Viral infection has been associated with the development of type 1 diabetes (T1D). Studying virus- associated diabetes in laboratory animals has been problematic due to differences in host species-specific susceptibility and immune responses to viral pathogens including Coxsackie B virus (CVB). In order to better evaluate CVB's impact on causing human T1D, we developed a viral infection model in immunodeficient mice bearing human islet grafts that are crucial for glycemic control. In this model, infection with CVB4 strain JVB leads to diabetes in nearly half of all infected animals. Human islet grafts from infected mice contained viral RNA, expressed viral protein, and exhibited mild to moderate cell degeneration compared to the islet grafts from mock-infected mice. Gene expression profiles from the human grafts revealed induction of interferon- stimulated genes and ER stress, as well as decreased expression of insulin and the transcription factor Pdx1. In the proposed study, we will use this human islet-engrafted mouse model along with complementary studies in cultured human beta cells to delineate the mechanisms of beta cell dysfunction and/or death following CVB infection. We will compare different CVB strains as well as mutant viruses to identify which viruses are more or less diabetogenic. The ultimate goal is to design a preventive vaccine against TID.

Public Health Relevance

Type 1 diabetes (T1D) is an immune-mediated disease driven by both genetic and environmental factors, including infection with viruses. In this research study, we will focus on a particular type of virus that can cause T1D. We will study what viral and human genetic factors are essential in the development of virus-mediated diabetes by altering both the virus and the human tissues. Specific genetic variations that are ?pro-diabetic? and ?anti-diabetic? will be identified so that fundamental elements that contribute to T1D development will be better defined and vaccine strategies optimized.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116920-03
Application #
9522130
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Bourcier, Katarzyna
Project Start
2016-08-12
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
Qaisar, Natasha; Jurczyk, Agata; Wang, Jennifer P (2018) Potential role of type I interferon in the pathogenic process leading to type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 25:94-100
Qaisar, Natasha; Lin, Suvana; Ryan, Glennice et al. (2017) A Critical Role for the Type I Interferon Receptor in Virus-Induced Autoimmune Diabetes in Rats. Diabetes 66:145-157
Nyalwidhe, Julius O; Gallagher, Glen R; Glenn, Lindsey M et al. (2017) Coxsackievirus-Induced Proteomic Alterations in Primary Human Islets Provide Insights for the Etiology of Diabetes. J Endocr Soc 1:1272-1286