The natural killer cell response against mouse cytomegalovirus infection

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Project Summary Natural killer (NK) cells are cytotoxic innate lymphocytes that protect the host against viruses. Newborns and immunocompromised individuals lacking NK cells and are extremely susceptible to viral infection, including herpesviruses such as human cytomegalovirus (HCMV). HCMV can be accurately modeled using mouse cytomegalovirus (MCMV) infection in mice, which represents a robust system for investigating antiviral NK cell responses. From the previous R01 funding period, my lab has discovered new cellular and molecular mechanisms underlying NK cell responses against MCMV. This current R01 renewal seeks to understand the transcriptomic, epigenetic, and metabolic control of the antiviral NK cell response, with studies centering around a novel role for the transcription factor IRF4. In exciting preliminary data, we find IRF4 is rapidly induced in NK cells during MCMV infection and plays a critical role in their effector response. For the proposed experiments, we have generated new transgenic mice with conditional Irf4 ablation. In Aim 1, we will determine how IRF4 is transcriptionally and epigenetically regulated in activated NK cells, and test how IRF4-deficiency impacts the function of NK cells against MCMV infection. Aim 2 will identify novel gene targets and binding partners of IRF4 in NK cells by integrating transcriptomic, epigenetic, and proteomic approaches. In Aim 3, we will investigate whether IRF4 drives antiviral NK cell responses by controlling overall metabolism and mitochondrial health. Altogether, the studies in this R01 renewal will advance our understanding of the molecular basis by which these powerful effector cells can mediate protection against pathogen invasion, and establish innovative clinical paradigms for how NK cells may be harnessed for therapeutic strategies against infectious disease.