Metabolic regulation of Natural Killer cells' anti-viral responses
Metabolism, Biochemistry and Genetics of Microorganisms
Virology
Final Report Abstract
Natural killer (NK) cells are innate immune cells and important early responders against viral infections and cancers. Changes in metabolism are crucial to fuel NK cell responses and altered metabolism is linked to NK cell dysfunction in obesity and cancer. It has been reported previously that a large neutral amino acid transporter, Slc7a5, is essential for the metabolic reprogramming of T cells and cytokine-activated NK cells. In addition to Slc7a5, the mineral iron has been described to be very important for immune functions and host defence as well as for essential cellular activities such as mitochondrial function including oxidative phosphorylation and enzymatic reactions that need iron as a cofactor. However, nothing is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Using the Friend retrovirus mouse model I show that following infection NK cells increase their fatty acid uptake as well as nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. I found that specific deletion of the amino acid transporter Slc7a5 in NK cells had discrete effects on NK cells, including reduced cytotoxicity. Furthermore, serum iron deficiency decreased the NK cell metabolic reprogramming and profoundly impaired antiviral functions leading to increased viral loads. The metabolic characteristics of memory-like NK cells differ from NK cells from the acute retrovirus infection. This study shows the requirement of nutrients and metabolism for the antiviral activity of NK cells and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2. Our results will be relevant for drug developments targeting the NK cell metabolism to enhance their cytotoxic capacity against viruses and cancer cells.
Publications
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2019 Natural Killer Cells Integrate Signals Received from Tumour Interactions and IL2 to Induce Robust and Prolonged Anti-Tumour and Metabolic Responses. Immunometabolism, Sep.
Kedia-Mehta N, Choi C, McCrudden A, Littwitz-Salomon E, Fox PG, Gardiner CM, Finlay DK
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2021 Metabolic requirements of NK cells during the acute response against retroviral infection. Nat. Commun., 12, Article number: 5376
Elisabeth Littwitz-Salomon, Diana Moreira, Joe N. Frost, Chloe Choi, Kevin T. Liou, David K. Ahern, Simon O’Shaughnessy, Bernd Wagner, Christine A. Biron, Hal Drakesmith, Ulf Dittmer, David K. Finlay
