Gates Grand Challenge - 2013-2015

GC6-2013: Systems biology to identify signatures of risk of TB disease in Gates Global Challenge 6-74 cohorts


Sponsor - The Bill and Melinda Gates Foundation
Principal Investigator - Willem Hanekom, University of Cape Town

Type of Study Observational
Design Nested case-control cohort
Project Site The Gambia, South Africa, Uganda, Ethiopia
Sample Size 100 incident TB cases and 400 matched controls
Population HIV negative adult household contacts with and without incident TB disease
Study Period 2013-2015
Interactions Incident TB cases and controls from the Uganda/TBRU component of GC6 will contribute samples to the GC6-2013 study. The unified GC6 database will be used for data analysis in GC6-2013

Goal of Study:

The goal of the study is to determine signatures of risk of tuberculosis (TB) disease, to ultimately be used for targeted therapy of persons subclinically infected with Mycobacterium tuberculosis (Mtb), and for targeted enrollment of participants into efficacy trials of new TB vaccines.

Objectives of Study:

  1. Addresses central biobanking and databanking. Blood products from all TB cases and 4 matched controls will be shipped from the African sites to the University of Cape for central biobanking.
  2. To determine and validate whole blood gene expression signatures of risk of TB disease. Unbiased examination of global gene expression patterns has proven an optimal approach for delineating correlates of risk of cancer and infectious disease. Gene expression signatures in whole blood of TB cases and of 2 matched controls will be determined by RNA Sequencing (RNA-Seq).
  3. to determine and validate plasma microRNA signatures of risk of TB disease. Multiple cancer studies have shown that plasma microRNA signatures are excellent predictors of disease. MicroRNA species will be assessed by microarray, and analysis completed by the Seattle Biomed group.
  4. addresses integration of gene expression, microRNA and metabolomics results into a meta-signature of risk of TB disease. As suggested in the literature, we propose that this combination will enhance performance of signatures. Metabolomics results from the same cohorts will be shared by our collaborators from Max Planck Institute for Infection Biology who are submitting a separate but aligned grant application the BMGF. Our analysis will be completed in collaboration with the Seattle Biomed group.
  5. addresses ongoing coordination and complementary activities of the original GC6-74 consortium, now to be called \x93GC6-2013\x94. The 7 African and 7 European/US sites initially involved will continue to work together.

Published Papers:

Weiner J 3rd, Maertzdorf J, Sutherland JS, Duffy FJ, Thompson E, Suliman S, McEwen G, Thiel B, Parida SK, Zyla J, Hanekom WA, Mohney RP, Boom WH, Mayanja-Kizza H, Howe R, Dockrell HM, Ottenhoff THM, Scriba TJ, Zak DE, Walzl G, Kaufmann SHE; GC6-74 consortium. Metabolite changes in blood predict the onset of tuberculosis. Nat Commun. 2018 Dec 6;9(1):5208. doi:10.1038/s41467-018-07635-7. PMID: 30523338; PMCID: PMC6283869.

Zak DE, Penn-Nicholson A, Scriba TJ, Thompson E, Suliman S, Amon LM, Mahomed H, Erasmus M, Whatney W, Hussey GD, Abrahams D, Kafaar F, Hawkridge T, Verver S, Hughes EJ, Ota M, Sutherland J, Howe R, Dockrell HM, Boom WH, Thiel B, Ottenhoff THM, Mayanja-Kizza H, Crampin AC, Downing K, Hatherill M, Valvo J, Shankar S, Parida SK, Kaufmann SHE, Walzl G, Aderem A, Hanekom WA; ACS and GC6-74 cohort study groups. A blood RNA signature for tuberculosis disease risk: a prospective cohort study. Lancet. 2016 Jun 4;387(10035):2312-2322. doi: 10.1016/S0140-6736(15)01316-1. Epub 2016 Mar 24. PMID: 27017310; PMCID: PMC5392204.

Suliman S, Thompson EG, Sutherland J, Weiner J 3rd, Ota MOC, Shankar S, Penn-Nicholson A, Thiel B, Erasmus M, Maertzdorf J, Duffy FJ, Hill PC, Hughes EJ, Stanley K, Downing K, Fisher ML, Valvo J, Parida SK, van der Spuy G, Tromp G, Adetifa IMO, Donkor S, Howe R, Mayanja-Kizza H, Boom WH, Dockrell HM, Ottenhoff THM, Hatherill M, Aderem A, Hanekom WA, Scriba TJ, Kaufmann SHE, Zak DE, Walzl G; GC6-74 cohort study team, The ACS cohort study team. Four-Gene Pan-African Blood Signature Predicts Progression to Tuberculosis. Am J Respir Crit Care Med. 2018 May 1;197(9):1198-1208. doi: 10.1164/rccm.201711-2340OC. PMID: 29624071; PMCID: PMC6019933.

Penn-Nicholson A, Hraha T, Thompson EG, Sterling D, Mbandi SK, Wall KM, Fisher M, Suliman S, Shankar S, Hanekom WA, Janjic N, Hatherill M, Kaufmann SHE, Sutherland J, Walzl G, De Groote MA, Ochsner U, Zak DE, Scriba TJ; ACS and GC6–74 cohort study groups. Discovery and validation of a prognostic proteomic signature for tuberculosis progression: A prospective cohort study. PLoS Med. 2019 Apr 16;16(4):e1002781. doi: 10.1371/journal.pmed.1002781. Erratum in: PLoS Med. 2019 Jul 18;16(7):e1002880. PMID: 30990820; PMCID: PMC6467365.

Duffy FJ, Weiner J 3rd, Hansen S, Tabb DL, Suliman S, Thompson E, Maertzdorf J, Shankar S, Tromp G, Parida S, Dover D, Axthelm MK, Sutherland JS, Dockrell HM, Ottenhoff THM, Scriba TJ, Picker LJ, Walzl G, Kaufmann SHE, Zak DE; GC6-74 Consortium. Immunometabolic Signatures Predict Risk of Progression to Active Tuberculosis and Disease Outcome. Front Immunol. 2019 Mar 22;10:527. doi: 10.3389/fimmu.2019.00527. PMID: 30967866; PMCID: PMC6440524.

Duffy FJ, Thompson E, Downing K, Suliman S, Mayanja-Kizza H, Boom WH, Thiel B, Weiner Iii J, Kaufmann SHE, Dover D, Tabb DL, Dockrell HM, Ottenhoff THM, Tromp G, Scriba TJ, Zak DE, Walzl G; GC6-74 Consortium. A Serum Circulating miRNA Signature for Short-Term Risk of Progression to Active Tuberculosis Among Household Contacts. Front Immunol. 2018 Apr 13;9:661. doi: 10.3389/fimmu.2018.00661. PMID: 29706954; PMCID: PMC5908968.

Penn-Nicholson A, Mbandi SK, Thompson E, Mendelsohn SC, Suliman S, Chegou NN, Malherbe ST, Darboe F, Erasmus M, Hanekom WA, Bilek N, Fisher M, Kaufmann SHE, Winter J, Murphy M, Wood R, Morrow C, Van Rhijn I, Moody B, Murray M, Andrade BB, Sterling TR, Sutherland J, Naidoo K, Padayatchi N, Walzl G, Hatherill M, Zak D, Scriba TJ; Adolescent Cohort Study team; GC6-74 Consortium; SATVI Clinical and Laboratory Team; ScreenTB Consortium; AE-TBC Consortium; RePORT Brazil Team; Peruvian Household Contacts Cohort Team; CAPRISA IMPRESS team. RISK6, a 6-gene transcriptomic signature of TB disease risk, diagnosis and treatment response. Sci Rep. 2020 May 25;10(1):8629. doi: 10.1038/s41598-020-65043-8. PMID: 32451443; PMCID: PMC7248089.