Stochastic variation in the initial phase of bacterial infection predicts the probability of survival in D. melanogaster.
Stochastic variation in the initial phase of bacterial infection predicts the probability of survival in D. melanogaster.
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DOI：
10.7554/elife.28298
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发表时间：
2017-10-12
期刊：
影响因子：
7.7
通讯作者：
Buchon N
中科院分区：
文献类型：
--
作者：
Duneau D;Ferdy JB;Revah J;Kondolf H;Ortiz GA;Lazzaro BP;Buchon N
感染生物学的一个核心问题是理解为什么暴露于相同感染的两个人会产生不同的结果。我们开发了一个实验模型，在该模型中，基因相同的共养果蝇在受到相同的全身感染后会经历不同的结果，一些个体死于急性感染，而另一些个体则以无症状持续感染的形式控制病原体。我们发现死亡时细菌负荷的差异并不能解释感染的两种结果。个体间生存差异源于宿主内细菌生长的差异，这是由免疫反应决定的。我们开发了一个模型，可以捕获细菌生长动态并确定预测感染结果的关键因素：细菌增殖率和宿主建立有效免疫控制所需的时间。我们的结果为研究控制感染进展并最终导致生或死的个体宿主病原体参数提供了一个框架。病人对感染的反应并不都相同。一个人可能会出现轻微症状并很容易康复，而另一个人可能会遭受毁灭性的疾病甚至死亡。通常认为许多因素可以解释这些差异，包括个体的性别、年龄和基因，以及个体所接触的环境的差异。然而，个体免疫系统与感染相互作用的随机变化也可能在康复中发挥重要作用。杜诺等人。现在研究了在相同环境中饲养的基因相同的果蝇如何应对不同的细菌感染。这使他们能够开发出一个数学模型来描述细菌感染如何在个体中发展。在初始阶段，细菌自由增殖。如果免疫防御及时激活以控制感染，果蝇中的细菌数量就会减少到恒定水平，感染就会进入长期或慢性阶段。这种情况发生得越早，苍蝇存活下来的可能性就越大。如果免疫控制发生得太晚，感染就会进入末期，一旦细菌数量增加到一定水平，苍蝇就会死亡。因此，该模型揭示了免疫系统控制细菌种群的精确时间（称为“控制时间”）决定了感染的结果。杜诺等人。通过将细菌注射到相同的果蝇中证实了这一点。控制时间的微小变化有时就决定了苍蝇的生与死。了解控制这种明显随机变化的因素是了解感染和开发针对多种疾病的更有效治疗方法的关键——不仅是由细菌引起的疾病，还包括由病毒和寄生虫引起的疾病，如艾滋病毒和疟疾。
A central problem in infection biology is understanding why two individuals exposed to identical infections have different outcomes. We have developed an experimental model where genetically identical, co-housed Drosophila given identical systemic infections experience different outcomes, with some individuals succumbing to acute infection while others control the pathogen as an asymptomatic persistent infection. We found that differences in bacterial burden at the time of death did not explain the two outcomes of infection. Inter-individual variation in survival stems from variation in within-host bacterial growth, which is determined by the immune response. We developed a model that captures bacterial growth dynamics and identifies key factors that predict the infection outcome: the rate of bacterial proliferation and the time required for the host to establish an effective immunological control. Our results provide a framework for studying the individual host-pathogen parameters governing the progression of infection and lead ultimately to life or death. Sick individuals do not all respond to an infection in the same way. One individual may experience mild symptoms and recover easily, while another may suffer devastating illness or even death. A number of factors are often assumed to account for these differences, including the sex, age and genes of the individuals, and differences in the environments the individuals have been exposed to. However, random variations in how an individual’s immune system interacts with the infection could also play an important role in recovery. Duneau et al. have now studied how genetically identical fruit flies who were raised in the same environment respond to different bacterial infections. This enabled them to develop a mathematical model that describes how a bacterial infection develops in an individual. In an initial phase, the bacteria proliferate freely. If the immune defenses activate in time to control the infection, the number of bacteria in the fly decreases to a constant level and the infection enters a long-term, or chronic, phase. The sooner this happens the more likely it is that the fly will survive. If the immune control happens too late, the infection enters a terminal phase and the fly will die once the number of bacteria increases to a certain level. The model therefore reveals that the precise time at which the immune system takes control of the bacterial population – termed the “Time to Control” – determines the outcome of the infection. Duneau et al. confirmed this by injecting bacteria into identical flies. A small variation in the Time to Control was sometimes the difference between a fly living or dying. Understanding what controls this apparently random variation is key to understanding infection and potentially developing more efficient treatments for a wide range of diseases – not just those caused by bacteria, but also those caused by viruses and parasites, like HIV and malaria.