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Characterizing the Role Toll Like Receptor 3 (TLR3) Plays in Viral-Mediated Type 1 Diabetes in Female Non-Obese Diabetic (NOD) Mice

Benner, Sarah E
http://orcid.org/0000-0002-8336-2976
http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1547131981099488

Abstract Details

2019, Doctor of Philosophy (PhD), Ohio University, Molecular and Cellular Biology (Arts and Sciences).
Type 1 diabetes (T1D) is on the rise globally, and both genetic and environmental factors are thought to play a role in triggering this disease. Female non-obese diabetic (NOD) mice are useful for studying T1D as they spontaneously develop T1D even when raised in a sterile environment. However, viruses, such as Coxsackievirus B4 (CVB4), will accelerate the onset of T1D in NOD mice when the infection occurs after a `threshold of insulitis’ has been reached, usually between eight to ten weeks of age. Viral-induced T1D and beta cell destruction is believed to be driven in part by viral triggering of toll-like receptor 3 (TLR3), an innate immune receptor that recognizes viral dsRNA and whose signaling results in the production of key cytokines, chemokines and other antigen presenting molecules that are known to play a role in the pathogenesis of T1D. It has been previously shown that TLR3 plays a critical role in viral acceleration of T1D in female NOD mice since female TLR3 knockout NOD mice are protected from CVB4-induced acceleration of T1D. However, the exact role(s) that TLR3 plays in the pathogenesis of CVB4-induced T1D is not yet known. We utilized a molecular and cellular biology and time-course approach in uninfected and CVB4-infected female wild-type and TLR3 knockout NOD mice to garner a better understanding of the mechanisms by which TLR3 is involved in viral-mediated T1D. Our studies reveal that in uninfected NOD mice, TLR3 is involved in establishment of the `critical threshold of insulitis’ by 1) increasing CD3+ T cell infiltration within the pancreas and 2) increasing downstream signaling of CXLC10 needed to recruit immune cells to the pancreatic islets. Additionally, TLR3 is involved in 1) limiting the proportions of T regulatory cells within the spleen, 2) mediating an increase in cytotoxic T cell infiltration and number of macrophages and dendritic cells within the pancreas, as well as 3) upregulating pancreatic chemokines and cytokines that enhance beta cell damage which is a necessary precursor for CVB4 to trigger the acceleration of T1D. Our data also show that TLR3 is necessary for CVB4 to 1) disrupt beta cell function, 2) increase islet infiltration (i.e., insulitis) and 3) increase cytokine and chemokine production, thus triggering viral-mediated T1D. Together these studies are the first to 1) provide evidence of the mechanisms by which TLR3 mediates viral-acceleration of T1D in NOD mice, 2) offer a definition of what constitutes the `critical threshold of insulitis’ necessary for viruses to trigger T1D in NOD mice, and 3) lay the foundation for future studies aimed at developing novel and improved diagnostic and therapeutic modalities for earlier detection and therapeutic intervention of individuals who are at risk for developing T1D.
Kelly McCall (Advisor)
217 p.
Endocrinology; Molecular Biology
type 1 diabetes; T1D; non-obese diabetic mice; NOD mice; Toll Like Receptor 3; TLR3; Coxsackievirus B4; CVB4; TLR3KO

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Citations

  • Benner, S. E. (2019). Characterizing the Role Toll Like Receptor 3 (TLR3) Plays in Viral-Mediated Type 1 Diabetes in Female Non-Obese Diabetic (NOD) Mice [Doctoral dissertation, Ohio University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1547131981099488

    APA Style (7th edition)

  • Benner, Sarah. Characterizing the Role Toll Like Receptor 3 (TLR3) Plays in Viral-Mediated Type 1 Diabetes in Female Non-Obese Diabetic (NOD) Mice. 2019. Ohio University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1547131981099488.

    MLA Style (8th edition)

  • Benner, Sarah. "Characterizing the Role Toll Like Receptor 3 (TLR3) Plays in Viral-Mediated Type 1 Diabetes in Female Non-Obese Diabetic (NOD) Mice." Doctoral dissertation, Ohio University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1547131981099488

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Ohio University and OhioLINK.