title: Toll-like receptor 3 is critical for coxsackievirus B4-induced type 1 diabetes in female NOD mice.
abstract: 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.
authors.affiliation: Departments of Specialty Medicine (K.D.M., M.C.C., W.M., N.D., B.N., F.L.S.) and Biomedical Sciences (K.D.M., F.B., C.B.L.J., R.M., N.K.) and Diabetes Institute (K.D.M., J.R.T., M.C.C., R.M., W.M., N.D., B.N., F.L.S.), Ohio University Heritage College of Osteopathic Medicine, Athens, Ohio 45701; Department of Biological Sciences (K.D.M.) and Molecular and Cellular Biology Program (K.D.M., F.B., C.B.L.J., R.M.), Ohio University College of Arts and Sciences, Athens, Ohio 45701; Biomedical Engineering Program (K.D.M., F.B., R.M., F.L.S.), Ohio University Russ College of Engineering and Technology, Athens, Ohio 45701; and Section of Endocrinology (L.W.), Department of Internal Medicine, The Anlyan Center for Medical Research and Education, Yale University School of Medicine, New Haven, Connecticut 06520.
authors.forename: Kelly D
authors.initials: KD
authors.lastname: McCall
authors.forename: Jean R
authors.initials: JR
authors.lastname: Thuma
authors.forename: Maria C
authors.initials: MC
authors.lastname: Courreges
authors.forename: Fabian
authors.initials: F
authors.lastname: Benencia
authors.forename: Calvin B L
authors.initials: CB
authors.lastname: James
authors.forename: Ramiro
authors.initials: R
authors.lastname: Malgor
authors.forename: Noriko
authors.initials: N
authors.lastname: Kantake
authors.forename: William
authors.initials: W
authors.lastname: Mudd
authors.forename: Nathan
authors.initials: N
authors.lastname: Denlinger
authors.forename: Bret
authors.initials: B
authors.lastname: Nolan
authors.forename: Li
authors.initials: L
authors.lastname: Wen
authors.forename: Frank L
authors.initials: FL
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D003384:Coxsackievirus Infections / Q000150:complications* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000821:virology*; D029822:Enterovirus B, Human / Q000302:isolation & purification; D005260:Female; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000821:virology; D011897:Random Allocation; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
chemical_list: C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3