核病的个体可能保留了小的耐药细菌亚群，一旦宿主用抗生素治疗，这些细菌可以繁殖。我们认为，这些类型的混合感染，通过增加低适应性耐药菌株的持续存在的能力，可能为补偿突变积累和相对适合的，高耐药的M菌株提供机会。肺结核出现。
Over the past decade, numerous studies have identified tuberculosis patients in whom more than one distinct strain of M. tuberculosis is present. While it has been shown that these mixed strain infections can reduce the probability of treatment success for individuals simultaneously harboring both drug-sensitive and drug-resistant strains, it is not yet known if and how this phenomenon impacts the long-term dynamics for tuberculosis within communities. Strain-specific differences in immunogenicity and associations with drug resistance suggest that a better understanding of how strains compete within hosts will be necessary to project the effects of mixed strain infections on the future burden of drug-sensitive and drug-resistant tuberculosis. In this paper, we develop a modeling framework that allows us to investigate mechanisms of strain competition within hosts and to assess the long-term effects of such competition on the ecology of strains in a population. These models permit us to systematically evaluate the importance of unknown parameters and to suggest priority areas for future experimental research. Despite the current scarcity of data to inform the values of several model parameters, we are able to draw important qualitative conclusions from this work. We find that mixed strain infections may promote the coexistence of drug-sensitive and drug-resistant strains in two ways. First, mixed strain infections allow a strain with a lower basic reproductive number to persist in a population where it would otherwise be outcompeted if has competitive advantages within a co-infected host. Second, some individuals progressing to phenotypically drug-sensitive tuberculosis from a state of mixed drug-sensitive and drug-resistant infection may retain small subpopulations of drug-resistant bacteria that can flourish once the host is treated with antibiotics. We propose that these types of mixed infections, by increasing the ability of low fitness drug-resistant strains to persist, may provide opportunities for compensatory mutations to accumulate and for relatively fit, highly drug-resistant strains of M. tuberculosis to emerge.
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DOI：
10.1073/pnas.140102797
发表时间：
2000-07-05
影响因子：
11.1
作者：
Dye, C;Williams, BG
通讯作者：
Williams, BG
影响因子：
3.8
作者：
Lipsitch, Marc;Colijn, Caroline;Cohen, Ted;Hanage, William P.;Fraser, Christophe
通讯作者：
Fraser, Christophe
影响因子：
24.3
作者：
Dobler, C. C.;Crawford, A. B. H.;Marks, G. B.
通讯作者：
Marks, G. B.
影响因子：
3.5
作者：
Colijn, Caroline;Cohen, Ted;Murray, Megan
通讯作者：
Murray, Megan
影响因子：
56.9
作者：
Björkman, J;Nagaev, I;Andersson, DI
通讯作者：
Andersson, DI