Trained immunity and childhood risk factors of cardiovascular and metabolic disease
Inflammatory Origins, Murdoch Children’s Research Institute, Royal Children’s Hospital, and Department of Paediatrics, University of Melbourne, Parkville, Australia
We apply a range of epidemiological, clinical and immunological techniques to a unique collection of longitudinal human cohorts and clinical trials in order to understand the relationship between environmental exposures and molecular mediators in modifying the risk of cardiovascular and metabolic risk and disease. We have several exposures of interest, including exposures in pregnancy, childhood infections and antibiotic use, childhood obesity, chronic inflammatory conditions, as well as Kawasaki disease, cystic fibrosis and dental health. Two projects in which we study trained immunity specifically are detailed below.
Trained immunity in childhood obesity
The prevalence of obesity in young children has increased markedly in the last 20 years and childhood obesity is robustly associated with an increased risk for metabolic and cardiovascular disease in adulthood. We are currently investigating the inflammatory phenotype of human monocytes and NK-cells as well as performing cardiovascular measurements in the COBRA cohort, a large cohort of obese children. In collaboration with the group of Professor Richard Saffery, we will study not only phenotypical but also transcriptomic and epigenetic changes in PBMCs from these children in comparison with healthy children to understand the mechanisms of obesity, inflammation and the subsequent cardiovascular risk.
Trained immunity in childhood infections
Inflammation is central to atherosclerosis pathogenesis and infections are a major inflammatory stimulus, especially in children. There are considerable epidemiological, clinical and animal data that infections increase CVD risk and events. Clinical translation of these observations into effective prevention and interventions requires an understanding of which infections are most deleterious and the biological mechanisms by which infections increase CVD risk.
In two major human cohort studies, we aim to investigate how common, well-characterised inflammation/infections in pregnancy and childhood impact on changes in the immune phenotype with subsequent increased CVD. (1) In the VASCFIND (VAascular Changes Following Infectious Diseases) study, the macro- and microvasculature will be analysed for preclinical vascular phenotypes at 2 weeks, 2 months and 6 months following well-defined severe infection presenting to hospital. We will also study the phenotype of monocytes and NK-cells and study whether severe infections induce a TRIM phenotype associated with adverse CV phenotypes. (2) In collaboration with A/Prof Jeff Craig and Prof Richard Saffery, we also study samples from the PETS (twin) cohort and PIES (preterm) cohort, two longitudinal cohorts studying inflammation during pregnancy and how this could contribute to the early development of atherosclerosis by activating early immune responses.
David Burgner, PhD, Professor and Group Leader
- Jessica Miller, PhD, Postdoctoral Fellow
- Mihiri Silva, PhD, Postdoctoral Fellow
- Siroon Bekkering, PhD, Postdoctoral Fellow
- Christoph Saner, Paediatrician and PhD student
- Tom Saunders, Paediatrician and PhD student
- Cerys Chau, Honours Student
- Meg Kaegi, Research Assistant
- Peter Vuillermin, Professor of Paediatrics and Researcher
- Nguyen MT, Vryer R, Ranganathan S, Lycett K, Grobler A, Dwyer T, Juonala M, Saffery R, Burgner D, Wake M. Telomere Length and Vascular Phenotypes in a Population-Based Cohort of Children and Midlife Adults. J Am Heart Assoc. 2019 Jun 4;8(11):e012707
- Bekkering S, Limawan AP, Nguyen MU, Widiasmoko LK, Lu H, Pepe S, Cheung MM, Menheniott TR, Wallace MJ, Burgner DP, Moss TJ. Postnatal inflammation following intrauterine inflammation exacerbates the development of atherosclerosis in ApoE-/- mice. Clin Sci (Lond). 2019 May 30;133(10):1185-1196.
- Saner C, Harcourt BE, Pandey A, Ellul S, McCallum Z, Kao KT, Twindyakirana C, Pons A, Alexander EJ, Saffery R, Burgner DP, Juonala M, Sabin MA. Sex and puberty-related differences in metabolomic profiles associated with adiposity measures in youth with obesity. Metabolomics. 2019 May 3;15(5):75.
- Collier F, Ellul S, Juonala M, Ponsonby AL, Vuillermin P, Saffery R, Burgner D; Barwon Infant Study Investigator Group. Glycoprotein acetyls (GlycA) at 12 months are associated with high-sensitivity C-reactive protein and early life inflammatory immune measures. Pediatr Res. 2019 Apr;85(5):584-585.
- Miller JE, Wu C, Pedersen LH, de Klerk N, Olsen J, Burgner D. Maternal antibiotic exposure during pregnancy and hospitalization with infection in offspring: authors' reply. Int J Epidemiol. 2018 Oct 1;47(5):1724
- de Jong E, Hancock DG, Wells C, Richmond P, Simmer K, Burgner D, Strunk T, Currie AJ. Exposure to chorioamnionitis alters the monocyte transcriptional response to the neonatal pathogen Staphylococcus epidermidis. Immunol Cell Biol. 2018 Sep;96(8):792-804.
- Chen KYH, Messina N, Germano S, Bonnici R, Freyne B, Cheung M, Goldsmith G, Kollmann TR, Levin M, Burgner D, Curtis N. Innate immune responses following Kawasaki disease and toxic shock syndrome. PLoS One. 2018 Feb 15;13(2):e0191830.
- Leentjens J, Bekkering S, Joosten LAB, Netea MG, Burgner DP, Riksen NP. Trained Innate Immunity as a Novel Mechanism Linking Infection and the Development of Atherosclerosis. Circ Res. 2018 Mar 2;122(5):664-669.
- Liu RS, Mensah FK, Carlin J, Edwards B, Ranganathan S, Cheung M, Dwyer T, Saffery R, Magnussen CG, Juonala M, Wake M, Burgner DP; Child Health CheckPoint Investigator Group. Socioeconomic Position Is Associated With Carotid Intima-Media Thickness in Mid-Childhood: The Longitudinal Study of Australian Children. J Am Heart Assoc. 2017 Aug 9;6(8).
- Rafferty AR, D'Arcy C, Cann L, Pyman J, Rogers P, Davis PG, Nowell C, Burgner D. Histological changes in the umbilical artery following severe chorioamnionitis and funisitis may be indicative of early atherosclerosis. Placenta. 2017 Feb;50:40-43.
- McCloskey K, Ponsonby AL, Collier F, Allen K, Tang MLK, Carlin JB, Saffery R, Skilton MR, Cheung M, Ranganathan S, Dwyer T, Burgner D, Vuillermin P The association between higher maternal pre-pregnancy body mass index and increased birth weight, adiposity and inflammation in the newborn. Pediatr Obes. 2018 Jan;13(1):46-53.
- McCloskey K, Vuillermin P, Carlin JB, Cheung M, Skilton MR, Tang ML, Allen K, Gilbert GL, Ranganathan S, Collier F, Dwyer T, Ponsonby AL, Burgner D; BIS Investigator Group. Perinatal microbial exposure may influence aortic intima-media thickness in early infancy. Int J Epidemiol. 2017 Feb 1;46(1):209-218.
- Miller JE, Hammond GC, Strunk T, Moore HC, Leonard H, Carter KW, Bhutta Z, Stanley F, de Klerk N, Burgner DP. Association of gestational age and growth measures at birth with infection-related admissions to hospital throughout childhood: a population-based, data-linkage study from Western Australia. Lancet Infect Dis. 2016 Aug;16(8):952-61.
- Qanitha A, de Mol BA, Pabittei DR, Mappangara I, van der Graaf Y, Dalmeijer GW, Burgner DP, Uiterwaal CS. Infections in early life and premature acute coronary syndrome: A case-control study. Eur J Prev Cardiol. 2016 Oct;23(15):1640-8.
- McCloskey K, Burgner D, Carlin JB, Skilton MR, Cheung M, Dwyer T, Vuillermin P, Ponsonby AL; BIS investigator group. Infant adiposity at birth and early postnatal weight gain predict increased aortic intima-media thickness at 6 weeks of age: a population-derived cohort study. Clin Sci (Lond). 2016 Mar;130(6):443-50.
- Burgner DP, Sabin MA, Magnussen CG, Cheung M, Kähönen M, Lehtimäki T, Hutri-Kähönen N, Jokinen E, Laitinen T, Taittonen L, Tossavainen P, Dwyer T, Viikari JS, Raitakari OT, Juonala M. Infection-Related Hospitalization in Childhood and Adult Metabolic Outcomes. Pediatrics. 2015 Sep;136(3):e554-62
- Nguyen MU, Wallace MJ, Pepe S, Menheniott TR, Moss TJ, Burgner D. Perinatal inflammation: a common factor in the early origins of cardiovascular disease? Clin Sci (Lond). 2015 Oct 1;129(8):769-84.
- Burgner DP, Cooper MN, Moore HC, Stanley FJ, Thompson PL, de Klerk NH, Carter KW. Childhood hospitalisation with infection and cardiovascular disease in early-mid adulthood: a longitudinal population-based study. PLoS One. 2015 May 4;10(5):e0125342.
- NHMRC GTN1064629 (research fellowship)
- NHMRC GTN1065494 (project grant)
- NHMRC GTN1164212 (project grant)
- NHMRC GTN1149047 (project grant)
- NHMRC GTN1109355 (project grant)
- National Blood Authority, (Australia) (project grant)
- Royal Children’s Hospital Foundation
- DHB Trustees
- Jam and Jelly Foundation
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