Bacterial pathogenesis: dissecting the early stages of cellular invasion by the obligate intracellular bacterium Orientia tsutsugamushi

在东南亚许多农村地区，恙虫病是因高热住院的主要原因之一。当病人被一种叫做螨虫的小型咬人节肢动物咬伤时，就会引起这种疾病，这种节肢动物会传播一种叫做恙虫病东方体的危险细菌。感染这种细菌会引起一系列症状，包括高烧、皮疹和肌肉疼痛。如果感染没有得到迅速和正确的治疗，它可能导致多器官衰竭和死亡。据估计，每年有10亿人面临风险，有100万人感染这种疾病。由于症状与许多其他热带传染病（如登革热和其他细菌或病毒感染）相似，患者经常被误诊，因此没有得到适当治疗。这对个别患者有严重并发症的风险，而且由于滥用抗生素治疗，也导致抗生素耐药性问题日益严重。鉴于这种疾病的高发病率和严重程度，我们详细研究导致这种疾病的细菌非常重要，因为这将有助于我们在未来开发更好的诊断、疫苗和治疗方法。为了充分了解一种传染病，从而改善对病人的护理，有必要了解引起这种疾病的有机体的基本生物学。尤其重要的是，要确切地了解这种有机体是如何在人体内生长的，以及它为什么会让这些人生病。人类体内每时每刻都生长着大约100万亿个细菌，其中绝大多数不会造成不良影响，实际上是有益的。对“致病性”的研究探讨了少数细菌如何以及为什么会引起人类疾病。以引起恙虫病的细菌恙虫病为例，其致病性的第一步是进入人体细胞内部。大多数细菌既可以在人体细胞内存活，也可以在环境中自由存活，但恙虫病虫体不能。恙虫病体只有在物理上位于另一个细胞中时才能存活和复制。因此，我们越了解这种细菌是如何进入人体细胞的，然后避免被它们杀死的，我们就越能探索阻止这一重要过程的方法，从而消除病人体内的细菌。在这项研究中，我们将探索恙虫病虫进入人体细胞的详细机制以及它在进入后的最初24小时内的行为。人类细胞已经发展出复杂的策略来消灭进入细胞内部的大多数细菌，但恙虫病虫已经学会了如何避免这些细菌。我们想知道它是如何做到的。我们将使用高通量筛选方法来研究这些发病机制的早期事件。这意味着我们将系统地观察人类基因组中的所有基因，试图找到细菌劫持的基因，以便进入细胞并在那里生存。一旦我们确定了这些重要的人类基因，我们将进行更多的实验，以了解细菌如何利用它们进入人体细胞并在人体细胞内生存的具体细节。这项研究的结果将是更详细地了解恙虫病o是如何进入人类细胞的，以及它是如何避免被人类细胞杀死的。这将有助于我们在未来制定新的策略来阻止这些过程。

Scrub typhus is one of the leading causes of hospitalisation from high fever in many rural parts of Southeast Asia. The disease is caused when a patient is bitten by a small biting arthropod called a mite, which transmits a dangerous bacterium called Orientia tsutsugamushi. Infection with this bacterium causes a range of symptoms that include high fever, rash and muscle pain. If the infection is not treated quickly and correctly it can result in multiple organ failure and death. It is estimated that 1 billion people are at risk and 1 million people are infected with this disease every year. Because the symptoms are similar to many other tropical infectious diseases - such as dengue fever and other bacterial or viral infections - patients are often misdiagnosed and therefore not treated properly. This risks severe complications for the individual patient and it also contributes to the growing problem of antibiotic resistance due to misuse of antibiotic treatments. Given the high incidence and severity of this disease, it is very important that we study the bacteria that causes it in detail as this will help us to develop better diagnostics, vaccines, and treatments in the future.In order to understand fully an infectious disease, and therefore improve patient care, it is necessary to understand the basic biology of the organism that causes the disease. In particular, it is important to understand exactly how that organism grows inside humans, and why it makes those humans sick. Humans have around 100 trillion bacteria growing on and inside them all the time, and the vast majority of them cause no ill effects and are actually beneficial. The study of 'pathogenicity' explores how and why a small minority of bacteria cause disease in humans. In the case of O. tsutsugamushi, the bacteria that causes scrub typhus, the first step in its pathogenicity is its entry to the inside of human cells. Most bacteria can survive either inside human cells or free in the environment: O. tsutsugamushi cannot. O. tsutsugamushi can only survive and replicate when it is physically located inside another cell. Therefore the more we can understand about how this bacteria gains initial access into human cells, and then avoids being killed by them, the more we can explore ways to block this essential process and therefore eliminate the bacteria from the patient.In this study we will explore the detailed mechanisms by which O. tsutsugamushi gets into humans cells and what it does in the first 24 hours after entry. Human cells have developed sophisticated strategies to eliminate most bacteria that get inside them, but O. tsutsugamushi has learned how to avoid these. We want to understand exactly how it does this. We will use a high-throughput screening approach to study these early events of pathogenesis. This means that we will systematically look at all the genes in the human genome to try and find the ones that the bacteria hijacks in order to get into the cells and survive there. Once we have identified these important human genes we will do more experiments to understand the details of exactly how the bacteria uses them in order to gain entry and then survive within the human cells. The outcome of this study will be a more detailed understanding of exactly how the bacterium O. tsutsugamushi gets into human cells, and how it avoids being killed by them. This will help us develop new strategies to block these processes in the future.