Persistent infection of thymic epithelial cells with coxsackievirus B4 results in a decreased expression of insulin-like growth factor 2

It has been hypothesized that a disturbance of central self-tolerance to islet β-cell may
play a role in the enteroviral pathogenesis of type 1 diabetes. Whether enteroviruses can
induce an impaired expression of β-cell self-antigens in thymic epithelial cells has been
investigated in a murine thymic epithelial (MTE) cell line. This cell line was permissive to
the diabetogenic strain CV-B4 E2 and spontaneously expressed type 2 insulin-like growth
factor (Igf2), the dominant self-antigen of the insulin family. In this model, a persistent
replication of CV-B4 E2 was obtained as attested by the prolonged detection of
intracellular positive and negative-strand viral RNA by RT-PCR, and capsid protein VP1
by IF and by the release of infectious particles in culture supernatant fluids. The chronic
stage of the infection was characterized by a low proportion of VP1-positive cells (1-2%)
whereas many cells harbored enteroviral RNA as displayed by RT-PCR without extraction
applied directly on a few cells. Igf2 mRNA and IGF-2 protein were dramatically decreased
in CV-B4 E2-infected MTE cultures compared with mock-infected cultures, whereas
housekeeping and Il6 genes expression were maintained and Igf1 mRNA was decreased but
at a lower extent. Inoculation of CV-B3-, CV-B4 JVB- or Echovirus 1 resulted in a low
level of IGF-2 in culture supernatant fluids as well, whereas HSV-1 stimulated the
production of the protein. Thus, a persistent infection of a thymic epithelial cell line with
enteroviruses, like CV-B4 E2 can result in a disturbed production of IGF-2, a protein
involved in central self-tolerance towards islet β-cells.