Metabolic Regulation of Antiviral Immune Responses in Macrophages

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Ahmed, Duale Abdinasir




It is increasingly clear that there is an intimate link between cellular metabolism and macrophage function. Several studies in the last decade have established that alterations in cellular metabolism both drive and regulate macrophage function, allowing them to mount a functional immune response against viruses by promoting viral resistance, antigen presentation and the production of inflammatory and antiviral cytokines. As a result, metabolic reprogramming of macrophages allows them to adapt the spectrum and magnitude of their response depending on the microenvironment, stimuli, and stage of infection. Yet, it is unclear how different viral ligands alter metabolism to induce specific immune responses and if specific metabolic components can act as rheostats to amplify these responses based on the microenvironment. The central hypothesis of my thesis is that cellular metabolism is crucial to regulating antiviral immune responses. Specifically, we hypothesized that differential mitochondrial reprogramming allows macrophages to modulate ligand-specific effector response. Moreover, mitochondria further function as rheostats, fine-tuning immune responses based on the microenvironment. First, we used publicly available microarray datasets to develop a metabolic signature associated with early IFN-a responses in mouse BMMs and human MDMs. >500 metabolic genes related to cellular bioenergetics, cellular redox status, amino acid, and lipid metabolism were identified. Next, we show that TLR3 and TLR4 engagement in mouse BMMs drive differential ETC remodeling, linked to differential mitochondrial activity and subsequent ROS generation, to support ligand-specific inflammatory and antiviral profiles. Furthermore, when exploring different types of TLR3 engagement, based on ligand length, they trigger distinct inflammatory and antiviral programs, due to unique regulatory mechanisms surrounding HIF-1α function as well as altered ETC architecture and function, respectively. The aim of this thesis to gain a more thorough understanding of the critical role of cellular metabolism in regulating macrophage antiviral responses. A systematic understanding of these critical processes to regulating effector function under non-diseased conditions can provide critical insights into the dysregulation of metabolic processes during chronic viral infections. The data presented may be the foundation towards the development of new antiviral therapeutics by targeting selective mitochondrial components.


Biology - Molecular




Carleton University

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