Persistent Infection of Human Pancreatic Islets by Coxsackievirus B Is Associated with Alpha Interferon Synthesis in β Cells

Chehadeh, Wassim; Kerr–Conte, Julie; Pattou, François; Alm, G.; Lefèbvre, J; Wattré, P; Hober, Didier

doi:10.1128/jvi.74.21.10153-10164.2000

Cited by 176 publications

(167 citation statements)

References 53 publications

(65 reference statements)

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“…In the current investigation, CV-B4 E2 infection did not damage the architecture of foetal thymic tissue and did not induce any obvious cell lysis, which is reminiscent of previously described in vitro studies of CV-B infections without cytopathic effect in human thymic epithelial cells [Brilot et al, 2002], pancreatic b-cells [Yoon et al, 1978;Chehadeh et al, 2000a], lymphoid cell lines [Matteucci et al, 1985], glomerular and tubular cells, or vascular endothelial cells [Conaldi et al, 1997a,b]. Altogether these data show that CV-B can infect various tissues without dramatic cell lysis in contrast with the effect of those viruses in continuous epithelial cell lines such as Hep-2, Vero and KB.…”

Section: Discussionsupporting

confidence: 84%

Coxsackievirus B4 infection of murine foetal thymus organ cultures

Brilot

Jaïdane

Geenen

et al. 2008

Journal of Medical Virology

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The infection of foetal thymus with coxsackievirus B4 (CV-B4) E2 has been studied ex vivo by using CD-1 mice on foetal day 14, as a ready source of organs for experimentation to investigate the hypothesis of the role of thymic viral infections in the pathogenesis of type 1 diabetes. The replication of CV-B4 E2 in murine foetal thymus organ cultures has been demonstrated by evaluating the levels of positive-and negativestranded viral RNA in cells by using a real-time quantitative RT-PCR method and by determining titres of infectious viral particles in culture supernatants for 7 days post-infection (p.i.). Staining of tissue sections with an anti-cytokeratin antibody and haematoxylin-eosin showed that CV-B4 infection had no visible effect on cell survival and organ integrity. Cell counts in mock-and virus-infected foetal thymus organ cultures increased from day 1 through day 7, and live cell numbers were comparable in both conditions as shown by Trypan blue exclusion test and 7-amino-actinomycin D staining of thymocytes. Compared with controls on day 7 p.i., cytofluorometric analyses on cells from CV-B4 E2-infected foetal thymus organ cultures displayed a marked increase in the percentage of the most immature CD3 À CD4 À CD8 À thymocytes, and a decrease in the percentage of immature CD3 À CD4 þ CD8 þ cells, together with an increase in the percentage of mature CD3 þ CD4 þ and CD3 þ CD8 þ cells. These data show that CV-B4 E2 disturbs T-cell maturation and differentiation processes in infected murine foetal thymus organ cultures and provide evidence of a suitable system to investigate the effect of viruses in T-cell differentiation.

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Section: Discussionsupporting

confidence: 84%

Coxsackievirus B4 infection of murine foetal thymus organ cultures

Brilot

Jaïdane

Geenen

et al. 2008

Journal of Medical Virology

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“…In some other studies serum containing culture medium has been used for human islet infections and this could explain the differences between their results [25] and those previously published by us [22].…”

Section: Discussionmentioning

confidence: 77%

“…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.…”

mentioning

confidence: 84%

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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“…Similarly, CVBinfected islets produced IFN-α in vitro [16] and this has been associated with hyperexpression of class I MHC [17].…”

Section: Introductionmentioning

confidence: 97%

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

et al. 2009

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Aims/hypothesis Evidence that the beta cells of human patients with type 1 diabetes can be infected with enterovirus is accumulating, but it remains unclear whether such infections occur at high frequency and are important in the disease process. We have now assessed the prevalence of enteroviral capsid protein vp1 (vp1) staining in a large cohort of autopsy pancreases of recent-onset type 1 diabetic patients and a range of controls. Methods Serial sections of paraffin-embedded pancreatic autopsy samples from 72 recent-onset type 1 diabetes patients and up to 161 controls were immunostained for insulin, glucagon, vp1, double-stranded RNA activated protein kinase R (PKR) and MHC class I. Results vp1-immunopositive cells were detected in multiple islets of 44 out of 72 young recent-onset type 1 diabetic patients, compared with a total of only three islets in three out of 50 neonatal and paediatric normal controls. vp1 staining was restricted to insulin-containing beta cells. Among the control pancreases, vp1 immunopositivity was also observed in some islets from ten out of 25 type 2 diabetic patients. A strong correlation was established between islet cell vp1 positivity and PKR production in insulin-containing islets of both type 1 and type 2 diabetic patients, consistent with a persistent viral infection of the islets. Conclusions/interpretation Immunoreactive vp1 is commonly found in the islets of recent-onset type 1 diabetes patients, but only rarely in normal paediatric controls. vp1 immunostaining was also observed in some islets of type 2 diabetes patients, suggesting that the phenomenon is not restricted to type 1 diabetes patients.

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Persistent Infection of Human Pancreatic Islets by Coxsackievirus B Is Associated with Alpha Interferon Synthesis in β Cells

Abstract: The interactions of coxsackievirus B3 (CVB3),

Cited by 176 publications

References 53 publications

Coxsackievirus B4 infection of murine foetal thymus organ cultures

Coxsackievirus B4 infection of murine foetal thymus organ cultures

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

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

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