Judith A. Smith, MD, PhD

Portrait of Judith A. Smith, MD, PhD
Associate Professor
4159 Microbial Sciences Building
1550 Linden Dr
Madison, WI 53706
(608) 263-1251
Focus Groups: 
MD, PhD, University of Chicago
Research Summary: 
Host-Pathogen interaction and ER stress
Research Detail: 

Overall theme: The endoplasmic reticulum stress response known as the “Unfolded Protein Response” (UPR) has been implicated in such diverse processes as viral infection, cancer, neurodegenerative disease, autoimmune diseases, diabetes and cardiovascular disease.

In our lab, we have noted that macrophages undergoing an Unfolded Protein Response produce synergistic levels of IFN-β, a cytokine that plays diverse roles in many aspects of autoimmune disease, and the pro-inflammatory cytokine IL-23. Beyond the impact on cytokine production, we have been determining the role of this fascinating stress response on host responses to bacterial and viral pathogens.

Current research areas:

1) Brucella: Brucellosis is the most prevalent zoonosis worldwide. 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. Current projects are investigating the role of the UPR in Brucella pathogenesis, and mechanisms of innate immune sabotage by Brucella.

2) Rhinovirus: Gene polymorphism at 17q21 is one of the most powerful predictors for the development of childhood asthma. One gene at that locus encodes an ER-resident protein ORMDL3 that regulates ER calcium and the UPR. We have identified a striking association between extent of ORMDL3 upregulation during infection and rhinovirus induced ER stress, type I IFN induction, and viral replication. Current efforts are aimed at teasing apart the causal mechanisms underlying the noted associations.

3) Spondyloarthritis: One form of arthritis, known as spondyloarthritis, is strongly linked to the MHC class I allele HLA-B27, a protein that misfolds and induces a UPR. 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 

Lab Members: Dr. Jerome Harms, Scientist, Dr. Yi-Ping Liu Ph.D. Assistant Scientist

Selected Publications: 
Brucella Peptide Cross-Reactive MHC I Presentation Activates SIINFEKL-Specific TCR Expressing T Cells.Harms JS, Khan M, Hall C, Splitter GA,Homan EJ, Bremel RD, Smith JA.Infect Immun. 2018 May 7. pii: IAI.00281-18. doi: 10.1128/IAI.00281-18. [Epub ahead of print]PMID: 29735518
Regulation of Cytokine Production by the Unfolded Protein Response; Implications for Infection and Autoimmunity.Smith JA.Front Immunol. 2018 Mar 5;9:422. doi: 10.3389/fimmu.2018.00422. eCollection 2018. Review.PMID: 29556237
Elevated fractional exhaled nitric oxide and blood eosinophil counts are associated with a 17q21 asthmarisk allele in adult subjects.Schwantes EA, Evans MD, Cuskey A, Burford A, Smith JA, Lemanske RF Jr, Jarjour NN, Mathur SK.J Asthma Allergy. 2017 Dec 19;11:1-9. doi: 10.2147/JAA.S149183. eCollection 2018.PMID: 29296089
Cat-Scratch Disease, a Diagnostic Consideration for Chronic Recurrent Multifocal Osteomyelitis.Harry O, Schulert GS, Grom AA, Frenck RW Jr, Woltmann JL, Shapiro AH, Smith JA.J Clin Rheumatol. 2017 Dec 12. doi: 10.1097/RHU.0000000000000653. [Epub ahead of print] No abstract available.PMID: 29239936
Brucella Lipopolysaccharide and pathogenicity: The core of the matter.Smith JA.Virulence. 2018 Jan 1;9(1):379-382. doi: 10.1080/21505594.2017.1395544. No abstract available.PMID: 29144201
Genetic and Functional Associations with Decreased Anti-inflammatory Tumor Necrosis Factor Alpha Induced Protein 3 in Macrophages from Subjects with Axial SpondyloarthritisLiu Y, Ye Z, Li X, Anderson JL, Khan M, DaSilva D, Baron M, Wilson D, Bocoun V, Ivacic LC, Schrodi SJ, Smith JA.Front Immunol. 2017 Jul 24;8:860. doi: 10.3389/fimmu.2017.00860. eCollection 2017.PMID: 28791018
The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response.Khan M, Harms JS, Marim FM, Armon L, Hall CL, Liu YP, Banai M, Oliveira SC, Splitter GA, Smith JA.
Infect Immun. 2016 Nov 18;84(12):3458-3470. Print 2016 Dec.PMID: 27672085
The Bench-to-Bedside Story of IL-17 and the Therapeutic Efficacy of its Targeting in Spondyloarthritis.Smith JA.Curr Rheumatol Rep. 2016 Jun;18(6):33. doi: 10.1007/s11926-016-0585-9. Review.PMID: 27105640
Space: A Final Frontier for Vacuolar Pathogens.Case ED, Smith JA, Ficht TA, Samuel JE, de Figueiredo P.Traffic. 2016 May;17(5):461-74. doi: 10.1111/tra.12382. Epub 2016 Feb 24. Review.PMID: 26842840
The role of the unfolded protein response in axial spondyloarthritis.Smith JA.Clin Rheumatol. 2016 Jun;35(6):1425-31. doi: 10.1007/s10067-015-3117-5. Epub 2015 Nov 14. Review.PMID: 26567900