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Human pancreatic islet endothelial cells express coxsackievirus and adenovirus receptor and are activated by coxsackie B virus infection

Maria M. Zanone^*,1, Enrica Favaro^*, Elena Ferioli, Guo C. Huang, Nigel J. Klein, Paolo Cavallo Perin^*, Mark Peakman, Pier G. Conaldi and Giovanni Camussi^*

^* Department of Internal Medicine, University of Torino, Italy;

Department of Medicine and Public Health, University of Insubria, Varese, Italy;

Department of Immunobiology and Diabetes, Guy’s, King’s and St. Thomas’s School of Medicine, London, UK; and

Department of Immunobiology, Institute of Child Health, London, UK

¹Correspondence: I Divisione Universitaria di Medicina, Dipartimento di Medicina Interna, Corso Dogliotti 14, 10126 Torino, Italy. E-mail: mmz{at}libero.it

Enteroviruses, such as the coxsackievirus (CV) group, have been linked to the induction of inflammatory and autoimmune diseases. Virus tropism and tissue access are modulated by endothelial cells. To examine the susceptibility of microvascular endothelial cells (MECs) derived from pancreatic islets to infection with CV group B (CVB), purified cultured human islet MECs were infected with CVB-4 strain, and the immunological phenotype of the infected cells was analyzed. CVB-4 persistently infected the islet MECs, which expressed the CV receptors human coxsackievirus and adenovirus receptor (HCAR) and decay accelerating factor (DAF) and maintained EC characteristics, without overt cytopathic effects. CVB-4 infection transiently up-regulated expression of the adhesion molecules ICAM-1 and VCAM-1 and increased production of the proinflammatory cytokines IL-1ß and IL-6, and chemokines IL-8 and lymphotactin, as well as IFN-. Mononuclear cell adhesion to CVB infected monolayers was increased, compared to uninfected monolayers. Moreover, infection up-regulated the viral receptors HCAR and DAF and coreceptor _vß₃ integrin on islet MECs, while down-regulating expression of HCAR on human aortic endothelial cells, indicating potential tissue-specific influence on the pathological outcome of infection. These results provide evidence that islet MECs are natural targets and reservoirs for persistent CVB infection resulting in acute endothelial cell activation by virus, which may contribute to selective recruitment of subsets of leukocytes during inflammatory immune responses, such as insulitis in type 1 diabetes.—Zanone, M. M., Favaro, E., Ferioli, E., Huang, G. C., Klein, N. J., Perin, P. C., Peakman, M., Conaldi, P. G., Camussi, G. Human pancreatic islet endothelial cells express coxsackievirus and adenovirus receptor and are activated by coxsackie B virus infection.

Key Words: autoimmunity • adhesion molecules • cytokines • viral infection

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