VALIDATE Winer Seminar: Targeting Immunometabolism in Host Defence Against Mycobacterium Tuberculosis

https://www.youtube.com/embed/rnWgmGNGk44

About the Seminar: A talk followed by an open forum/Q&A

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), remains a major global health problem accounting for millions of deaths annually. Although our immune system is endowed with immune cells specialized in controlling bacterial growth (e.g., M1 macrophages), M.tb has developed different strategies to impair the functionality of these cells. Moreover, M.tb can also disrupt the adaptive immune response by impairing the activation of naïve T cells induced by dendritic cells (DCs). Several studies have recently revealed that the cellular metabolism may determine the effector functions of immune cells. For instance, upon bacterial infection, M1 macrophages switch their metabolism toward aerobic glycolysis, which is coordinated by the Hypoxia-Inducible Factor 1-alpha (HIF-1α) and leads to faster production of ATP as well as metabolic intermediates that support the production of proinflammatory cytokines and antimicrobial peptides. On the contrary, how the metabolism influences human dendritic cell biology is much less explored.

In this seminar, Dr Luciana Balboa discussed how her team focused on unravelling the immunometabolic pathways that regulates leucocytes’ functions and their impact on the control of TB. To study the impact of TB-associated microenvironment on the functionality of M1 macrophages, they used the acellular fraction of pleural effusions from TB patients (TB-PE). Interestingly, they found that M1 macrophages exposed to TB-PE displayed a lower expression of HIF-1α and a reduced glycolytic activity, impairing the control of the bacterial growth.

Dr Balboa's team have also shown that the pharmacological stabilization of HIF-1α expression restores glycolysis and pro-inflammatory properties resulting in a better control of the M.tb burden. Importantly, the down modulation of HIF-1α was driven by omega-3-derived lipids mediators. Regarding to the metabolic regulation of DCs function, the team showed that M.tb triggers glycolysis in DCs, which promotes their migration into lymph nodes in a HIF-1α-dependent manner. Interestingly, DCs from TB patients displayed a reduced glycolytic capacity and are unable to migrate upon M.tb stimulation, while HIF-1α stabilization restores these properties. These findings may explain the delayed accumulation of activated CD4+ T cells in the lung reported in TB. In summary, a further understanding of the metabolism of immune cells and their specific functions during TB pathogenesis can lead to the development of immunotherapies capable of promoting M.tb clearance. 

About the Speaker

DrLuciana Balboa is an Associate Researcher and the Institute of Experimental Medicine (IMEX) - CONICET in Argentina.

 

Luciana's research interest involves deciphering molecular aspects of the human immune response to Mycobacterium tuberculosis, the etiological for tuberculosis disease, which controls or contributes to the development and for the chronicity of the infection.  Her team at CONICET focuses on the biology of antigen presenting cells: monocytes, dendritic cells and macrophages, specifically on the modulation of their activation programs by the pathogen. 

 

 

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