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Teaser, summary, work performed and final results

Periodic Reporting for period 3 - TB-ACCELERATE (Integrating genomics, epidemiology and evolution to accelerate tuberculosis eradication)

Teaser

Tuberculosis (TB) is already the main cause of death among infectious diseases and is among the top ten causes of death globally. At the rate at which global incidence of TB is declining elimination will not be achieved for the next 200 years. TB control starting in the...

Summary

Tuberculosis (TB) is already the main cause of death among infectious diseases and is among the top ten causes of death globally. At the rate at which global incidence of TB is declining elimination will not be achieved for the next 200 years. TB control starting in the nineties has reached a plateau, slow down is mainly contributed by our inability to stop transmission. Transmission is still significant in low-burden countries but rampant in high-burden countries. To accelerate TB elimination we need new control tools (diagnostics, vaccines, antibiotics) as well as new interventions based on sound epidemiological predictions. Whole genome sequencing of the pathogen, unlike previous molecular approaches, is a tool that in addition to measure transmission has the potential to redefine interventions and even be used in on-going interventions. TB-ACCELERATE is developing different approaches to make full use of whole genome sequence data to find new ways to stop transmission. Those approaches are aimed to 1. use whole genome sequencing data of the pathogen to evaluate transmission in low and high burden countries; 2. develop algorithms to obtain a high resolution picture on how transmission has occurred within transmission clusters; 3. identify pathogenic signatures of virulence by studying transmission across countries and by studying the evolution of the pathogen within the host and 4. develop methods to integrate culture negative samples in whole genome epidemiological studies. The overall aim is to contribute to global and local TB control by revealing the patterns on how transmission occurs and by direct action on active transmission clusters.

Work performed

Our translational research involves a wide range of disciplines including clinical, epidemiological, genomic and evolutionary research. Because of that there is people in our project involved in genomics, bioinformatics, mathematical modelling, clinicians, public health officials, molecular and evolutionary biologist. The project has allowed to hire one postdoc and two lab managers for biosafety experiments in the BSL3 and for library preparation and whole genome sequencing. In our local setting (Spain, low-burden country) we have been working on transmission reconstruction algorithms to obtain a high-resolution picture of TB transmission. Those algorithms does not only allow to identify transmission clusters but also to assign index and secondary cases to individuals. In parallel we are working with datasets from high-burden countries where the TB epidemic is different to identify differences in the population dynamics. All together we are using the data to understand individual transmission risk factors and to identify new molecular determinants of virulence and transmission.

Final results

Our developments has already led us to describe the TB population dynamics in the high burden country of Ethiopia where we show that TB was present before main colonial movements of the XIXth century. We are also using population-based genomic dataset to obtain a high resolution picture of tuberculosis transmission. For example, in Valencia Region (Spain) we have identified between 20-30% of on-going recent transmission. We have developed approaches to look at individual transmission cases so we can for the first time assign transmission risk potentials to individual cases. We have also studied the evolution of the bacteria during infection where we are estimating mutation rates in chronic patients. For example, we have been able to diagnose a multidrug resistant strain that was not detected by routine clinical approaches and which showed a highly unexpected population dynamics within the host. By analyzing global diversity and transmission datasets and comparing with other mycobacteria we have identified relevant mutations in a key virulence regulator that are important for transmission potential. The next steps in the project are aimed at transferring the tools to analyze transmission in high burden countries. We believe that a comparative phylodynamic approach will allow us to disentangle new key determinants of the epidemic in different settings. To do so we have team-up with laboratories across different continents as well with epidemiological modelers so we can quantitatively estimate differences across countries.