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eSymposia | Tuberculosis: Science Aimed at Ending the Epidemic


Monocyte fatty acid transcriptional programs and AMPK polymorphisms associate with resistance to TST/IGRA conversion


Dec 2, 2020 12:00am ‐ Dec 2, 2020 12:00am

Description

Monocyte fatty acid transcriptional programs and AMPK polymorphisms associate with resistance to TST/IGRA conversion J.D. Simmons1*, P.T. Van2, C.M. Stein3,4, V. Chihota5,6, T. Ntshiqa6, P. Maenetje6, G.J. Peterson1, P. Benchek3, K. Velen6, K.L. Fielding5.7, A.D. Grant5,7,8, A.D. Graustein1, F.K. Nguyen1, C. Seshadri1, R. Gottardo2, H. Mayanja-Kizza9, R.S. Wallis6, G. Churchyard6, W.H. Boom4 and T.R. Hawn1 1) TB Research & Training Center, Department o­­­­­f Medicine, University of Washington, Seattle, WA, USA. 2) Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 3) Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. 4) Department of Medicine, Case Western Reserve University, Cleveland, OH, USA. 5) School of Public Health, University of Witwatersrand, Johannesburg, South Africa. 6) The Aurum Institute, Parktown, South Africa. 7) TB Centre, London School of Hygiene & Tropical Medicine, London, United Kingdom. 8) Africa Health Research Institute, School of Nursing and Public Health, University of KwaZulu-Natal, Durban, South Africa 9) Department of Medicine, School of Medicine, Makerere University, Kampala, Uganda. After extensive exposure to Mycobacterium tuberculosis (Mtb), most individuals acquire latent Mtb infection (LTBI) defined by a positive tuberculin skin test (TST) or interferon-g release assay (IGRA). To identify mechanisms of resistance to Mtb infection, we compared transcriptional profiles of monocytes isolated from highly exposed contacts who resist TST/IGRA conversion (resisters, RSTRs) and controls with LTBI using RNAseq. Gene sets related to central carbon metabolism and the macrophage transcriptional response to free fatty acids (FFAs) strongly enriched across two independent RSTR cohorts suggesting that RSTR and LTBI monocytes have distinct metabolic or activation states. To explore whether FFAs modulate intracellular Mtb replication, we treated healthy donor monocyte-derived macrophages (MDMs) with FFA following Mtb infection and found that palmitic acid (PA) enhanced intracellular growth whereas oleic acid (OA) had no effect. Secretion of TNFa, IL6 and IL1b in Mtb-infected MDMs was inhibited by PA and not OA, which suggests that PA inhibits host-protective pro-inflammatory responses. By limiting the activation of adenosine monophosphate-activated protein kinase (AMPK), PA was previously shown to inhibit autophagy and modulate the pro-inflammatory response. We found that Mtb growth restriction in PA-treated macrophages was restored by co-treatment with an AMPK activator. As a central regulator of carbon metabolism, we explored whether polymorphisms in AMPK associate with RSTR (n=74) or LTBI (n=189) phenotypes. Seven SNPs in the AMPK subunit gene PRKAG2 associated with RSTR status (OR 2.3 – 3.2, p

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