Associate Research Scientist
Dr. Sefik is an assistant professor in the Department of Immunobiology at Yale University School of Medicine. She received her B.S. from Yale College and her PhD from Harvard University.
For her doctoral dissertation, she worked with Dr. Christophe Benoist and Dr. Diane Mathis and collaborated with Dr. Dennis Kasper at Harvard University. Her research supported by the Boehringer Ingelheim Fonds PhD Fellowship explored host-microbe interactions from a tolerogenic perspective, focusing on maintaining tissue-level homeostasis. To investigate how microbiota aid the maturation of the host immune system and how their dys regulation can drive inflammatory intestinal disease, she conducted apioneering large-scale screen which involved colonizing germ-free mice with 63individual bacterial strains from the human gastrointestinal tract. She showed that various microbial species shape the host immune system through cytokine responses, alterations in immune cell composition, and induction of stromal and metabolic genes. Taxonomically unrelated bacteria elicited similar immune phenotypes and metabolic effects, while related microbes sometimes hadopposite consequences, with no uniform effects shared by all microbes. Through focused analysis, she uncovered microbiota-dependent transcriptional control mechanisms affecting Rorγ expressing Foxp3+ regulatory T cells and IL17-producing T cells.Her findings challenged earlier research on Rorγ and Foxp3, suggesting a collaborative rather than competitive transcriptional regulation, facilitated by microbiota.
For her post-doctoral training, Dr. Sefik joined the laboratory of Dr. Richard Flavell at Yale University as an HHMI-Damon Runyon postdoctoral fellow. In the Flavell laboratory, she has devoted her time and efforts to using MISTRG6 humanized mouse platform to model human-microbe interactions during chronic infections and inflammatory diseases.She modeled severe COVID-19 in humanized mice, which exhibited persistent lung pathology similar to that in human patients. Mechanistic studies of this model revealed a cascade of events highlighting the unique contributions of human immune cells, particularly macrophages, to lung pathology. She showed that the inflammatory cascade initiates with infection of human lung macrophages with SARS-CoV-2. SARS-CoV-2 replicates in these macrophages generating replicative intermediates which activate an inflammatory program which involves activation of inflammasomes, production and release of inflammatory cytokines/chemokines.More importantly, targeting inflammasome mediated hyper inflammation prevented immunopathology associated with chronic SARS-CoV-2 infection in vivo.Taken together, this unique model allowed for the first time the study of severe disease due to infection with SARS-CoV-2 in real time and provided alive view into the effector mechanisms of disease morbidity.
Her work emphasizes the delicate balance maintained by host-microbe interactions; a balance critical for immune system development yet vulnerable to chronic inflammatory stimuli. Dr. Sefik is further reengineering humanized mice to test the roles of IFNG, IL-15, and MHC in the development of celiac disease using the MISTRG6 system. This system provides the micro environment necessary for developing an immune system susceptible to celiac disease. Her goal is to continue elucidating complex biological mechanisms, contributing to collective knowledge and potential therapeutic advancements.