New mechanism to balance the production of type I interferon and proinflammatory cytokines in response to viral infections Authors: Hector Huerga Encabo 1; Laia Traveset 1; Jordi Argilaguet 2; Ana Angulo 3; Estanislao Nistal-Villán 4; Rahul Jaiswal 5; Carlos R. Escalante 5; Christos Gekas 6; Andreas Meyerhans 2; Jose Aramburu 1; Cristina López-Rodríguez 1 1- Immunology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain 2- Infection Biology Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain 3- Immunology Unit, Department of Biomedical Sciences, Medical School, University of Barcelona, Barcelona, Spain 4- Microbiology Section, Departamento de Ciencias, Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU San Pablo, CEU Universities, Madrid, Spain 5- Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 6- Program in Cancer Research, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona, Spain Abstract body: Type I interferon (IFN-I) and proinflammatory cytokine production are the two main transcriptional responses activated upon viral infection. Activation of both antipathogen responses must be fine-tuned in order to fight the infection without causing the development of immunopathologies. The identification of safeguard mechanisms to ensure the correct balance between IFN-I and proinflammatory responses is key to solve the pathology of certain viruses like SARS-CoV-2. We want to present here our recent findings that describe how NFAT5, a transcription factor known to induce inflammatory responses, is also a repressor of IFN-I activity. NFAT5 occupies a distinct functional niche in the control of antipathogen responses by attenuating IFN-I gene induction while enhancing expression of proinflammatory mediators. NFAT5 reaches this unique duality by, in the one hand, opposing the master transcription factor of IFN-I expression (IRF3) while, in the other hand, cooperating with NF-KB in the upregulation of proinflammatory cytokines. The ability of NFAT5 to enhance or repress different antipathogen responses connects with the notion that the immune system has been tuned through evolution to safely balance effectiveness of antipathogen responses against their potential harmful effects to the organism. These findings can lead to a new strategy to target specific viral infections that produce an imbalance between type I interferon and inflammatory responses as the ones observed in COVID19.