Toll-like receptor 3 is critical for coxsackievirus B4-induced type 1 diabetes in female NOD mice

Endocrinology. 2015 Feb;156(2):453-61. doi: 10.1210/en.2013-2006. Epub 2014 Nov 25.


Group B coxsackieviruses (CVBs) are involved in triggering some cases of type 1 diabetes mellitus (T1DM). However, the molecular mechanism(s) responsible for this remain elusive. Toll-like receptor 3 (TLR3), a receptor that recognizes viral double-stranded RNA, is hypothesized to play a role in virus-induced T1DM, although this hypothesis is yet to be substantiated. The objective of this study was to directly investigate the role of TLR3 in CVB-triggered T1DM in nonobese diabetic (NOD) mice, a mouse model of human T1DM that is widely used to study both spontaneous autoimmune and viral-induced T1DM. As such, we infected female wild-type (TLR3(+/+)) and TLR3 knockout (TLR3(-/-)) NOD mice with CVB4 and compared the incidence of diabetes in CVB4-infected mice with that of uninfected counterparts. We also evaluated the islets of uninfected and CVB4-infected wild-type and TLR3 knockout NOD mice by immunohistochemistry and insulitis scoring. TLR3 knockout mice were markedly protected from CVB4-induced diabetes compared with CVB4-infected wild-type mice. CVB4-induced T-lymphocyte-mediated insulitis was also significantly less severe in TLR3 knockout mice compared with wild-type mice. No differences in insulitis were observed between uninfected animals, either wild-type or TLR3 knockout mice. These data demonstrate for the first time that TLR3 is 1) critical for CVB4-induced T1DM, and 2) modulates CVB4-induced insulitis in genetically prone NOD mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coxsackievirus Infections / complications*
  • Coxsackievirus Infections / metabolism
  • Diabetes Mellitus, Type 1 / metabolism
  • Diabetes Mellitus, Type 1 / virology*
  • Enterovirus B, Human / isolation & purification
  • Female
  • Mice, Inbred NOD
  • Mice, Knockout
  • Pancreas / virology
  • Random Allocation
  • Toll-Like Receptor 3 / metabolism*


  • TLR3 protein, mouse
  • Toll-Like Receptor 3