Using host-responses and pathogen genomics to improve diagnostics for tuberculosis in the Philippines

Lead Research Organisation: London Sch of Hygiene and Trop Medicine
Department Name: Infectious and Tropical Diseases

Abstract

Tuberculosis disease (TB) is a major public health issue in the Philippines with over 300,000 cases and 22,000 deaths in 2016 alone. Worldwide, the World Health Organisation estimates that there are nine million new TB cases and nearly two million deaths each year. The increasing prevalence of multi-drug resistance strains is making disease control difficult. Until today, diagnosing active TB, especially in the early stages, is difficult and requires a sputum sample. In addition, current treatment takes more than 6 months of therapy, with diagnostics unable to help identify early treatment failure. An eventual diagnosis of drug resistance may mean extended further treatment for 2 years.

This project seeks to identify a new diagnostic assay that uses a small blood sample to measure the patient's response to the tuberculosis infection, instead of looking for the tuberculosis bacterium directly. This assay could be able to identify patients earlier and monitor their treatment response. This would allow earlier treatment and more rapid ability to alter therapy to a more appropriate regimen.

This project will link the Research Institute for Tropical Medicine with the London School of Hygiene and Tropical Medicine - two institutions at the forefront of infectious disease research - to enable world class research. The project will also allow for the training of Philippine researchers in genomic technologies and analysis to allow local capacity building.

Technical Summary

Tuberculosis disease (TB), caused by M. tuberculosis (Mtb), is an important global public health issue. The Philippines remains one of the 22 high-TB burden countries in the world. Improving diagnostic tools for TB could assist the identification of active disease and evaluation of the response of anti-tuberculosis treatments, ultimately leading to disease control. Our study aims to use next-generation sequencing and bioinformatic techniques to characterise the human response to Mtb infection, which has previously been shown to offer an accurate and sensitive diagnostic for active TB. However, previous work has not assessed the impact of Mtb strain on diagnostic ability, or converted these signatures into useable in-house assays, such as PCR. In this project, we will seek to generate a human blood transcriptome based risk score, measured by a PCR assay that can be used in the Philippines across their strain diversity and local environments. Insights from this work could lead new diagnostics and control policy. This project will also capacity build in the Philippines for genomic technologies and analysis.

Planned Impact

The economy
Advances in sequencing technology now allow the genomic characterisation of Tuberculosis (TB) on an unprecedented scale, and have the potential to greatly accelerate research aimed at understanding the biology of the disease. The knowledge generated in the project and application of the research could ultimately benefit the pharmaceutical industry and those developing TB diagnostics and vaccines, as well as communities in the Philippines, UK, and other countries exposed to the disease. Ultimately, through reduced TB occurrence, the knowledge gained in this study could improve the health and wealth of the both participating nations and globally. The methods used in this project could have application beyond TB, so help more widely in the control and prevention of infectious diseases, with associated economic benefits.

The general public
TB kills ~2 million people globally each year, and drug resistant forms are making control difficult. The Philippines is a high-TB burden country, where TB affects predominantly the working population. Knowledge generated in the project could lead to better access to safer and more effective medicines, vaccines and improved methods of rapid diagnosis. Genomics insights could lead ultimately to improved control measures adopted globally. The project therefore specifically addresses the MRC strategic aim to impact positively on global health, and to assist with bringing the health impacts of fundamental research to people more quickly.

Academic and industrial organisations
New sequencing technologies have the ability to generate vast amounts of data, but there is a need to translate this information into knowledge useable by other research scientists and industry. Our work will provide tools useful for genomic data analysis, which can be utilized across diseases and in different settings. An understanding of genomic tools to uncover new diagnostics could lead to improved tests for detecting transmissible forms, and insights for academics involved in disease outbreaks and public health policy formulation (e.g. Philippine's National TB Control Program). Scientific developments arising would enhance the commercial private sector for the production of diagnostics, vaccines and other control measures. We have links with some of these companies (e.g. GSK) and will work through the technology transfer offices to ensure pipelines to translation tool production and exploitation are in place. Developing a basic understanding of the genomic pathways will not only be important for understanding TB, but also, any important findings and technology developed may have enormous implications for policy makers.

Training
The proposal will employ and train and develop scientists in the Philippines and UK with diverse experience with an 'omic mentality that can be applied in academia, the public sector and industry. The multidisciplinary project team will add to the Philippines and UK science base in an important and economically vital research area. The researchers working on the project will develop team working and project management skills, which they can apply in all employment sectors. Importantly, the scope for multidisciplinary interactions in this proposal should not be underestimated. The UK-based researchers employed to carry out the planned activities will have unique opportunities for engagement with experts (e.g. in the LSHTM TB Centre) in TB biology, biotechnology, clinical care, genomic epidemiology, and public health.
 
Title A pipeline for the analysis of RNAseq data 
Description This is an analysis toolkit to identify human transcriptome signatures that allows for the differentiation between latent infections and active TB cases, as well as treatment outcomes (prognosis). 
Type Of Material Improvements to research infrastructure 
Year Produced 2019 
Provided To Others? No  
Impact Differentiating between latent infections and active TB cases, as well as TB prognosis, will assist clinical management and disease control. The markers identified will lead to new diagnostic tools. 
 
Title Algorithms to profile TB from genomic data 
Description We have developed and migrated algorithms for the profiling of TB bacteria for drug resistance and outbreaks from genome sequencing data. 
Type Of Material Improvements to research infrastructure 
Year Produced 2020 
Provided To Others? Yes  
Impact It has enabled the RITM to identify drug resistance mutations and transmission hotspots in the Philippines, thereby assisting disease control and policy stakeholders. 
 
Title Tools for electronic data capture using tablets or mobile technologies 
Description We have developed electronic forms for the project, enabling the rapid and accurate capture of data from clinics and patients in the study. 
Type Of Material Technology assay or reagent 
Year Produced 2020 
Provided To Others? Yes  
Impact This is enabling the rapid analysis and tracking of study data. Therefore assisting with study project management and providing more timely insights into transmission patterns. The forms and technologies will be made available to other studies. 
 
Title Whole genome sequencing and drug resistance database 
Description This includes whole genome sequencing and drug assay data from >18,000 TB samples 
Type Of Material Database/Collection of data 
Year Produced 2018 
Provided To Others? Yes  
Impact The identification of drug resistance markers will personalise the care of TB patents. 
 
Description TB Clinics in Manilla 
Organisation Government of the Republic of the Philippines
Department Research Institute for Tropical Medicine (RITM) Phillippines
Country Philippines 
Sector Public 
PI Contribution Training in genomic sequencing. The transfer of algorithms for genomic data analysis. The development of electronic forms for data capture.
Collaborator Contribution The recruitment of individuals from clinics, and collection of samples for 'omics analysis.
Impact This is multi-disciplinary (clinical, genomics, informatics, statistics and epidemiology). The outputs include: genomics data, upskilling in the local workforce leading to onsite data generation, electronic data capture systems, and the development of a database to assist decision making.
Start Year 2019
 
Description Asian TB Network meeting in Manilla 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact This was a meeting of Southeast Asian TB researchers and policy makers, with an interest in applying genomic tools for diagnosis, as well as the development of a joint genomic database across the region to assist with identifying important mutations for drug resistance and transmission. The meeting was hosted by the RITM in Manilla (March 2019).
Year(s) Of Engagement Activity 2019