ARGENT: ARgentinian GEnomics for Tuberculosis

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The biggest cause of deaths due to infectious disease (over 1 million/year) and drug-resistant infections (~0.5 million/year) is the bacterium Mycobacterium tuberculosis, which causes tuberculosis (TB). About one third of deaths caused by drug-resistant infections are due to TB. This is possibly the single biggest infectious public health threat the world faces, with 1.6 million reported deaths globally due to TB in 2017 (https://www.who.int/gho/tb/en/). As drug resistance leads to treatment failure, the standard-of-care is to test a bacterial sample from a patient, to determine which drugs are likely to be effective. The gold standard culture-based approach is slow (taking many weeks) and expensive, so many countries use a fast (hours) test based on DNA amplification to detect resistance to rifampicin, the recommended treatment for non-drug-resistant TB. If they see resistance to rifampicin they pragmatically assume the sample is also resistant to isoniazid, and therefore multi-drug resistant (MDR). When this assumption is wrong, the patient is being subjected to 18 months of inappropriate treatment with brutal side-effects.There is an alternative: the bacteria causing the infection can be isolated from (usually) the sputum of a patient, and the bacterial DNA decoded by a process called whole genome sequencing. Because drug resistance is caused by specific changes to the DNA sequence (mutations) in the bacterium, sequencing provides a comprehensive output describing the resistance profile of the bacteria. There are many roads to drug resistance, and decoding the whole genome allows access to all of these mutations. A secondary benefit to whole-genome sequencing is that closely related bacteria have very similar DNA, and if one person infects another, their bacterial strains are closely related. Thus one can decode the mutation patterns in TB samples from many patients - this provides actionable information that can direct the prevention and management of outbreaks.The challenge is turning whole-genome sequencing into a production system that runs in a public health lab or hospital, with acceptable error rates and outputs that make sense to doctors, nurses and public health practitioners. The only country in the world to have adopted whole genome sequencing for TB diagnosis, patient management and outbreak surveillance is the UK. Through the GCRF-funded CABANA-project, EMBL-EBI is collaborating with the Argentinian National Reference Lab, which is responsible for confirming all the TB diagnoses in Argentina and in neighbouring countries. This project, named ARGENT, will achieve two things. First, it will enable us to perform a feasibility study of whole-genome sequencing for diagnosis and management of TB in Argentina, working closely with the experts dealing with the TB cases. Introduction of such a service into routine use requires very careful validation and accreditation, which is beyond the scope of this project. However, by specifically introducing a software workflow which is heavily tested, and being developed in the UK into an accredited workflow specifically designed to be shared with other countries. Second, the project will build a global, open, web platform (Mykrobe Atlas) incorporating all (>50000) global TB genomes, allowing users to upload their own samples and immediately compare theirs with all that have gone before. Since several countries have legal blocks preventing sharing of pathogen sequence data, a key sub-study will be to trial a hub-and-spoke model that allows a country to participate in Atlas while retaining their raw sequence data in country.Through the supranational network with other countries in Latin America, led by the Argentinian lab, we will share our learning with other national labs in the region, and also in those countries with the greatest burden of disease - in Africa and Asia.