Our research focuses on how the response of innate immune cells which engulf the tuberculosis bacteria, namely macrophages and neutrophils, is dysregulated by known TB risk factors and viral co-infection with HIV-1 and SARS-CoV-2.
We combine analysis of clinical cohort samples to identify novel pathways of pathogenesis in humans, with in vitro models of TB, HIV and SARS-CoV-2 infection to determine the molecular mechanism underlying disease risk.
This includes genetic and epigenetic changes in both the host and bacteria and how these impact the inflammatory response during infection. We are particularly interested in the regulation of various cell death pathways and the heterogeneity of cellular responses which we probe with single cell techniques and advanced live cell imaging.
We are currently screening small molecule inhibitors to target various pathways of interest which we hope to develop into new preventative treatments for TB. We also conduct biomarker discovery in at-risk populations using whole genome RNAseq and DNA methylation analysis to identify novel blood-based diagnostics for identifying individuals infected and at risk of disease.
Our goal is to develop a screening tool we can use to identify infected people who will have the greatest benefit from these new preventive therapies, based on their own individual risk profile.
Australia, Adelaide University, BSc (Hons)
Australia, QUT, PhD
2018 Claude Leon Merit Award for Early-Career Researchers
2016-2017 Africa Science Leadership Fellow, Future Africa
2014-2019 Elected Member, Global Young Academy
2014-2015 Sydney Brenner Fellow, Academy of Science of South Africa
2008-2012 UK Medical Research Council Career Development Fellow, National Institute of Medical Research
2021 Research Support Grant, Australian Respiratory Council
2020-2021 Innovation Builder Fund, University of Cape Town
2020-2022 Global Health Trials Development Grant co-investigator, MRC NIHR DfID Wellcome
2015-2021 Tuberculosis Research Unit (TBRU) Consortium co-investigator, National Institute of Health (NIH)
2014-2021 South African Medical Research Council-Strategic Health Innovation Partnership (SHIP) – Tuberculosis Vaccine Development, Bill and Melinda Gates Foundation
2021 Melbourne Tuberculosis Community, co-founding member
2021 Immunology Group of Victoria (IgV), committee member
2021 African BioImaging Consortium (ABIC), working group on education and awareness
2020-2021 Young Indigenous Women in Science, Technology, Engineering and Mathematics Academy (YIWSA), Mentor
2015-2018 Executive Committee, Global Young Academy
Sheerin D, Abhimanyu A, Wang X, Johnson WE, Coussens AK. Immunopathogenic Overlap and Shared Therapeutic Targets for Covid-19 and Tuberculosis Predicted from Transcriptomic Meta-Analysis. Cell Rep Med. 2021; Sneak peak [https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3815987]
Waters R, Ndengane M, Abrahams MR, Diedrich CR, Wilkinson RJ, Coussens AK. The Mtb-HIV syndemic interaction: why treating M. tuberculosis infection may be crucial for HIV-1 eradication. Future Virol. 2020 Feb;15(2):101-125. doi: 10.2217/fvl-2019-0069. PMID: 32273900
Seddon JA, Chiang SS, Esmail H, Coussens AK. The Wonder Years: What Can Primary School Children Teach Us about Immunity to Mycobacterium tuberculosis? Front Immunol. 2018 Dec 3;9:2946 PMID: 30619306
Scriba T, Coussens AK, Fletcher H. Human Immunology of Tuberculosis. In Tuberculosis and the Tubercle Bacillus, ed. McShane H, Jacobs WR, Mizrahi V, Orme IM, ASM Press. 2017 Feb; doi: 10.1128/microbiolspec.TBTB2-0016-2016 ISBN: 9781555819552 PMID: 27740453
Coussens AK, Mason PH, Oni T. Socio-political prescriptions for LTBI are required to prevent re-activation of TB. Int J Infect Dis. 2017 May;58:115-116. PMID: 28161463
Esmail H, Lai RP, Lesosky M, Wilkinson KA, Graham CM, Coussens AK, Oni T, Warwick JM, Said-Hartley Q, Koegelenberg CF, Walzl G, Flynn JL, Young DB, Barry CE 3rd, O’Garra A, Wilkinson RJ. [18F]-fluorodeoxyglucose combined positron emission and computed tomographic characterisation of progressive HIV-associated tuberculosis. Nat Med. 2016 Oct;22(10):1090-1093. PMID: 27595321
Coussens AK, Wilkinson RJ, Martineau AR. Phenylbutyrate is bacteriostatic against Mycobacterium tuberculosis and regulates the macrophage response to infection, synergistically with 25-hydroxy-vitamin D3. PLOS Pathog. 2015 Jul 2;11(7):e1005007. PMID: 26133770
Coussens AK, Naude C, Goliath R, Chaplin G, Wilkinson RJ, Jablonski N. High-dose vitamin D3 reduces deficiency due to low UVB exposure and limits HIV replication in urban Southern Africans. Proc Natl Acad Sci U S A. 2015 Jun 30;112(26):8052-7. PMID: 26080414
Coussens AK, Wilkinson RJ, Nikolayevskyy V, Elkington PT, Hanifa Y, Islam K, Timms PM, Bothamley GH, Claxton AP, Packe GE, Darmalingam M, Davidson RN, Milburn HJ, Baker LV, Barker RD, Drobniewski FA, Mein CA, Bhaw-Rosun L, Nuamah R, Griffiths CJ, Martineau AR. Ethnic variation in inflammatory profile in tuberculosis. PLoS Pathog. 2013 Jul 4;9(7):e1003468. PMID: 23853590
Coussens AK, Wilkinson RJ, Hanifa Y, Nikolayevskyy V, Elkington PT, Islam K, Timms PM, Venton TR, Bothamley GH, Packe GE, Darmalingam M, Davidson RN, Milburn HJ, Baker LV, Barker RD, Mein CA, Bhaw-Rosun L, Nuamah R, Young DB, Drobniewski FA, Griffiths CJ, Martineau AR. Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment. Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15449-54. PMID: 22949664
Our analysis of whole blood transcriptional and epigenetic signatures from TB, HIV and COVID-19 patients has identified the role of multiple cell death pathways in disease risk.
We use in vitro infection models of primary human monocyte-derived macrophages and neutrophils to investigate the regulation of pyroptosis, apoptosis and extracellular trap formation during TB, HIV and SARS-CoV-2 infection.
We use a variety of molecular techniques, coupled with single-cell analysis by confocal microscopy, super-resolution microscopy, Totalseq, and spectral cytometry to identify the regulators of these pathways and their impact on inflammatory programmed cell death.
We are also testing numerous small molecule inhibitors to prevent death via these different pathways.
Team members: George Ashdown, Dylan Sheerin, William Vo, Kha Phan, Aisah Amelia Resti, Catherine Chen, Nashied Peton, in collaboration with the Pellegrini Lab, the Mueller Lab, and the Centre for Dynamic Imaging at WEHI, and the Poon Lab at La Trobe University.
Humans have co-evolved with Mycobacterium tuberculosis (Mtb), such that different strains can be found in different regions of the world, and these have been classified into ancient and modern lineages. Some ‘modern’ strains have been shown to be more inflammatory than others.
We are testing whether genetic variations in lipid metabolizing genes which would affect the bacterial cell wall, as well as secreted virulence factors under the control of various ESX systems, cause some strains to be hyper-inflammatory.
We are investigating the effect of strains with interesting genetic and inflammatory phenotypes on their ability to modulate the composition of phagocyte cell membranes as well as impact the replication co-infecting viruses (HIV-1 and SARS-CoV2). We also study whether the ability of different Mtb strains to cause greater tissue-destructive cell death associates with differences in pulmonary and extra pulmonary TB presentation.
Team members: George Ashdown, Dylan Sheerin, William Vo, Mthawelanga Ndengane, in collaboration with the Bahlo Lab at WEHI; Dr Ranaivomanana and Prof Rakootosamimanana at Institute Pasteur Madagascar.
Working in South Africa, we are currently conducting a household contact study of individuals who live with people with drug-resistant TB.
Using a highly sensitive screening technology called 18Fluorodeoxyglucose positron emission and computerised axial tomographic scanning (PET/CT), we are identifying household members with subclinical stages of infection. This is imaging on their lungs or lymph nodes which may indicate they have a current infection, whilst they have not yet developed symptoms of disease.
We are using whole genome RNAseq and DNA methylation analysis to develop and validate a biosignature for recent infection or re-infection that may be of great utility for clinical studies designed to test preventative therapies.
Team members: Dylan Sheerin, Nomfundo Sibiya, in collaboration with Professor Robert Wilkinson at the Wellcome Centre for Infectious Diseases in Africa, Associate Professor Hanif Esmail at University College London, Dr Abhimanyu at Baylor College of Medicine, Associate Professor Evan Johnson at Boston University, Professor Padmini Salgame at Rutgers University
We have shown that deficiency in serum vitamin D impairs the innate and adaptive immune responses to M. tuberculosis and HIV infection, increasing pathogen replication in infected cells and increasing a broad inflammatory response. In order to understand the mechanism of vitamin D regulation we are studying the seasonal changes in DNA methylation in blood cells and how vitamin D supplementation modifies these epigenetic changes.
With the idea that vitamin D can enhance innate immunity to prevent M.tb infection, we are collaborating on a Phase III Trial randomizing 5400 children to receive either weekly vitamin D or placebo, for three years. We are investigating whether and how vitamin D modifies the ability of innate and adaptive immune cells from these children to control bacterial replication.
Project resource: VidiKids is a Phase 3 trial of vitamin D to prevent TB in children, in Cape Town, South Africa.
Team members: Dylan Sheerin, William Vo, Robyn Waters, Nashied Peton, Mthawelanga Ndengane, in collaboration with the Wellcome Centre for Infectious Diseases in Africa, Adrian Martineau at Queen Mary University of London (Trial PI), and Dr Keren Middlekoop at Desmond Tutu HIV Centre (Site PI).