The major focus of the Smith lab is an intracellular stress response originating from the endoplasmic reticulum (ER) called the “Unfolded Protein Response” or “UPR”. The UPR has been implicated in such diverse processes as viral infection, cancer, neurodegenerative disease, autoimmune diseases, diabetes and cardiovascular disease. We have been most interested in understanding the immune consequences of UPR activation, specifically as it impacts inflammatory cytokine production. Macrophages undergoing a UPR produce greatly augmented type I IFN, TNF-α and IL-23 in response to infectious stimuli.
Major Ongoing Projects
One form of arthritis, known as spondyloarthritis, is strongly linked to the MHC class I allele HLA-B27, a protein that misfolds. We have found that macrophages from spondyloarthritis patients produce greatly increased IL-23, even apart from obvious UPR induction. Current efforts are focusing on understanding the genetic and biochemical mechanisms supporting cytokine dysregulation in these patients.
Brucellosis is the most prevalent zoonosis worldwide. Spondyloarthritis is a major complication of this disease. To replicate, the causative organism, Brucella spp. invades macrophages and forms an ER derived vacuole. Brucella also induces a massive reorganization of the ER (imaged by anti-calreticulin staining in the figure) and triggers a UPR. The UPR may affect multiple aspects of pathogenicity, including cytokine production, bacterial replication, host cell apoptosis, antigen presentation and memory. This project is an active collaboration with the Splitter lab on the UW campus.
A new project has begun in collaboration with Childhood Origins of Asthma (COAST). A recently identified gene polymorphism at 17q21 is one of the most powerful predictors for the development of childhood asthma. One gene at that locus ORMDL3 potentially regulates the UPR. We are determining if subjects with different genotypes have altered UPR induction in response to Rhinovirus and show related consequences for viral infection.