Enterovirus Infection of Cultured Human Pancreatic Islets
The factors involved in viral tropism for pancreatic islets and islet response to infection can be studied in an experimental model utilizing pancreatic islets isolated from organ donors and cultivated as free-floating preparations. Enteroviruses, in general, have a tropism for human pancreatic islets in vitro. Both lytic and persistent enterovirus infections have been characterized under different experimental conditions and viruses have been detected in both insulin-producing and non-insulin-producing cells. Delayed (secondary) necrosis after initial pyknosis is the major mechanism of cell death during lytic enterovirus infection in cultured human pancreatic islets, whereas apoptosis appears to play only a minor role. Pancreatic beta-cell tropism and the ability to induce beta-cell dysfunction and death probably depends both on the genetic properties of the virus and on the host cell response to the infection. Viral properties are likely to affect the phenomenon since some enterovirus strains are highly cytolytic whereas others show progeny production with no apparent islet destruction in vitro. Even for highly destructive virus strains, there is a significant delay between viral progeny production and pancreatic islet destruction in vitro, suggesting a role for secondary, virus-induced, host factors in the process.
KeywordsPancreatic Islet Enterovirus Infection Human Pancreatic Islet Human Enterovirus Host Cell Response
This work is supported by grants from the European Union (EP7-HEALTH-2007, DIAPREPP N202013), the Juvenile Diabetes Research Foundation (USA), The Academy of Finland, and Päivikki and Sakari Sohlberg Foundation.
- Dotta F, Censini S, van Halteren AG, Marselli L, Masini M, Dionisi S, Mosca F, Boggi U, Muda AO, Prato SD, Elliott JF, Covacci A, Rappuoli R, Roep BO, Marchetti P (2007) Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci USA 104:5115–5120PubMedCrossRefGoogle Scholar
- Knowles NJ, Hovi T, Hyypiä T, King AMQ, Lindberg M, Pallansch MA, Palmenberg AC, Simmonds P, Skern T, Stanway G, Yamashita T, Zell R. (2012). Picornaviridae. In Virus Taxonomy: Classification and Nomenclature of Viruses: Ninth Report of the International Committee on Taxonomy of Viruses pp. 855–880. Edited by King AMQ, Adams MJ, Carstens EB. & Lefkowitz EJ. San Diego: ElsevierGoogle Scholar
- Pallansch MA, Roos RP (2001) Enteroviruses: polioviruses, coxsackieviruses, echoviruses and newer enteroviruses. Lippincot, Williams and Wilkins, PhiladelphiaGoogle Scholar
- Roivainen M, Ylipaasto P, Savolainen C, Galama J, Hovi T, Otonkoski T (2002) Functional impairment and killing of human beta cells by enteroviruses: the capacity is shared by a wide range of serotypes, but the extent is a characteristic of individual virus strains. Diabetologia 45:693–702PubMedCrossRefGoogle Scholar
- Yin H, Berg AK, Westman J, Hellerstrom C, Frisk G (2002) Complete nucleotide sequence of a coxsackievirus B-4 strain capable of establishing persistent infection in human pancreatic islet cells: effects on insulin release, proinsulin synthesis, and cell morphology. J Med Virol 68:544–557PubMedCrossRefGoogle Scholar
- Ylipaasto P, Kutlu B, Rasilainen S, Rasschaert J, Salmela K, Teerijoki H, Korsgren O, Lahesmaa R, Hovi T, Eizirik DL, Otonkoski T, Roivainen M (2005) Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets. Diabetologia 48:1510–1522PubMedCrossRefGoogle Scholar
- Ylipaasto P, Eskelinen M, Salmela K, Hovi T, Roivainen M (2010) Vitronectin receptors, alpha v integrins, are recognized by several non-RGD-containing echoviruses in a continuous laboratory cell line and also in primary human Langerhans’ islets and endothelial cells. J Gen Virol 91:155–165PubMedCrossRefGoogle Scholar