Using host-responses and pathogen genomics to improve diagnostics for tuberculosis in Bandung, Indonesia
Lead Research Organisation:
London School of Hygiene & Tropical Medicine
Department Name: Infectious and Tropical Diseases
Abstract
Tuberculosis disease (TB) is a major public health issue in Indonesia with over one million cases and 123,000 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 Dr. Hasan Sadikin Hospital, Faculty of Medicine Universitas Padjadjaran (DHSH-UNPAD), with the Eijkman Institute for Molecular Biology and the London School of Hygiene and Tropical Medicine - three institutions at the forefront of infectious disease research - to enable world class research. The project will also allow for the training of Indonesian researchers in genomic technologies and analysis to allow local capacity building.
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 Dr. Hasan Sadikin Hospital, Faculty of Medicine Universitas Padjadjaran (DHSH-UNPAD), with the Eijkman Institute for Molecular Biology and the London School of Hygiene and Tropical Medicine - three institutions at the forefront of infectious disease research - to enable world class research. The project will also allow for the training of Indonesian 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. Indonesia 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 Indonesia 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 Indonesia 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 Indonesia, the 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. Indonesia 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, such as those in the Eijkman Institute, 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. Indonesia'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 Indonesia 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 Indonesian 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; The Applied Genomics Centre) in TB biology, biotechnology, clinical care, genomic epidemiology, and public health.
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 Indonesia, the 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. Indonesia 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, such as those in the Eijkman Institute, 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. Indonesia'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 Indonesia 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 Indonesian 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; The Applied Genomics Centre) in TB biology, biotechnology, clinical care, genomic epidemiology, and public health.
Publications
Perdigão J
(2020)
Emergence of multidrug-resistant Mycobacterium tuberculosis of the Beijing lineage in Portugal and Guinea-Bissau: a snapshot of moving clones by whole-genome sequencing.
in Emerging microbes & infections
Elias R
(2023)
Emergence of KPC-3- and OXA-181-producing ST13 and ST17 Klebsiella pneumoniae in Portugal: genomic insights on national and international dissemination.
in The Journal of antimicrobial chemotherapy
Elias R
(2022)
A phylogenomic approach for the analysis of colistin resistance-associated genes in Klebsiella pneumoniae, its mutational diversity and implications for phenotypic resistance.
in International journal of antimicrobial agents
Description | We have developed protocols for clinical data and sample collection and processing. This includes electronic data capture systems using tablets and mobile devices. All TB patient recruitment is completed. Human RNA and TB bacterial DNA has been extracted and ready for sequencing. Due to COVID-19, there have been delays in the sequencing of samples by the Eijkman Institute. Further, a number of local staff have been seconded to the COVID-19 emergency response. |
Exploitation Route | If we identify markers of disease severity and treatment outcome, we will be in a position to develop new diagnostics. Future work could also assess the validity of the markers in other populations (e.g. in a parallel Philippines study), as well as use genomic sequencing to investigate TB transmission networks nationwide. These ideas could form the basis of future funding applications. The development of a nationwide database of genomic sequences and important drug resistance markers will inform both clinical and infection control decision making. |
Sectors | Healthcare Government Democracy and Justice |
Description | They are assisting policy makers, including in the application of genomics for identifying hotspots of disease transmission and drug resistance, and therefore informing disease control. Further, it reinforcing with governmental agencies the benefits of using 'omics for assisting with personalised medicine. Ultimately, the identification of genetic signatures for TB patient prognosis and treatment outcomes, will assist with clinical care and infection control. |
First Year Of Impact | 2020 |
Sector | Healthcare,Government, Democracy and Justice |
Impact Types | Cultural Policy & public services |
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 bacteria from genomic data |
Description | Bioinformatic pipelines to profile TB bacteria for drug resistance and presence in a transmission chain. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | By knowing whether a TB sample is drug resistant or part of a transmission chain will assist with personalising treatment and informing infection control. |
Title | Statistical models and biomarkers for predicting patient outcome |
Description | A statistical model that predicts treatments outcomes and patient groups (e.g. latent infection vs. active disease) using RNA seq data. |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2022 |
Provided To Others? | No |
Impact | If validated, the bio-signatures could be used in the clinic. Ongoing work is attempting to implement a PCR-based detection approach of the biomarkers. |
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 | A clinical database with integrated 'omics data |
Description | This database consists of all clinical data, human RNA and TB bacteria profiles. |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | No |
Impact | 'Omics mechanism discovery, including markers associated with TB drug resistance and human disease status and treatment outcome. |
Description | Dr. Hasan Sadikin Hospital clinical sample collection and processing |
Organisation | Padjadjaran University |
Country | Indonesia |
Sector | Academic/University |
PI Contribution | Training in sequencing and genomic data analysis. Development of study protocols. |
Collaborator Contribution | TB clinical samples. |
Impact | Collection of human RNA and TB DNA samples and meta data ready for sequencing and analysis. |
Start Year | 2019 |
Description | Sequencing in Indonesia |
Organisation | Eijkman Institute |
Country | Indonesia |
Sector | Public |
PI Contribution | Biological specimens and laboratory consumables, sequencing protocols and analysis techniques. |
Collaborator Contribution | RNA sequencing. |
Impact | Samples have been sent for sequencing, with data pending. |
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 |
Description | Workshop on genomic data analysis in London |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | This was a 3 day infectious disease 'omics workshop in September 2019, which was attended by collaborators and students. |
Year(s) Of Engagement Activity | 2019 |