TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats.
Virus infection is hypothesized to be an important environmental "trigger" of type 1 diabetes in humans. We used the BBDR rat model to investigate the relationship between viral infection and autoimmune diabetes. BBDR rats are diabetes-free in viral Ab-free housing, but the disease develops in approximately 30% of BBDR rats infected with Kilham rat virus (KRV) through a process that does not involve infection of pancreatic beta cells. Pretreatment with polyinosinic-polycytidylic (poly(I:C)), a ligand of TLR3, acts synergistically to induce diabetes in 100% of KRV-infected rats. The mechanisms by which KRV induces diabetes and TLR3 ligation facilitates this process are not clear. In this study, we demonstrate that activation of the innate immune system plays a crucial role in diabetes induction. We report that multiple TLR agonists synergize with KRV infection to induce diabetes in BBDR rats, as do heat-killed Escherichia coli or Staphylococcus aureus (natural TLR agonists). KRV infection increases serum IL-12 p40 in a strain-specific manner, and increases IL-12 p40, IFN-gamma-inducible protein-10, and IFN-gamma mRNA transcript levels, particularly in the pancreatic lymph nodes of BBDR rats. Infection with vaccinia virus or H-1 parvovirus induced less stimulation of the innate immune system and failed to induce diabetes in BBDR rats. Our results suggest that the degree to which the innate immune system is activated by TLRs is important for expression of virus-induced diabetes in genetically susceptible hosts.
Zipris
Danny
D
Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Lien
Egil
E
Xie
Jenny X
JX
Greiner
Dale L
DL
Mordes
John P
JP
Rossini
Aldo A
AA
D000818:Animals; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D010088:Oxidoreductases / Q000276:immunology; D010321:Parvoviridae / Q000276:immunology; D010322:Parvoviridae Infections / Q000276:immunology*; D017992:Parvovirus / Q000276:immunology*; D011070:Poly I-C / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014615:Vaccinia / Q000276:immunology; D014616:Vaccinia virus / Q000276:immunology
D007378:Interleukins; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D007371:Interferon-gamma; D010088:Oxidoreductases; D011070:Poly I-C; C422042:interleukin 20