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

Abstract

Aims/hypothesis. Direct infection of beta cells could explain the diabetogenic effect of enteroviruses. Primary adult human beta cells are susceptible to coxsackievirus infections, which could result in impaired beta-cell function or cell death (coxsackieviruses B3, B4, B5) or both, or no apparent immediate adverse effects (coxsackievirus A9). We extended these studies to additional enterovirus serotypes including several echoviruses, some of which have been associated clinically with the development of Type I (insulin-dependent) diabetes mellitus. Methods. The patterns and consequences of enterovirus infections were investigated in cultured adult human isolated islets. Cell type-specific infection and viability were assessed by immunocytochemical methods. Beta-cell function was studied by perifusion. Results. Poliovirus type 1/Mahoney, coxsackievirus A13, human parechovirus 1 and several echoviruses (serotypes 6, 7, 11) were capable of causing significant functional impairment (p<0.05) and beta-cell death. In contrast, echovirus serotypes 9 and 30 were not destructive. However, when several different field isolates of echovirus 30 were investigated, some of them were found to be clearly more destructive than the corresponding prototype strain. This was also true for echovirus 9. A strain isolated from a 6-week-old baby suffering from acute Type I diabetes was functionally more destructive than either of the echovirus 9 prototype strains. Conclusion/interpretation. These observations indicate that the capacity of an enterovirus to kill human beta cells or impair their function is not entirely defined by the serotype, but in addition by as yet unidentified characteristics of the virus strain involved. Moreover, any serotype could potentially be diabetogenic. [Diabetologia (2002) 45:693-702]

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

“…On the other hand, during true virus infection of islets in nature, the infection may also induce changes in non-beta cell genes that may be relevant in the pathogenesis of type 1 diabetes mellitus. CBV-5 was selected out of more than 65 enterovirus serotypes capable of infecting humans, based on our previous results indicating that this prototype strain is one of the most destructive serotypes primarily infecting human beta cells [13,14] and on epidemiological studies supporting an association between CBV-5 infection and type 1 diabetes [10,30,31]. Because of space limitations, only some of the genes shown in Tables S2 and S3 are discussed here; additional information on some of these genes can be found in our previous publications dealing with microarray analysis of rat beta cells [28,32].…”

“…Likewise, cultured primary human beta cells are highly susceptible to infections caused by several enterovirus serotypes, representing different genetic subgroups and known to act through a number of different receptor families [9]. Of note, even the most cytolytic enterovirus strains kill beta cells only after several days in culture [13,14], suggesting a role for cytokines or other secondary virus-induced factors in the process.…”

“…IFIT1: 2 and 4 interferon-induced protein with tetratricopeptide repeats 1, 2 and 4 . IFITM1: interferon-induced transmembrane protein 1 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) . IFNB1: interferon β1, fibroblast .…”

Environmental Triggers and Determinants of Type 1 Diabetes

“…The biological significance of enterovirus tropism has been demonstrated by the highly specific nature of the motorneuron damage in poliomyelitis, and it is possible that viral tropism could also explain the specificity of ␤-cell damage in type 1 diabetes. In vitro studies have shown that enteroviruses infect ␤-cells easily and induce functional impairment and cell death (49,50). Such a capacity seems to be shared by a wide range of serotypes, but the extent of the cellular lesions appears to be characteristic of individual virus strains.…”

Interleukin-13 Pathway Alterations Impair Invariant Natural Killer T-Cell–Mediated Regulation of Effector T Cells in Type 1 Diabetes

“…The enterovirus Coxsackievirus B4 was considered of etiological significance in T1D because it leads to functional impairments and b-cell damage (42). Evidence suggests that human islet cells can sustain an enteroviral infection in patients with T1D.…”