Coxsackievirus B3 infection and type 1 diabetes development in NOD mice: insulitis determines susceptibility of pancreatic islets to virus infection.
Group B coxsackieviruses (CVB) are believed to trigger some cases of human type 1 diabetes (T1D), although the mechanism by which this may occur has not been shown. We demonstrated previously that inoculation of young nonobese diabetic (NOD) mice with any of several different CVB strains reduced T1D incidence. We also observed no evidence of CVB replication within islets of young NOD mice, suggesting no role for CVB in T1D induction in the NOD mouse model. The failure to observe CVB replication within islets of young NOD mice has been proposed to be due to interferon expression by insulin-producing beta cells or lack of expression of the CVB receptor CAR. We found that CAR protein is detectable within islets of young and older NOD mice and that a CVB3 strain, which expresses murine IL-4, can replicate in islets. Mice inoculated with the IL-4 expressing CVB3 chimeric strain were better protected from T1D onset than were mock-infected control mice despite intraislet viral replication. Having demonstrated that CVB can replicate in healthy islets of young NOD mice when the intraislet environment is suitably altered, we asked whether islets in old prediabetic mice were resistant to CVB infection. Unlike young mice in which insulitis is not yet apparent, older NOD mice demonstrate severe insulitis in all islets. Inoculating older prediabetic mice with different pathogenic CVB strains caused accelerated T1D onset relative to control mice, a phenomenon that was preceded by detection of virus within islets. Together, the results suggest a model for resolving conflicting data regarding the role of CVB in human T1D etiology.
Drescher
Kristen M
KM
Department of Medical Microbiology and Immunology, Creighton University, Omaha, NE 68178, USA.
Kono
Ken
K
Bopegamage
Shubhada
S
Carson
Steven D
SD
Tracy
Steven
S
D000367:Age Factors; D000818:Animals; D045744:Cell Line, Tumor; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D003384:Coxsackievirus Infections / Q000150:complications* / Q000821:virology; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D029822:Enterovirus B, Human / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007372:Interferons / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use; D007515:Islets of Langerhans / Q000378:metabolism / Q000821:virology*; D051379:Mice; D016688:Mice, Inbred NOD; D011991:Receptors, Virus / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D014774:Virulence
C568771:CLMP protein, human; C568772:CLMP protein, mouse; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D011991:Receptors, Virus; D015847:Interleukin-4; D007372:Interferons