Medical and biological significance of exhaled M. tuberculosis detected by community level face mask sampling in Pretoria. Globally, tuberculosis (TB) is the greatest cause of disease and death by a single bacterial agent. Over one quarter of humanity is estimated to be infected with Mycobacterium tuberculosis (Mtb), the agent of TB; however, more than 80% of those infected never develop the disease because the infection remains quiescent and does not produce symptoms. In order to survive, Mtb must spread from person to person in droplets exhaled by infected individuals. The standard view has been that this only occurs in people who have symptoms of lung TB such as coughing, weight loss and fever. Detecting, diagnosing and treating these individuals as early as possible after they become infectious has been the major priority of the global campaign to eradicate TB. Nonetheless, authorities such as the World Health Organisation (WHO) recognise that many millions of newly infectious cases are missed every year; these undoubtedly fuel the continuing epidemic. Researchers are now questioning whether people with quiescent TB may also transmit the infection. Evidence for such 'incipient' forms of TB comes from sophisticated lung imaging and direct detection of Mtb in some individuals without symptoms.   Our research team has been working for several years on the use of adapted face masks to detect exhaled Mtb. Masks containing a Leicester-developed synthetic sampling matrix are worn for 30 minutes then the matrix is taken out and analysed for captured Mtb by detecting its DNA in the WHO-recommended Gene Xpert system. Combined with evidence that the face mask sampling (FMS) approach can detect early lung TB, the simplicity, convenience and low cost of FMS led us to investigate whether it could be used to detect infection in a community sampling programme. In a currently active MRC project, the Leicester-Pretoria team have found an unexpectedly high Mtb detection rate: while prior estimates led us to expect a positive rate of up to 1%, in practice this has exceeded 15%.  Our study is based in the Tshwane district where the Pretoria team have developed a community oriented primary care (COPC) programme directed to patient and household centred health promotion. Community Health Workers (CHWs) have been trained in FMS and gather relevant related demographic and clinical data. A youtube video (Breathcatcher) explains the approach to both CHWs and clients.. We have responded by refocussing the current study on caring for those with positive samples. Although we have clear evidence that people with FMS-detected Mtb can progress to conventionally recognised disease within 1-2 months, this has not been detected so far in the current study where our capacity for follow up is very limited. (Ongoing clinical support is provided by the COPC) In the new study we aim to provide detailed follow up on 50 participants providing Mtb positive masks (CASES) for a full year and to compare their clinical and laboratory status with a comparator group whose mask result is negative (CONTROLS). Tests additional to FMS (including blood and lung imaging) will allow us to compare our evaluations against current diagnostic standards. Review will be monthly for cases and 3 monthly for controls. This approach will allow us to detect different patterns with which individuals exhale Mtb over time and whether their infections progress to active disease. Our work will be supervised by an international monitoring group who will scrutinise our results and advise on the best management of individuals with evidence of disease. In this way they will receive the earliest treatment justified by accepted standards. This work will provide a description of exhaled Mtb in the Tshwane community and its relation to clinical disease. If, as we suspect, many people without symptoms are contributing to transmission of the infection, a major refocussing of control and treatment will be necessary. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.