Antimicrobial drugs, such as antibiotics, antivirals and antifungals, revolutionised medicine. They are essential for fighting diseases, and make surgery and cancer therapies safer. Unfortunately, many of the microbes which these drugs fight are becoming 'resistant' and the antimicrobial drugs no longer work. Worldwide, more than 700,000 people each year die due to antimicrobial drug-resistant disease. Antimicrobial resistance (AMR) is increasing rapidly; the United Nations predicts that number of deaths due to antimicrobial drug-resistant disease may climb to as many as 10 million deaths per year by 2050 if no action is taken. Our work focuses on AMR in Shigella bacteria. Shigella are the main cause of severe diarrhoea among children in low-and middle-income countries and also cause sexually transmissible illness in men who have sex with men. Over 200 million people become ill from Shigella each year and over 200,000 people die. There is no widely available vaccine against Shigella and, like many other bacteria, they are becoming resistant to antimicrobials. The World Health Organisation list Shigella as one of twelve priority organisms for antimicrobial resistance (AMR). When bacteria reproduce, they typically divide into two daughter cells. The process by which AMR genes are passed from parent to daughter cells is well understood and monitored. However, many bacterial species are also able to transfer genes for AMR between different cells using mobile genetic elements (MGEs). This is called 'transmissible AMR' and - as the name suggests - involves direct transfer of genes between two bacteria. Our pilot work shows that about half of the AMR in Shigella is transmissible. We don't fully understand how MGEs move about in bacterial populations, but it is clear that some AMR-MGEs stay in bacteria which go on to cause lots of infections, while others don't. Understanding how AMR MGEs spread amongst bacterial populations, and which MGEs will be successful is challenging; we need to consider the AMR gene, the MGE, the bacteria, and the human hosts. Shigella is an excellent model to study transmissible AMR because Shigella infections are already tracked by national public health surveillance teams, and because it only causes infections in humans (so we don't need to consider the effects of different hosts). This means that we can use routine surveillance data to understand how the bacteria and the human hosts interact. This project will, for the first time, create a global overview of the most important Shigella bacteria in their human hosts. It will characterise all the MGEs carrying medically important AMR to understand which ones are causing the most infections and how the MGEs are moving through the bacterial populations. We will then study which types, and what features, of MGEs are the most important factors for driving this transmissible AMR in the real-world. This will enable us to understand the biology of AMR-MGEs and identify features that might act as 'early warning signs' for the emergence of new AMR bacteria. We want our research to make health systems better by identifying newly emerging AMR and understanding which groups of people are at most risk from Shigella AMR. In the future this will enable these people to be given specialised healthcare, such as screening and tailored antimicrobial recommendations. We have built a team that includes academic researchers specialising in AMR and public health specialists who are responsible for disease surveillance across four countries. This will ensure that our new findings and new approaches are useful for public health practitioners and that they will be adopted for use in real-world settings in the near term. Although this project focuses on Shigella, our new methods will be designed to make them easy to use for other bacterial species in the future.

Scrub typhus is a bacterial infection causing febrile illness in many tropical and subtropical countries in East, South East and South Asia. Countries where scrub typhus occurs include India, China, Bangladesh, Pakistan, Indonesia, Vietnam, Thailand, Japan and Australia. The bacterium (Orienta tsutsugamushi) is transmitted by the larvae of mites during blood-feeding. Scrub typhus can lead to severe complications including lung failure, kidney failure and brain infection. Scrub typhus appears to be very common in affected regions, accounting for up to a third of all fever cases in some settings. Nevertheless, little is known with respect to the transmission of scrub typhus. Scrub typhus is one of the most neglected tropical infections in terms of research, clinical management and prevention. We do not know how many cases develop fever after infection and how many cases with fever develop complications. We further do not know how scrub typhus infection is transmitted in the community and what role rodents play in attracting mite larvae. This study is the first large scale cohort study specifically designed to gain a fundamental understanding of scrub typhus epidemiology in a region that is highly affected by the disease. While the main emphasis of this study is on scrub typhus as the most important infection, we will study two less common infections caused by very similar bacteria called Rickettsia: flea-borne murine typhus and tick-borne spotted fever. The study will be conducted in South India (Tamil Nadu) and follows up 40,000 people living in affected villages. Participants will be followed up at 2 monthly intervals to ask for the occurrence of fever in the past 2 months. We will take blood samples of all identified fever cases and test for the three infections (scrub typhus, murine typhus and spotted fever). They will be asked to proactively come to study clinics in the case of any fever or subfebrile temperature. In these ongoing fever cases we will do additional blood tests including polymerase chain reaction to understand the genetic variety of Orienta tsutsugamushi. Participants will be asked questionnaires regarding living conditions, socio-economic data and occupational factors. We will use satellite images and GPS data to study the geographical risk factors for scrub typhus and Rickettsia infections. We will catch rodents (the main carriers of infected mite larvae) at different locations in the study area and explore whether there is a relationship between the number of infected mite larvae on rodents and the occurrence of human cases in the neighbourhood. The data collected in this study will be used to estimate the incidence of scrub typhus and severe scrub typhus in the community. We will calculate household and spatial risk factors for scrub typhus and the economic impact of scrub typhus in the community. While expected case numbers for murine typhus and spotted fever may be lower, we aim at estimating most of these same parameters for these two infections as well alongside scrub typhus. The data from this study will help doctors to decide on treatment approaches and public health services to decide on intervention efforts. The immunological data will help vaccine developers to understand better how scrub typhus infection confers immunity. Data on rodents and mites will help inform disease control policies. Data on murine typhus and spotted fever will provide a basic understanding of the epidemiology of these rarely studied infections.