Dr. Orvedahl cares for children with infectious diseases and associated complications. He has a particular interest in immunocompromised hosts, inborn errors of immunity, emerging viral infections, and immune dysregulation disorders including sepsis.
Dr. Orvedahl's research interests are in cell-intrinsic immunity and the role of cytosolic quality control pathways in the regulation of inflammatory responses. Current studies aim to identify the basic mechanisms underpinning cell survival during macrophage responses to the cytokines, interferon-gamma and tumor necrosis factor, and the physiological significance of these factors in models of fatal systemic inflammation, such as septic shock. Using genome-wide CRISPR/Cas9 screening approaches, we found that autophagy genes were critical to protect myeloid cells against cytokine induced cell death. Mice with myeloid cell autophagy gene deficiency also succumbed more readily to TNF-induced shock. We are using multi-omics approaches to dissect the mechanisms by which autophagy genes protect against cytokine-induced cell death in vitro and in vivo. Further, we are characterizing additional identified genes that had not been previously linked to cell death or sepsis, which implicate immunometabolism as a central regulator of these processes. Additional studies seek to understand the contributions of cytosolic nucleic acid metabolism and endogenous retroviruses during viral infections and interferon responses.