Functional and Molecular Analysis of Scout Cell Awakening

描述(申请人提供)：对于许多细菌，休眠和活动之间的生命周期，我们最近提出了一个新的模型，在这些状态之间的转换。我们认为，休眠的退出不是对环境线索的反应，不是微生物孢子、植物休眠种子、冬眠动物等的特征，而是一个低频率、表观遗传、噪声驱动的随机过程。觉醒后，被称为“童子军”的细胞会探索环境条件是否适合生长。侦察策略保证了即使是最小的种群在环境挑战的条件下也能继续生存，并成为人体内致病种群的一个特别重要的特征。我们提出了强有力的证据，表明至少有一些非芽胞形成物种，如污垢分枝杆菌，以及一系列环境分离株的行为确实符合童子军模型。我们表明，被测试物种的细胞可以保持休眠数周和数月，在截然不同的时间点从休眠中醒来，并在建立一个小的增殖群体后，产生促进生长的化合物，使其休眠的亲属复活。在这个项目中，我们将研究觉醒过程的动力学，并阐明生长诱导因子的化学性质(S)。所获得的知识将在未来用于研究结核分枝杆菌等生长缓慢的病原体的生物学。这可能最终导致更好的疾病控制工具，尤其与潜伏感染有关。

DESCRIPTION (provided by applicant): For many bacteria, life cycles between dormancy and activity, and we have recently advanced a new model for the switch between these states. We proposed that dormancy exit is not a response to environmental cues, a characteristic of microbial spores, resting seeds of plants, hibernating animals, among others, but a low frequency, epigenetic, noise-driven, and stochastic process. After awakening, the cells termed "scouts" explore whether or not the environmental conditions are appropriate for growth. The scout strategy guarantees the continued existence of even the smallest population under conditions of environmental challenge, and becomes a particularly important characteristic of pathogenic populations in human body. We present strong evidence that at least some non-spore forming species, such as Mycobacterium smegmatis, and a range of environmental isolates do behave in accordance with the scout model. We show that cells of tested species can remain dormant for weeks and months, wake up from dormancy at dramatically different time points, and after establishing a small proliferating population, produce growth inducing compounds that revive their dormant kin. In this project, we will examine the kinetics of the awakening process and elucidate the chemical nature of the growth inducing factor(s). The gained knowledge will be used in the future to study the biology of slow growing pathogens such as Mycobacterium tuberculosis. This may ultimately lead to better tools for disease control, and is especially relevant to latent infections.