Acute Onset of Type I Diabetes Mellitus after Severe Echovirus 9 Infection: Putative Pathogenic Pathways

Abstract

Enterovirus infections have been implicated in the development of type I diabetes mellitus. They may cause beta cell destruction either by cytolytic infection in the pancreas or indirectly by contributing to autoimmune reactivity. We sought evidence for these 2 mechanisms in a case of acute-onset diabetes mellitus that occurred during severe echovirus 9 infection. The virus was isolated and administered to cultured human beta cells. No viral proliferation was observed, and no beta cell death was induced, while parallel exposure to Coxsackie B virus serotype 3 resulted in viral proliferation and massive beta cell death. Although the viral protein 2C exhibited a sequence similar to that of the beta cell autoantigen glutamic acid decarboxylase (GAD(65)), no cross-reactive T cell responses were detected. The patient did not develop antibodies to GAD(65) either. Absence of evidence for direct cytolytic action or an indirect effect through molecular mimicry with GAD(65) in the present case raises the possibility of another indirect pathway through which enteroviruses can cause diabetes mellitus.

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

“…Recently we described an infant who developed immune-mediated Type I diabetes in utero already and according to our serological analysis the pathogenic process might have been induced by echovirus 6 infection during pregnancy [20]. Another echovirus, EV-9 DM, was recently isolated from a 6-week-old girl with an acute onset of Type I diabetes [21] and according to our present results, high multiplicity infection by this isolate results in impaired beta-cell function. The isolate was clearly more destructive than the corresponding prototype strains Barty or Hill.…”

“…The isolate was clearly more destructive than the corresponding prototype strains Barty or Hill. In contrast to these results, the same stool isolate has been tested in islets without further passaging in BGM cells, and was found to be incapable of growing or causing beta-cell death in cultured human islets, infected at a multiplicity of 1 [21]. This contradiction is not yet solved.…”

“…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.…”

“…The strain was isolated in tertiary monkey kidney cell [21] and passaged twice in Buffalo Green Monkey cells before use in the present experiments. The serotypes of all isolates were confirmed by using serotype-specific neutralising antiserum.…”

“…The results suggest that several out of the 64 human enterovirus serotypes should be considered potentially diabetogenic [1,17]. Observational studies revealing post-enterovirus-epidemic peak incidences of Type I diabetes [18,19] and case reports [20,21] support this view. It is possible that the relative extent of diabetogenicity can vary within a serotype as genetic variation between field strains of a given enterovirus serotype is extensive.…”