Human immune dysregulation in viral defense

Persistent, recurrent, life-threatening or fatal viral infections in neonates, infants and toddlers with inborn errors of immunity sadly exemplify the importance of certain gene products in protecting the body from these infectious agents. Some of these inborn diseases are characterized by immune dysregulation as well as susceptibility to (or poor control of) viral infections. We hypothesize that pediatric patients with severe inflammatory complications temporally associated with viral infections bear monogenic inborn errors of immunity. We aim to discover novel inborn errors of immunity underlying these multisystem inflammatory syndromes (MIS) triggered by viral infections and we aim to characterize the novel gene variants on a molecular, cellular and systemic level.Our preparatory work for the present application is strong, as we have established a workflow, which has already been successful in discovering and characterizing inborn errors of immunity with MIS and we have already included more than 50 pediatric patients in our study with very severe or lethal multisystem inflammatory complications temporally associated with viral infections. We have performed whole exome sequencing in all these study participants, including their parents and healthy siblings. This severe disease entity is rare. Nevertheless, we expect to include another 15 patients in our study, during the course of the herein proposed project, thanks to international collaborations and thanks to our role as a national reference laboratory for these diseases. Importantly, we have already discovered very rare, damaging variants in genes hitherto not known to be implicated in immune regulation which shall be further characterized during the course of the present project.To discover novel inborn errors of immunity, we are applying genome-wide association approaches. Once we have shown the deleteriousness of the mutant allele(s) and the link between the genotype and the cell phenotype, we aim to investigate the mechanism of inflammation by studying (a) patients' serum and cells, (b) cells that recapitulate the patient's genotype and/or (c) murine models that recapitulate the patient's genotype and phenotype. We will determine (i) whether these candidate genes are linked to previously reported MIS-disease-causing genes, and (ii) how they operate in either of the two cell types that are crucial for immune regulation in the context of a viral infection, i.e. cytotoxic lymphocytes and/or target cells (antigen-presenting cells and/or infected cells). On the cellular level, our hypothesis is that MIS is either caused by a lymphocyte-intrinsic defect and/or defect of the antigen-presenting or infected cell, since the latter has an intrinsic or adopted increase in killing resistance or a dysregulation in innate defense mechanisms. Our in-depth, experiment-based, mechanistic studies shall prove the relevance of the gene products as important immune system's components for human immune regulation during viral defense. This will pave the way for personalized therapies in life-threatening severe inflammatory conditions according to causally tested links between the molecular underpinnings and the cellular behaviors characterizing a disease. Our study shall result in breakthrough discoveries in the field of multisystem inflammatory complications triggered by viral infections. Furthermore, the results will also shed light on the pathogenesis of more common inflammatory complications triggered by viral infections, such as in the setting of COVID-19, which contribute to the global burden of disease and death..