Predicting tuberculosis transmission, drug resistance and disease from pathogen and host sequence data

This proposal will build upon the principal applicant's experience of 15 years of research work in Lima, Peru. The province of Callao, Lima, has a tuberculosis incidence above 150 per 100,000 people whilst Peru has the highest burden of multidrug-resistant tuberculosis in the Americas. Mycobacterium tuberculosis is the focus of this work, although the concepts are equally applicable to many pathogens. This proposal has three key aims:

- To apply hybrid genome sequencing to understand tuberculosis transmission.

- To quantify the clinical impact of tuberculosis pre-resistance.

- To define the association between pathogen genotype and the host transcriptomic response to tuberculosis infection and disease.

Comprehensive population-level surveys of Mycobacterium tuberculosis combined with prospective household cohort studies and the latest in genome sequencing technology will address these aims. The potential for hybrid deep sequencing to unravel tuberculosis who-infected-whom transmission chains has never been evaluated. Similarly, pathogen pre-resistance first described by the principal applicant has never been evaluated in a clinical setting. The association between the pathogen genome and gene expression following tuberculosis infection has never been adequately addressed. Understanding the importance of pathogen lineage and the trajectory of the host transcriptome following infection could improve prediction of tuberculosis progression from latency to disease.