Tuberculosis is an important disease responsible, in 2019, for 1.4 million deaths worldwide. Fifteen percent of cases occur outside the lungs and of these disease forms, pericardial and meningeal disease are the most severe with mortality ranging from 8-40% or higher[1, 2]. Neither condition is satisfactorily modelled in animals and relatively little in-depth understanding has come from human studies hitherto[3, 1].
Our research programme at Crick is strongly linked to the Wellcome Centre for Infectious Diseases Research in Africa at the University of Cape Town. In South Africa we are conducting two clinical trials of intensified antibiotic therapy for pericardial (IMPI-3, US NIH funded) and CNS (Intense-TBM, EDCTP funded) tuberculosis that will recruit 80 and 228 participants respectively over the next two years. A rich clinical phenotype predicated by the investigational nature of these trials is augmented by access to advanced imaging at the Cape Universities Body Imagining Centre (CUBIC) and we are including both Cardiac MRI to assess sequelae of pericardial disease; and both comprehensive MRI sequences and magnetic resonance spectroscopy (MRS) to non-invasively determine selected brain metabolites (Glutamate and GABA).
Both clinical trials are assembling comprehensive biobanks from both blood and site of disease. These will be used in downstream multi-omic (transcriptomic, proteomic, metabolomic) laboratory analyses that will seek correlates of outcome, HIV-1 co-infection status, and treatment allocation and thereby lead to new understanding of pathogenesis. Specific hypotheses in pericardial tuberculosis centre on relationships between pericardial Mtb-specific T cells, and Mtb-induced markers of host cell death pathways, and bacterial load. These studies benefit collaboration with intramural investigators at the National Institutes of Health, Bethesda, MD, USA. In tuberculous meningitis we have documented enrichment of transcripts associated with neuronal excitotoxicity and cerebral damage leading us to pursue a hypothesis that inflammation sets up detrimental metabolic changes that contribute to brain injury and which may be targeted by novel adjunctive therapies.
The opportunity exists therefore particularly (but not restricted to) for a Neurologist, Microbiologist, Cardiologist, Microbiologist or Radiologist in training to join the team as a Clinical PhD student. The projects are highly multidisciplinary and multifaceted and the candidate would have ample opportunity to define niche prior to taking up the Fellowship. We envisage training will include ICH-Good clinical practice, clinical trials conduct, non-invasive imaging, Immunology, Bioinformatics, and Metabolomics. COVID-19 travel restrictions permitted, there would be opportunity to join the clinical team in South Africa during the early part of the Fellowship. However, in keeping with the nature of Crick, the bulk of time would be expected in laboratory work in close collaboration with the Bioinformatic, Metabolomic, Biostatistic, Advanced sequencing and Flow cytometric Science Technology Platforms and with our collaborating scientists. Whilst not therefore being prescriptive at the application stage one example project would be the relationship at the single cell (sc) level of T cell phenotype to bacterial load in the pericardium. This can range from being culture negative to containing over 10e6 bacilli/mL. We will have precise quantitative estimates and the ability to sort cells for scRNAseq. Work on peripheral blood has revealed much greater diversity than hitherto. Thus a hypothesis would be that the T cell response associated with no detectable or low bacillary content may differ from that in multibacillary disease and thus provide insight into protective immunity.
The partner institution for this project is Imperial College London.
- Howlett, P., Du Bruyn, E., Morrison, H., Godsent, I. C., Wilkinson, K. A., Ntsekhe, M. and Wilkinson, R. J. (2020) The immunopathogenesis of tuberculous pericarditis. Microbes Infect 22: 172-181. PMID 32092538
- Wilkinson, R. J., Rohlwink, U., Misra, U. K., van Crevel, R., Mai, N. T. H., Dooley, K. E., et al. (2017) Tuberculous meningitis. Nat Rev Neurol 13: 581-598. PMID 28884751
- Davis, A. G., Rohlwink, U. K., Proust, A., Figaji, A. A. and Wilkinson, R. J. (2019). The pathogenesis of tuberculous meningitis. J Leukoc Biol 105: 267-280. PMCID PMC6355360
- Matthews, K., Deffur, A., Ntsekhe, M., Syed, F., Russell, J. B., Tibazarwa, K., . . . Wilkinson, K. A. (2015) A Compartmentalized Profibrotic Immune Response Characterizes Pericardial Tuberculosis, Irrespective of HIV-1 Infection. Am J Respir Crit Care Med 192: 1518-1521. PMCID PMC4731721
- Rohlwink, U. K., Figaji, A., Wilkinson, K. A., Horswell, S., Sesay, A. K., Deffur, A., et al. (2019) Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity. Nat Commun 10: 3767. PMCID PMC6704154