Rat pancreatic beta cells and cytomegalovirus infection.
OBJECTIVE
Cytomegalovirus (CMV) infection has been suggested to accelerate beta-cell destruction and thereby to contribute to new-onset diabetes and failure of islet allografts in both humans and rodents. Surprisingly, direct CMV infection of beta cells has received only minor attention. Therefore, we investigated the susceptibility of rat beta cells for rat CMV (RCMV) infection and the direct effects on the regulation of immune cell-activating ligands.


METHODS
Primary rat beta cells, the rat beta-cell line Rin-m5F, and fibroblasts were RCMV-infected in vitro. The viral gene and protein expression levels were determined as a measure for RCMV susceptibility. Gene expression levels of intracellular adhesion molecule 1, lymphocyte function associated antigen 3, rat major histocompatibility complex region A, rat major histocompatibility complex region E, toll like receptor 2, and clustered domain 14 were determined as a measure for cellular immunogenicity.


RESULTS
We demonstrate that beta cells are susceptible for RCMV infection but allow only low levels of viral gene expression. In contrast, infected fibroblasts demonstrated productive viral infection and formation of viral progeny. After RCMV infection, beta-cell immunogenicity was markedly increased, as demonstrated by the increased cellular expression of immune cell-activating ligands.


CONCLUSIONS
Direct beta-cell infection by RCMV and subsequent low-grade viral gene expression may lead to increased immunogenicity of native or transplanted beta cells in vivo. An infection-induced enhanced beta-cell recognizability may have important consequences for beta-cell survival and the development of diabetes or rejection of islet grafts.
Smelt
Maaike J
MJ
Division of Medical Biology, Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands. m.j.smelt@med.umcg.nl
Faas
Marijke M
MM
de Haan
Bart J
BJ
Hofstede
Jeroen
J
Cheung
Chi-Wai
CW
van der Iest
Hanna
H
de Haan
Aalzen
A
de Vos
Paul
P
D000818:Animals; D015153:Blotting, Western; D018968:CD58 Antigens / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism / Q000821:virology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology*; D005434:Flow Cytometry; D015870:Gene Expression; D006649:Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D054884:Host-Pathogen Interactions; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000821:virology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics / Q000378:metabolism; D008854:Microscopy, Electron; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000235:genetics
D018968:CD58 Antigens; D006649:Histocompatibility Antigens; D018950:Lipopolysaccharide Receptors; C495343:Tlr2 protein, rat; D051195:Toll-Like Receptor 2; D014764:Viral Proteins; C038353:histocompatibility antigens RT, rat; D018799:Intercellular Adhesion Molecule-1