Andrew Wang, MD/PhD, AB

Project Title: Understanding the Type I Interferon Response to Amanitin Poisoning

Acute poisonings are a significant cause of mortality and morbidity worldwide, yet modern treatment options are lacking and often limited to supportive care. A prototypical, increasingly common cause of poisoning is amanitin poisoning, which is caused by accidental ingestion of mushrooms of the amanitin genus. Amanitin poison causes fulminant liver and kidney injury, and current therapies are all limited to supportive care and organ transplantation. Whether our immune system, which protects us from pathogenic infection and wounding, also protects us from poisoning is an unknown fundamental question in biology. Additionally, the logic underlying how cells sense poisons, if tailored immune responses to different classes of poisons exist, and how these classes would be organized, remains undefined. To explore this, we selected 24 natural poisons mice in natural environments may accidentally ingest while foraging for food that are simultaneously relevant to human health and disease. These poisons included fungal-derived poisons like amanitin, plant-derived poisons like triptolide and colchicine, and soil bacteria-derived poisons like oligomycin. Mice were poisoned with a single dose based on exposures quantities described in humans, and RNA sequencing was performed on the liver, the major detoxifying organ, of poisoned mice four hours post-poisoning in order to capture the early transcriptional response. Principle components analyses revealed class-specific anti-poison immunologic transcriptional responses, which surprisingly were organized based on the cellular process known to be disrupted by the poison. We discovered a specific immune response against aminitin, a frequent cause of human poisoning leading to intensive care hospitalization, and other chemically distinct transcriptional inhibitors for which there are no therapies beyond supportive care and liver transplantation. Therapeutic manipulation of this immune response greatly reduced liver damage and mortality in animal models. This project seeks to dissect the mechanisms of immune activation by transcriptional poisons like aminitin and how it contributes to host protective host defense that can become pathophysiologic and drive fatal liver disease.