Metabolic regulation of Natural Killer cells' anti-viral responses

• Applicant: Professorin Dr. Elisabeth Littwitz-Salomon
• Subject Area: Immunology ; Metabolism, Biochemistry and Genetics of Microorganisms ; Virology
• Term: from 2019 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426320240

Infections with viral pathogens cause millions of deaths worldwide. Natural Killer (NK) cells are a type of immune cells that is important in our body’s response to viruses. They induce cytotoxic killing of virus-infected cells, but some viruses evade the NK cell-mediated immune pressure. NK cells are important for the immune response against herpesviruses and retroviruses although the NK cell response is distinct for each infection, e.g. in terms of clonal expansion and required cytokine milieu. Recent research highlights the importance of cellular metabolism, the processes that a cell uses to make energy and building materials, for optimal NK cell function. However, the role of these metabolic processes in NK cells during viral infections is unknown. I aim to identify new ways to improve the functions of NK cells through modulation of their metabolism towards generating new anti-viral therapies.This project will study the metabolic changes that occur in NK cells during viral infections using mice infected with retrovirus (Friend Virus, FV) and/or herpesvirus (mouse cytomegalovirus, MCMV). This will be achieved by measuring the uptake of fuels into NK cells, the activity of important metabolic regulators and determining the levels and fitness of the mitochondrial machinery with the use of flow cytometry, confocal microscopy and imaging flow cytometry during viral infections. The importance of metabolism for NK cells’ anti-viral responses and the development of memory-like NK cells will be investigated using novel and state-of-the-art transgenic mice to block these metabolic processes specifically in NK cells, and not in other cells and will be determined by cytotoxic parameters and viral loads in mice infected with viruses. In addition, this project will measure metabolic processes of human NK cells from retrovirus (HIV-1) -infected and herpesvirus (CMV) co-infected patients. In these patients, NK cells are not working properly, and I predict this is because they have failed metabolic processes. I anticipate that restoring normal metabolism in these cells will act to rescue the anti-viral functions of these NK cells. Ultimately, this project aims to reveal new strategies to enhance anti-viral responses through targeting the NK cell metabolism. This pioneering new approach has the potential to enable new NK-cell based immunotherapies for the treatment of virus-infected individuals worldwide.

• DFG Programme: Research Fellowships
• International Connection: Ireland
• Host: Professor Dr. David K. Finlay