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Mycobacterial Diseases Research Directorate (MDRD)

Background MDRD

The Armauer Hansen Research Institute was established with the main purpose of conducting research in leprosy particularly in leprosy immunology and had contributed a lot towards the global control efforts in 1980's. Following the decrease in prevalence of leprosy and as a result of TB becoming the leading cause of morbidity and mortality, AHRI expanded its research effort towards TB and it has been the major research area of the institute in the last three decades. Since the re-establishment of AHRI in 2016, research activities in TB and leprosy are being managed by the Mycobacterial Diseases Research Directorate (MDRD).

The mission of MDRD is to generate scientific evidences in TB and leprosy that contribute towards diagnosis, prevention and control of the diseases. Most of ongoing and newly initiated research activities in MDRD address epidemiology of the diseases, diagnostics, therapeutics and characteristics of the etiologic agents including host-pathogen interactions. Considering the current gaps in early detection of the diseases particularly of those "asymptomatic" ones, the directorate takes "early diagnosis of TB and leprosy" as a flagship.

Major areas of Research at MDRD

The Directorate categorizes its research activities under five thematic areas:

1. Basic Biomedical Research

2. Diagnostics

3. Biomarkers

4. Epidemiological Research

5. Operational Research

Current research projects/studies/activities

1. TBGEN-Africa

Africa has the highest level of genetic diversity amongst all human populations.  It also has the highest level of genetic diversity amongst populations of the pathogen that causes tuberculosis (TB). Phylogenetic analysis shows that Mycobacterium tuberculosis (MTB) emerged with modern humans in Africa ~70 thousand years ago, and has spread and diversified in close association with humans during their migration out of Africa. The project proposed that the long history of co-evolution of host and pathogen genomes contributes to the diverse outcome following MTB infection, as reflected in the variable percentage of individuals progressing to active TB and varying efficiencies of ongoing transmission. To test this hypothesis, the distribution of MTB genotypes alongside the genotypes of genetically-distinct human populations in four African countries will be mapped. Comparison of paired host and bacterial genomes will identify loci that have co-evolved. This information will have fundamental importance in understanding the influence of host genetics on disease susceptibility and will highlight novel factors that impact on TB pathogenesis and pathology. It has been anticipated that the influence of co-evolutionary adaptation will be over-ridden in the context of HIV-induced immunosuppression. Loss of host-pathogen associations in HIV-infected populations will therefore provide a further test of our hypothesis.

AHRI is leading the project and Eritrea, Sudan and Cameroon are members of the consortium. The project is funded by African Academy of Sciences/ Wellcome Trust as part of the H3Africa Consortium.

For further reading: tbgen.ahri.gov.et

2. Tuberculosis Research Units Network (TBRU) Ethiopia 

The Tuberculosis Research Units Network (TBRU-N) is a consortium project involving partners from USA and other parts of the world to study the role of antigen specific T cell responses in the control of tuberculosis (TB). AHRI is involved in this consortium to study the spectrum of

Mycobacterium tuberculosis (Mtb)-antigen specific immune responses in contacts of pulmonary TB patients, which ultimately contribute to the development of tools that help identifying  people who are at higher risk of progression to active TB and make priorities for preventive interventions. The study is an observational study, involving contacts of pulmonary TB patients and conducted at selected health facilities in Addis Ababa, Ethiopia. This collaborative project is funded by NIH.

More information can be found at: http://tbru.emory.edu/

 

TBRU team Ethiopia

3. Screen TB

A consortium project funded by the second European and Developing Countries Clinical Trials Partnership (EDCTP2). The main goal was to develop a point-of-care, hand-held, rapid screening test for tuberculosis (TB) that can be conducted on finger-prick blood in a laboratory-free manner. Rapid diagnostic screening tools for point-of-care (POC) application, particularly non-sputum-based biomarker tests are vital to combating tuberculosis and controlling transmission. Availability of such tests would significantly accelerate and streamline diagnostic approaches, improve cost-efficiency and decrease unnecessary costly GeneXpert referrals.

A multiplex lateral flow (LF) strip was developed for simultaneous and quantitative measurement of 6 serum proteins in a single sample at LUMC. This signature included apolipoprotein-A1 (Apo-A1), C-reactive protein (CRP), ferritin, interferon-g induced protein 10 (IP-10), serum amyloid A (SAA) and Iinterleukin-6 (IL-6).

Collaborators: Stellenbosch University (Gerhard Walzl- PI), Makerere University , MRC The Gambia, University of Gambia,  Leiden University of Medical Centre,  London School of Hygiene and Tropical Medicine.

The project is completed and the findings are published.

4. ETHICOBOTS

Ethiopia Control of Bovine Tuberculosis Strategies (ETHICOBOTS) project is funded under Zoonoses & Emerging Livestock Systems (ZELS) programme, a research initiative in the UK, which is jointly funded by six research bodies (BBSRC, Dstl, DfID, ESRC, MRC and NERC). There are currently 8 institutions participating in ETHICOBOTS, including 4 Ethiopian research institutions, all led by the University of Cambridge. The main objective of this project is to minimize the zoonotic impact on poor high risk groups, including dairy farm workers and their families and those at risk as the emergent dairy livestock system continues to expand.

More information on https://ethicobots.com/

5. AHRI-APOPO Tuberculosis Research Project

This project, being conducted under a partnership agreement between AHRI and APOPO (a non-profit organization that trains and deploys detection rats for humanitarian purposes; www.apopo.org) has two wings:

  1. enhanced TB case finding in Addis Ababa and
  2. improved TB/HIV screening in Ethiopian prisons. Special features of the project are the research into the use of TB detection rats (African giant pouched rats, bred and trained in Tanzania) as a TB diagnostic tool, and the improvement of services along the TB care cascade in line with the global efforts to “Find. Treat All” and ending TB.

Currently, there are 58 TB diagnostic centers in Addis Ababa participating in project (A). Sputum samples are collected from TB diagnostic health centers in Addis Ababa that use microscopy as a diagnostic tool. Samples collected from new presumptive patients who consent to participate, are included in the study. After partner clinics have tested them using locally available microscopy, samples are transported to the project facility by motorbike that has a triple packaging system. Once arrived at the project facility in the ALERT hospital campus in Addis Ababa, samples are heat-inactivated, cooled down and screened by trained TB detection rats. Those samples that are smear negative at the health facility but positive by the rats are subjected to a WHO-endorsed confirmatory test. Samples that are confirmed to be positive are reported back to the health facility to call back the patient and begin immediate treatment.

This project is conducted in collaboration with the National TB Control Program and Addis

Ababa City Administration Health Bureau and financially supported by Skoll Foundation.

The objectives of the prison project are

  • to conduct mass screening of around 52,500 inmates and staff in 35 prisons across the country for TB and HIV
  • to enhance the capacity of the participating prison health units to the level that enables them to conduct entry, exit and outpatient screening for both TB and HIV
  • to sustainably link the clinics to the nearby public health facility for treatment follow up of identified cases.

This three-year project is funded by Elton John AIDS Foundation and is being implemented in collaboration with the National TB Control Program, the German Leprosy and Tuberculosis Relief Association in Ethiopian (GLRA-Ethiopia) and the Federal Prisons Administration Commission.   

                                

6. VALUE-TB Ethiopia: Costing the delivery of tuberculosis services in Ethiopia from a health systems’ perspective

Ethiopia is characterized by a high burden of tuberculosis (TB) and a spreading multidrug resistant TB (MDR-TB).  In order to have an impact on lowering the burden of TB, there needs to be an improvement in the allocation of resources to and within TB programs.  However, this requires good quality and current unit cost data for TB service provision in Ethiopia, which is scarce.  Such data is also needed to inform governmental and non-governmental partners on planning for TB service investments in Ethiopia, as well as conduct efficiency analyses and economic evaluations of TB service provision strategies or interventions. 

This study therefore is planned to be conducted jointly by Armauer Hansen Research Institute and London School of Hygeine and Tropical Medicine(LSHTM), through an agreement between Federal Ministry of Health (TB & Leprosy case team) and the LSHTM. The study aims to estimate the unit costs of a comprehensive set of TB services in Ethiopia from a health providers’ perspective, using a sustainable cost data collection framework for TB in Ethiopia.  This will be achieved by conducting a cost analysis in 30 healthcare facilities throughout Ethiopia.  The health facilities were selected using multistage, stratified random sampling.  For a time horizon of one patient episode of care, data will be collected using structured interviews with staff, timesheets completed by staff, observation guides and through document review.  All unit costs will be publicly accessible through a global unit cost data database.

The primary aim of the study is to estimate the costs of TB services to inform the Federal Ministry of Health and important stakeholders and to allocate resources, both to and within TB, in an efficient and equitable way. To achieve this aim, three specific objectives have been defined:

1. To estimate the unit costs of a comprehensive set of TB services in Ethiopia from a health providers’ perspective.

2. To develop a sustainable cost data collection framework (in terms of tools and processes) for the TBL in Ethiopia.

3. To facilitate the estimation of technical efficiency of TB services

The cost data collected through this exercise takes a health provider perspective. This includes costs incurred by the TB Leprosy case team of MOH, other MOH entities, devolved government agencies, and public and private facilities.

7. Post Exposure Prophylaxis for leprosy (PEP4LEP )

"Chemoprophylaxis  for leprosy: comparing the effectiveness and feasibility of a skin camp intervention to a health centre based intervention; An implementation trial in Mozambique, Ethiopia and Tanzania" (PEP4LEP) is a newly initiated EDCTP and LRI funded consortium among ILEP members (NLR, GLRA), Erasmus Medical centre and three African Countries. AHRI, the National TB Leprosy Program (MOH), and GLRA-Ethiopia are consortium members from Ethiopia. The general objective of the project is to contribute towards interrupting the transmission of M. leprae by identifying the most effective and feasible method for screening of people at risk of developing leprosy and administering chemoprophylaxis (a single dose rifampicin; SDR) in Ethiopia, Mozambique, and Tanzania.

8. Active case detection of leprosy and tracing household contacts in hotspot areas

One of the priority areas in leprosy research is early detection of leprosy. The delay in leprosy case diagnosis and the presence of asymptomatic individuals at high risk of developing leprosy are the reasons for ongoing transmission of leprosy in the population. Since 1994, leprosy management is integrated with the health system where each health facility is responsible in the management of leprosy system. However, lack of dermatologists and trained health professionals in leprosy management, the low health seeking behavior of our community and stigma compromised the leprosy detection and control activities.

The recent strategy of WHO and national control program is to conduct active case detection and contact tracing activities in hot-spot sites. Currently we are conducting such activities in West Arsi zone (Kokosa wereda) and in east Hararghe zone (Fedis wereda). The activity includes KAP assessment, training of HEW and TBL focal persons in leprosy management, house to house survey and close follow up of contacts and laboratory based assessments.

9. Intracellular Signaling and T cell-Antigen Presenting Cell Interactions

     Meseret Habtamu (PhD summary)

Tuberculosis (TB) remains a serious global public health challenge primarily in the developing world. It is a chronic disease where protective immunity and mycobacterial containment relies on a wide range of innate and adaptive immune response. Identification of immunologic factors responsible for protection or susceptibility could help in developing new and improved control strategies. Phenotypic and functional characterization of TB specific T cells appears to be the common approach in this regard. However, measuring TB specific T cell response alone may underestimate the magnitude and complexity of immune response against Mycobacterium tuberculosis (Mtb). This thesis aimed at characterizing T cell-APC (antigen presenting cell) interaction in a greater detail using Imaging flow cytometry (IFC).

In this study, we first established a novel in vitro assay that enabled us to characterize T cell-monocyte interaction, synapse formation and NF-κB nuclear translocation in the interacting T cell using PBMC from buffy coats of healthy blood donors stimulated with ds-Red expressing BCG. The results showed that IFC is a potential tool in characterizing multiple aspects of immune cell functions from both the T cell and monocyte sides upon mycobacterial challenge. We then recruited well-defined study cohorts of patients with active pulmonary TB (pTB) and healthy controls from a disease endemic setting, (Addis Ababa, Ethiopia). Here, we applied the IFC based in vitro assay to identify, enumerate and characterize TB antigen reactive cells. The results from this study revealed that T cells displaying NF-κB nuclear translocation were more abundant among those that had already conjugated with monocytes in samples from patients with active pTB cases. Nonetheless, the frequency of T cell-monocyte conjugates with established synapse was lower in this study group. The Lck-Itk scaffold T cell specific adaptor protein (TSAd) is known to regulate T cell activation, possibly via the actin cytoskeleton. We thus investigated whether synapse polarization was also influenced by TSAd using CD4+ T cells from Sh2d2a+/+ and Sh2d2a-/- C57/BL6 transgenic mice as a model system. The results revealed the important roles of TSAd in regulating polarization of cytoskeletal and polarity molecules as demonstrated by reduced polarization of F-actin, TCR as well as members of the PAR3 complex to the synapse in TSAd deficient CD4+ T cells. This has implications on synapse formation between T cells and APC, as well as proliferation and differentiation of activated T cells. Altered polarization of IFN-γ in conjugated T cells has also been described in TSAd deficient cells.

The findings from this work show that T cell function monitored via T cell interaction with APC can be used in monitoring immune competence of both the T cell and the APC. Furthermore, the unique ability of IFC analysis to determine the intracellular localization of signaling molecules allows to distinguish qualitative differences in T cell responses. This may help in advancing our understanding of which cells are likely to be affected and further develop new approaches in assessing immune activity. In addition, these data underscore the value of considering multiple immunological parameters in the search for correlates of immune protection against TB.

10. Monocyte Function in TB, HIV and TBHIV Co-Infected Patients

    Wegene Tamene (PhD work)

People living with HIV are 20-30 times more at risk to develop active TB than HIV negative people. Cells of the monocyte-macrophage lineage are crucial cells in the pathogenesis and protection of TB disease, as well as to pathogenesis of HIV disease. Studies have suggested that HIV infected patients have reduced monocyte function and abnormal distribution of subsets of peripheral blood monocytes even after ART, which may contribute to increased susceptibility and/or progression to TB. Thus, this project aimed to investigate the role of TB, HIV and TB/HIV co-infection on phenotypic and functional properties of subsets of peripheral blood monocytes in Ethiopian patients.

This study focuses on characterization of monocytes subsets defined by the expression of CD14 and CD16 on cell surface. This includes phenotyping, plasma marker analysis (host and mycobacterial), Vitamin D axis mRNA measuring. Accordingly, one hundred twenty study participants have been recruited. We evaluated toll like receptors (TLR2, 4 & 9), chemokine receptors (CCR 2, 4, 5, 7 and CX3CR1) and activation/death markers (HLADR, CD54, PD-L1 & PD-1) surface expression on monocyte subsets using flow cytometry. 

11. Molecular Epidemiology, drug resistance pattern of M. tuberculosis and clinical     outcome evaluation in Woldiya region, Ethiopia

     Elena Hailu (PhD work)

The causative agent of human tuberculosis, Mycobacterium tuberculosis complex (MTBC), comprises seven phylogenetically distinct lineages associated with different geographical regions. Lineage 7 of M. tuberculosis, recently characterized at ARHI, is restricted to Ethiopia and it represents a phylogenetic branch intermediate between the ancient and modern lineages of M. tuberculosis. It was shown that modern lineages are generally more virulent and more globally successful, compared to other more geographically restricted lineages. Differences in immunogenicity, severity of disease, and transmission consistently indicated that Lineages 2 and 4 are more virulent than Lineages 1 and 6 but nothing is known about Lineage 7.

The aim of this study is to investigate Lineage 7 of M. tuberculosis experimentally and in clinical settings. The experimental part includes the infection of THP-1 macrophage cell line and macrophages isolated from healthy donors with Lineages 1, 3, 4 and 7 of M. tuberculosis found and isolated in Ethiopia following the analysis of cytokine response to the above mentioned lineages.

Publications

https://www.ncbi.nlm.nih.gov/pubmed/?term=Armauer+Hansen+Research+Institute+

https://www.ncbi.nlm.nih.gov/pubmed/?term=M.+leprae+Armauer+Hansen+Research+Institute