5 Exploring the Impact of HDV on Sjogren’s Disease Development: A Murine Model Study

Faculty Mentor: Melodie Weller (Dentistry, University of Utah)

Abstract

Sjogren’s Disease (SjD) is a chronic autoimmune disease affecting approximately 0.1% of the United States population. Clinical classification of SjD includes reduced tear and saliva excretion, accumulation of lymphocyte foci in the salivary gland tissue, and the detection of antibodies against Ro (SSA), La (SSB), and nuclear proteins. The cause of SjD is unknown, though it is hypothesized that pathogens, including viruses and bacteria, may play a role. Previous studies have detected Hepatitis Delta Virus (HDV) in the minor salivary gland of patients with SjD (1,2); without the typical presence of a Hepatitis B virus coinfection. In this study, murine models were transduced with Adeno-associated virus containing expression cassettes for Luciferase (control), small, large, or a combination of both small and large HDV antigens to evaluate the impact of HDV antigen expression on salivary gland function and SjD autoimmune disease development. After a ten- or four-month period, the models were analyzed for disease phenotype development and changes in the gene expression profiles within the salivary gland tissue. Findings included a significant increase of inflammation in mice expressing both small and large HDV antigens, a significant increase of anti-SSA(Ro) antibodies in samples expressing the short HDV antigen, and a correlation between increased overall inflammation and decreased overall saliva flow. HDV transcripts within submandibular glands were quantified by qPCR and matched with transcriptomic sequencing. Analyses identified an increase in glycolysis and beta oxidation metabolism in models with detectible HDV antigen expression. The models showed significantly increased IgM expression in the HDV murine models, without significant change of other antibodies.

Future plans include an ELISA diagnostic assay to verify the antibody levels and further sequencing analyses. With this information we can build a better picture of the direct mechanisms of HDV-mediated changes in salivary gland dysfunction and determine the extent that HDV is inducing systemic SjD symptoms.

References

1. Hesterman M.C, Furrer S.V., Fallon B.S., Weller M.L. Clinical and In Situ Characterization of Hepatitis Delta Virus in Sjörgen’s Syndrome.bioRxiv 2022doi: https://doi.org/10.1101/2022.12.03.518993

2. Weller M.L., Gardener M.R., Bogus Z.C., Smith M.A., Astorri E., Michael D.G., Michael D.A.,Zheng C., Burbelo P.D., Lai Z., Wilson P.A., Swaim W., Handelman B., Afione S.A., Bombardieri M., Chiorini J.A. Hepatitis Delta Virus Detected in Salivary Glands of Sjogren’s Syndrome Patients and Recapitulates a Sjogren’s Syndrome-Like Phenotype in Vivo. Pathog Immun. 2016 doi:10.20411/pai.v1i1.72.