My long-term research interest centers on understanding the genetic determinants of human immunity. Though it has been clear since the early 20th century that pathogen exposure is necessary but not sufficient to cause infectious disease, the host determinants of immunity that underlie this clinical heterogeneity are poorly understood. Similarly, little is known about the specific genetic lesions and molecular mechanisms of most autoimmune and inflammatory diseases, despite ample evidence that genetic factors contribute to these conditions. I am bringing my accumulated expertise in genetics, molecular biology, and immunology to bear on these fundamental questions. My early work focused on genetic determinants of type 1 diabetes in a mouse model, and interactions between the host immune system and environmental modifiers, especially the gut microbiome, in disease pathogenesis (Markle et al., Science 2013). Next, I worked to discover new host genetic determinants of infectious disease susceptibility by studying children with rare and life-threatening mycobacterial infections. This work integrated genome-wide sequencing data with mechanistic studies of candidate gene mutations to discover how these mutation impact molecular, cellular, and immune system functions (Okada and Markle et al., Science 2015; Martinez-Barricarte and Markle et al, Science Immunology 2018). As an independent investigator, my work now focuses on leveraging my skills in human genetics and immunology to tackle the causes and mechanisms of genetically mediated immunological diseases, especially severe auto-inflammatory and autoimmune diseases affecting children. As an independent PI, I have established a unique cohort of patients with rare inflammatory diseases and used Whole Exome Sequencing (WES) to identify novel rare genetic lesions. Work in my lab is now focused on establishing the biological impact of these variants in order to both clarify their significance to human health and to better understand fundamental mechanisms of immunity.