Soil survival and re-emergence: the continued threat of plague

鼠疫耶尔森氏菌是引起鼠疫的细菌，可能是人类已知的最具破坏性的传染病，可能比历史上(例如在黑死病期间)导致更多的人死亡。它的成功归功于这样一个事实，即它具有极强的传染性，如果不进行治疗，通常会在1-2天内死于腺鼠疫、肺炎鼠疫或败血症鼠疫。啮齿动物、跳蚤和人与人之间的肺炎传播通常被认为是其迅速传播的基础，尽管很优雅，但有几个事实与这个过于简化的模型不一致。例如，很明显，鼠疫可以从疫区消失，但在最初的疫情停止后几个月或经常几十年才会卷土重来。在这些从宿主和媒介种群中消失的时期，鼠疫居住在哪里，以及是什么导致它重新出现，还没有详细研究。一些鼠疫杆菌菌株现在已经获得了对多种抗生素的耐药性，这些菌株的传播激增将对人类健康构成严重威胁，因此我们需要了解可能导致重大复发事件发生的条件。鼠疫杆菌是从一个几乎相同的、自由生活的土壤传播的假结核耶尔森菌进化而来的，因此土壤被认为是鼠疫杆菌的宿主，但它是如何在这种环境中生存并从这种环境传播的还没有得到充分的研究。在鼠疫杆菌生命周期的这一土壤阶段，可以通过嵌入自我衍生的保护性“粘液层”(生物膜)来保护鼠疫杆菌，使细菌细胞能够与土壤中的其他细菌、阿米巴或线虫形成保护性的结合。在这项研究中，我们把重点放在土壤作为重要的环境水库，鼠疫杆菌在土壤中采取坐等的生存方式，在条件允许的情况下，它可以重新进入啮齿动物/人类种群。我们的目标是确定支持鼠疫在土壤中存活并从土壤中重新出现的环境和生物触发因素。要做到这一点，我们需要广泛地观察土壤环境，包括小气候、土壤类型和土地覆盖等因素，并测试线虫和阿米巴对鼠疫生存的影响。我们的工作将填补我们对鼠疫生态学认识上的重大和潜在危险的差距，特别是考虑到世界卫生组织最近将鼠疫列为一种重新出现的人畜共患病病原体。以马达加斯加为案例研究，由于其有良好的鼠疫暴发历史记录，我们将使用广泛的科学方法来解决这一认识差距。我们将使用基于计算机的建模技术，使我们能够预测鼠疫如何在长时间保持沉默，然后重新出现为新的疾病爆发。模型输入将通过测量马达加斯加的啮齿动物洞穴温度、湿度和当地气候条件，以及气候、土地覆盖和土壤类型数据集来获得。这些模型还将使用我们将在受控实验室条件下获得的鼠疫杆菌土壤生存实验数据。我们还将使用基因测序技术来调查与鼠疫杆菌共生的土壤细菌种群，并揭示导致土壤生存的鼠疫杆菌基因。我们的数据将有助于监测战略的实施，并通过推断在世界其他鼠疫流行地区预测鼠疫爆发的环境标志的确定，以及提供关于鼠疫持续时间、传播以及在疫情死灰复燃之前或之后的潜在控制措施的信息。

Yersinia pestis (Y. pestis) the bacterium responsible for plague, is probably the most devastating infectious diseases known to humanity and may be responsible for more human deaths than any other micro-organism in history (e.g. during the Black Death). Its 'success' is attributed to the fact that it is extremely contagious, and when untreated, death normally occurs in 1-2 days from bubonic, pneumonic or septicaemic plague. Rodents, fleas and person to person pneumonic transmission are generally considered as fundamental to its rapid spread and although elegant, several facts are inconsistent with this hugely oversimplified model. For example, it is clear that plague can vanish from an epidemic area, only to undergo a resurgence, months or often decades after the original outbreak ceased. Where plague resides during these periods of absence from host and vector populations, and what causes it to re-emerge, has not been studied in detail. Some Y. pestis strains have now acquired multi-antibiotic resistance and an upsurge in transmission of these strains would pose a severe risk to human health, so we need to understand the conditions that might cause a significant re-emergence event to occur.Y. pestis evolved from a near identical, free-living soil-borne ancestor, Yersinia pseudotuberculosis, and soil is therefore thought to be a reservoir for Y. pestis, but how it survives in, and then spreads from this environment has not been adequately investigated. Y. pestis may be protected during this soil stage of its life cycle by embedding in a self-derived protective 'slime' layer (biofilm) enabling the bacterial cells to form a protected association with other bacteria, amoebae or nematodes in the soil. In this study we focus on soil as the important environmental reservoir in which Y. pestis adopts a 'sit and wait' survival lifestyle from where it can re-enter the rodent/human population when conditions are favorable. We aim to identify the environmental and biological triggers that underpin plague survival in, and re-emergence from, soil. To do this we need to take a wide view of the soil environment including factors such as microclimate, soil type, and land cover in association with testing the impact of nematode worms and amoebae on plague survival. Our work will plug a significant and potentially dangerous gap in our understanding of plague ecology, especially important given that the World Health Organization has recently classified Y. pestis as a re-emerging zoonotic pathogen.Using Madagascar as our case study, due to its well recorded plague outbreak history, we will address this knowledge gap using a wide range of scientific approaches. We will use computer based modeling techniques to enable us to predict how plague remains silent for long periods before re-emerging as a new disease outbreak. The model inputs will be obtained by measuring rodent burrow temperatures, humidity and local climate conditions in Madagascar, in conjunction with climate, land cover and soil-type datasets. The models will also use data from Y. pestis soil survival experiments which we will obtain under controlled laboratory conditions. We will also use genetic sequencing techniques to investigate the bacterial soil populations that co-habit with Y. pestis as well as uncovering the genes in Y. pestis that are responsible for soil survival.Our data will aid the implementation of surveillance strategies, and identification of the environmental signposts that can predict plague outbreaks, both in Madagascar, and by inference in other plague endemic parts of the world, as well as providing information about plague persistence, spread and therefore potential control measures either before or following a resurgent outbreak.