Virus-induced diabetes mellitus. XV. Beta cell damage and insulin-dependent hyperglycemia in mice infected with coxsackie virus B4.

Yoon, Ji‐Won; Onodera, Takashi; Notkins, Abner Louis

doi:10.1084/jem.148.4.1068

Cited by 177 publications

(100 citation statements)

References 26 publications

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“…Our previous results have shown that primary human beta cells are susceptible to infections by prototype strains of several coxsackie viruses (CV) and that the infection could result in either impaired beta-cell function or beta-cell death (CBV-3, CBV-4 and CBV-5) or both, or has no apparent immediate adverse effects, as shown for CAV-9 [22]. Susceptibility of primary human beta cells to CBV-3, 4 and 5 have also been shown in some other studies [21,23,24,25]. In our study, we assessed diabetogenic properties of different enteroviruses including several serotypes of echoviruses.…”

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confidence: 86%

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

et al. 2002

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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]

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confidence: 86%

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

et al. 2002

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“…Thus, the in vitro susceptibility of B cells may not be a true reflection of their in vivo susceptibility. Nonetheless, when Coxsackie viruses B3 and B4 and reovirus type 3 were passaged multiple times in murine pancreatic B cell cultures, these viruses infected and destroyed B cells to produce a diabetes-like syndrome in susceptible mice [10,25,26]. These studies suggest that under appropriate circumstances, a number of viruses can infect and destroy insulin-producing B cells.…”

Section: Discussionmentioning

confidence: 99%

Infection of cultured human pancreatic B cells with reovirus type 3

et al. 1981

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Summary. The capacity of reovirus type 3 to infect insulin-producing B cells was studied in human pancreatic cell cultures. Antibody to reovirus was labelled with fluorescein isothiocyanate and antibody to insulin was labelled with tetramethyl rhodamine isothiocyanate. By using a double-labelled immunofluorescent antibody technique, it was shown that only about 6% of the insulin-containing human B cells in culture became infected when inoculated with unpassaged reovirus type 3. However, by repeated passage of the virus in human pancreatic B cell cultures, the percentage of infected B cells increased to 27%, and the virus titre in cultures rose from 8.0 x 104 pfu/ml in the first passage, to 4.9 x 106 pfu/ml in the 5th passage. As measured by radioimmunoassay, the intracellular immunoreactive insulin began to decrease at 24h after infection. This decrease roughly paralleled the increase in virus titre. In contrast, there was relatively little change in immunoreactive insulin in cultures inoculated with unpassaged reovirus type 3. These studies show that the ability of reovirus type 3 to infect human B cells is enhanced by serial passage in human pancreatic cell cultures and that the infection resulted in the destruction of B cells and release of insulin.Key words: Virus-induced diabetes mellitus, human pancreatic B cell cultures, double-labelled immunofluorescent antibody staining, reovirus type 3, virus passage. study, it was shown that a Coxsackie virus B4 variant, isolated from the pancreas of a 10-year-old child who died of diabetic ketoacidosis, produced diabetes in mice by infecting and destroying B ceils [7].It is difficult, however, to demonstrate in vivo that viruses replicate in human B cells and produce diabetes in man. As a practical model, an in vitro system has been developed to determine if viruses are capable of infecting human B cells. By use of a double-labelled immunofluorescent antibody technique, it has been shown that human B cells grown in culture were susceptible to infection by mumps [8], Coxsackie virus B3 [9], and Coxsackie virus B4 [7].We have previously shown that reovirus type 3, passaged in murine pancreatic B cell cultures, produced an insulitis when inoculated into 1 to 2 week old mice [10]. In the present investigation, the double-labelled immunofluorescent antibody technique has been used to determine whether or not human B ceils grown in culture were permissive to reovirus type 3, and whether the capacity of the virus to infect human B cells was enhanced by repeated passage in human B cell cultures. Radioimmunoassay for immunoreactive insulin was used to evaluate the effect of the infection on intracellular and extracellular insulin. Materials and Methods Pancreatic B Cell CulturesThe possibility that viruses might cause some cases of insulin-dependent diabetes (IDD) by infecting and destroying pancreatic B cells has received considerable attention. Of the numerous viruses implicated, mumps and members of the Coxsackie virus B group (particularly B4) have been most often suggest...

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“…In humans, infection is associated with either an increased risk (as with CVB1 infection) or a decreased risk (as with CVB3 and CVB6 infection) [82,83]. CVB infects isolated human and murine beta cells [84][85][86]. In human islets, beta cell infection is associated with IFNα production [17].…”

Section: How Might Bystander Lymphocyte Activation Contribute To Diabmentioning

confidence: 99%

Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes

Pane

Coulson

2015

Diabetologia

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Viruses are considered to be potential key modulators of type 1 diabetes mellitus, with several possible mechanisms proposed for their modes of action. Here we discuss the evidence for virus involvement, including pancreatic infection and the induction of T cell-mediated molecular mimicry. A particular focus of this review is the further possibility that virus infection triggers bystander activation of pre-existing autoreactive lymphocytes. In this scenario, the virus triggers dendritic cell maturation and proinflammatory cytokine secretion by engaging pattern recognition receptors. These proinflammatory cytokines provoke bystander autoreactive lymphocyte activation in the presence of cognate autoantigen, which leads to enhanced beta cell destruction. Importantly, this mechanism does not necessarily involve pancreatic virus infection, and its virally non-specific nature suggests that it might represent a means commonly employed by multiple viruses. The ability of viruses specifically associated with type 1 diabetes, including group B coxsackievirus, rotavirus and influenza A virus, to induce these responses is also examined. The elucidation of a mechanism shared amongst several viruses for accelerating progression to type 1 diabetes would facilitate the identification of important targets for disease intervention.

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Virus-induced diabetes mellitus. XV. Beta cell damage and insulin-dependent hyperglycemia in mice infected with coxsackie virus B4.

Cited by 177 publications

References 26 publications

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

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

Infection of cultured human pancreatic B cells with reovirus type 3

Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes

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