Bacterial pathogenesis: dissecting the early stages of cellular invasion by the obligate intracellular bacterium Orientia tsutsugamushi 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. The Newton Fund builds research and innovation partnerships with developing countries across the world to promote the economic development and social welfare of the partner countries.