Ongoing projects at the Centre for Tuberculosis Research
TB elimination in low incidence countries, with special focus on TB and migration
In line with the priority areas identified in WHO’s framework for TB elimination in low-incidence countries, this theme includes multi-centre studies aimed to assess the effectiveness and cost-effectiveness of approaches to improve access to care, TB screening, and case management of active TB and LTBI, with a special focus on migrants.
National partners include the Department of Public Health Sciences and the Department of Medicine at KI, the Swedish Public Health Agency, the Stockholm County Council’s Unit for Epidemiology and Community Medicine, and other counties.
External partners include the ECDC, WHO Global TB Programme and the Regional Office for Europe, and research institutions and national TB programme in several low-incidence countries with TB elimination strategies, such as the UK, Netherlands and Italy. Domestic funding (The Swedish Heart Lung Foundation and FORTE) as well as EU funding (CHAFEA) exist for these activities. For more information, please see the Social medicine, infectious diseases and migration research group.
Social protection and TB
A Social Protection Action Research & Knowledge Sharing network (SPARKS) has been established, with secretariat at the Department of Public Health Sciences.
WHO’s new global TB strategy identifies social protection as a key intervention to improve health care access and to ensure financial risk protection for all. The strategy has set an ambitious target that “no TB affected household should experience catastrophic cost”, while acknowledging that the interventions required to achieve this, as well as the methodology for monitoring progress towards this target needs to be further developed.
SPARKS facilitates research aimed to assess the effectiveness and operational challenges of social protection interventions, as well as methodology development for the monitoring progress. This is done in close collaboration with WHO. The first SPARKS consultation was held at KI in December 2016.
A WHO Collaboration Centre is being set up to pursue SPARKS and related research with WHO. Research funding is in place for several consortia projects, including from EU H2020 and Wellcome Trust.
Point-of-care diagnostics and biomarkers for risk of activation of latent infection
This theme includes development of new and sensitive point-of-care (POC) tests for active and latent TB. Presently available markers/tests for its diagnosis present severe limitations, and none of the tests are of the most urgently needed POC type. Neither is there a reliable test to differentiate between latent and active TB, and in particular to predict which patients with latent TB (LTBI) will progress to active disease.
The WHO defined the target product profile (TPP) of the most urgently needed tests for TB. Besides the need for a diagnostic test, WHO defined as one of the highest priorities a POC triage test, for systematic screening, able to distinguish individuals who need referral for further confirmatory testing. These new tests are absolutely needed to reach the WHO goal of eliminating TB by 2035. Work on developing such tests is in progress at MedS with funding from Hjärt-Lungfonden, Vetenskpsrådet, The European & Developing Countries Clinical Trials Partnership (EDCTP) and Bill and Melinda Gates Foundation.
WGS/MICs/Phenotypic Drug-Susceptibility Testing (DST)
Next generation sequencing (NGS), including both whole genome sequencing (WGS) and targeted sequencing, when combined with high quality bacteriological investigations of drug resistance in M tuberculosis (DST and MIC determinations), offers very interesting research possibilities.
These techniques are increasingly not only extending our understanding of emergence of resistance in bacterial strains, their virulence and transmission between patients, but also creates a knowledge base for developing new rapid diagnostic tools for early detection of drug resistant TB with high sensitivity and specificity. Such an early detection of patients with resistant TB strains is crucial for a better control of the increasing global problem with difficult-to-treat TB.
Therapeutic drug monitoring for MDR-TB prevention and treatment
The rapid increase of multidrug-resistant (MDR) and extensively drug resistant (XDR) TB strongly suggests that the present strategies to control TB have to be urgently improved. Treatment outcomes for the WHO long course MDR-TB treatment regimen under programmatic condition world-wide is dismal, only 52% worldwide. Acquired drug resistance is not only caused by poor compliance and inconsistent drug supply. Pharmacokinetic variability in patients resulting in low drug exposure has also recently been identified as an important contributing factor.A standard dose of TB drugs will not be adequate for all patients, necessitating the measure of drug blood concentrations.
Therapeutic drug monitoring (TDM) involves measuring drug blood concentrations and adjusting dosages in order to optimise therapy, avoid suboptimal drug concentrations and reduce adverse-effects. True TDM, i.e. combining drug exposure with MICs for TB treatment, is a poorly researched but promising research field. Preventing further increase of MDR-TB not only requires effective treatment for patients with drug resistance, but also to accurately and rapidly diagnosing, treating and curing patients with drug sensitive TB. This will only be possible through the development and uptake of new tools for the rapid diagnosis, treatment and prevention that presently have severe limitations. If urgent actions are not taken regarding novel tools for TB treatment the window of opportunity to prevent further development and spread of drug resistant TB will be missed.
Dendritic cell responses to mycobacteria
The arrival of mycobacteria in the draining lymph node is necessary for initiating protective, T-cell responses against the bacilli, but this remains poorly understood for both M. tuberculosis and Bacille Calmette-Guérin (BCG), the live TB vaccine. Upon microbial encounter, Dendritic cells at the site of infection become activated and migrate to the draining lymph node where they activate or prime naïve T cells. Indeed, DC mobilization to the lymph node and the transport of mycobacteria to the lymph node are key events in priming.
We are interested in the role played by different Dendritic cells in this process, including the mechanisms by which Dendritic cells mobilize to the lymph node in response to BCG, their ability to ferry BCG to the lymph node, and to trigger the activation CD4+ T cells therein. Understanding the above is critical for deciphering the basis of productive T-cell responses and for advancing our capacity to improve BCG and other vaccines of low-to-modest efficacy that rely on such responses.
This work is funded by the Swedish Research Council VR. For more information, see Antonio Rothfuchs research group.
Development of a bio-aerosol sampler for M. tuberculosis
Very little is known about M. tuberculosis in air, the transmissible form of the pathogen. This is largely due to the lack of adequate tools for sampling M. tuberculosis from aerosols.
A tool for collecting bacilli from air would enable the study of the transmissible form of the organism; help identify TB hotspots of transmission; improve case-finding and make it affordable for developing countries. This would impact transmission and prompt the discovery and deployment of novel intervention strategies against TB.
We are developing an air-sampling device that uses ionization technology to capture airborne mycobacteria. In a uniquely tailored aerobiology chamber, we are testing and refining the ability of our device to sample aerosols containing mycobacteria, to create a prototype suitable for field trials. This work is funded by the Bill and Melinda Gates Foundation and Karolinska Innovations. For more information, see Antonio Rothfuchs research group.
Molecular characterization of essential metabolic pathways and early drug discovery
Due to the emergence of multi- and totally drug-resistant strains, Mycobacterium tuberculosis poses a major threat to human health and new antimicrobial drugs against this pathogen are urgently needed. This project builds on our recent advances in understanding, at the molecular level, of fundamental and important aspects of the biology of M. tuberculosis.
The major objective is to develop new tight-binding inhibitors against validated drug targets from the cell-wall remodeling, fatty acid and cysteine biosynthetic pathways in M. tuberculosis, essential processes for the long term survival of the pathogen in the host. Previously, we have developed inhibitors with a new mode of action that show bactericidal activity against replicating and non-replicating M. tuberculosis.
We will extend our approach for inhibitor design, i.e. a combination of small-molecule screening, structural biology, biochemistry, organic chemistry and cell biology to develop strong binding inhibitors against other targets from these pathways. Lead compounds will be tested in vitro and in vivo with respect to target inhibition and antibacterial potency against replicating and non-replicating M. tuberculosis. Inhibitor development is expected to generate compounds for pre-clinical assessment as lead candidates with the potential to be further developed into anti-mycobacterial drugs, and thus improve therapies for M. tuberculosis infections.
This project is supported by VINNOVA.
Studies on immunopathogenesis and host-directed therapies in human TB
Our main objectives is to resolve the immunopathogenic pathways and regulatory mechanisms involved in the progression of TB and associated co-morbidities such as HIV, diabetes and helminths, but also to study the immunological impact of drug-resistance in patients with MDR-TB.
We explore if novel host-directed therapy using immunomodulatory compounds can support standard treatment with anti-TB antibiotics via induction of potent antimicrobial responses. Immune profiling of patient samples obtained in well-designed clinical studies in Sweden, Ethiopia and Bangladesh are combined with functional studies of host-TB interactions using an in vitro macrophage infection model and also an organotypic lung tissue model to dissect immune polarization of macrophages and T cells in TB. Identification of novel immune signatures of active TB and especially MDR-TB may increase our in-depth understanding of TB pathogenesis and define the mechanisms and consequences of an imbalanced immune response.
This research will open new opportunities to monitor and predict TB outcome and to find new targets suitable for host-directed therapies.