Impaired Ca2+ response to glucose in mouse β-cells infected with Coxsackie B or Echo virus

Uppsala University, Uppsala, Uppsala, Sweden
Virus Research (Impact Factor: 2.32). 10/1994; 33(3):229-40. DOI: 10.1016/0168-1702(94)90105-8
Source: PubMed


Five strains of Coxsackie B4 virus and one of Echo 11 virus were tested with regard to their ability to replicate in pancreatic mouse beta-cells and interfere with the alterations of the cytoplasmic Ca2+ concentration ([Ca2+]i) induced by glucose. All strains except one both multiplied and caused cytopathic effect. In a control group 68% of the beta-cells responded to 11 mM glucose with large amplitude oscillations of [Ca2+]i. After inoculation with the infectious strains these oscillations appeared in only 5% of the beta-cells, whereas the non-infectious strain did not modify the glucose effect on [Ca2+]i. Despite the virus interference with the glucose response, [Ca2+]i was increased after depolarization with excessive extracellular K+ and the oscillations were induced in most beta-cells when glucose was combined with the insulin-releasing sulfonylurea tolbutamide.

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    • "Infections with the coxsackievirus serotype B4 (CB4) have been etiologically linked to type 1 diabetes in humans , and CB4 was isolated from patients who died shortly after being diagnosed with the disease (Szopa et al., 1993). Several CB4 isolates can infect human and murine pancreatic ␤-cells and cause cellular dysfunction and/or death in vitro (Frisk et al., 1994; Roivainen et al., 2000; Szopa et al., 1986, 1990; Yoon et al., 1979). Moreover , some clinical isolates, after several passages through mouse pancreatic ␤-cell cultures, fulfilled Koch's postulate by inducing a diabetes-like syndrome in susceptible strains of mice (Toniolo et al., 1982; Yoon et al., 1978). "
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    ABSTRACT: Coxsackieviral infections have been linked etiologically to multiple diseases. The serotype CB4 is associated with acute pancreatitis and autoimmune type 1 diabetes. To delineate the mechanisms of host survival after an acute infection with CB4 (strain E2), we have investigated the role of nitric oxide (NO), generated by the inducible form of nitric oxide synthase (NOS2), in viral clearance and pancreatic β-cell maintenance. Mice deficient in NOS2 (NOS2−/− mice) and their wild-type (wt) counterparts were injected with CB4, after which both groups developed severe pancreatitis, hepatitis, and hypoglycemia within 3 days. Within 4 to 7 days postinfection (p.i.), most of the NOS2−/− mice died and at a strikingly higher mortality rate than wt mice. Histological examination of pancreata from both infected NOS2−/− and infected wt mice revealed early and complete destruction of the pancreatic acinar tissue, but intact, insulin-stained islets. When examined up to 8 weeks p.i., neither surviving NOS2−/− mice nor surviving wt mice developed hyperglycemia. However, the clearance of infectious CB4 was different between the mice. The spleens of NOS2−/− survivors were cleared of infectious virus with kinetics similar to that of wt mice, but the livers, pancreata, kidneys, and hearts of the NOS2−/− groups cleared virus more slowly than those of the wt group. This delayed clearance was particularly prominent in the livers of infected NOS2−/− mice, which also showed prolonged histopathological features of viral hepatitis. Taken together, this outcome suggests that NOS2 (and NO) is not required for the prevention of pancreatic β-cell depletion after CB4 infection. Instead the critical actions of NOS2 apparently occur early in the host immune response, allowing mice to survive and clear virus. Moreover, the data support the existence of an organ-specific dependency on NO for a rapid clearance of CB4.
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    ABSTRACT: Considerable differences in antibody responses measured by capture-IgM RIA and neutralization tests (NT) were seen in children with newly diagnosed type I (insulin-dependent) diabetes mellitus (IDDM) when five different strains of Coxsackie B4 virus (CBV-4) were used. The IgM positivity of the 160 patients varied between 3.7 and 10.0% (P < 0.05) and with the use of all strains, IgM was found in 13.2%. Matched controls showed a significantly lower frequency (P < 0.05), but there were no apparent differences between the strains, although no IgM was found against two strains. In the NT different results were also obtained in the IDDM children with use of the five strains. However, these results differed considerably from those of the RIA, indicating that different epitopes on the virus were involved. Serum specimens from 75 patients with aseptic meningitis from whom enteroviruses had been isolated, also showed varying IgM frequencies, ranging from 13.3 to 18.7%, but the differences between the strains were different to those found in the IDDM patients. We speculate that only certain strains of a serotype of CBV may be used to distinguish IDDM pathogenesis from that of other diseases.
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    ABSTRACT: The mechanisms that regulate susceptibility to virus-induced autoimmunity remain undefined. We establish here a fundamental link between the responsiveness of target pancreatic beta cells to interferons (IFNs) and prevention of coxsackievirus B4 (CVB4)-induced diabetes. We found that an intact beta cell response to IFNs was critical in preventing disease in infected hosts. The antiviral defense, raised by beta cells in response to IFNs, resulted in a reduced permissiveness to infection and subsequent natural killer (NK) cell-dependent death. These results show that beta cell defenses are critical for beta cell survival during CVB4 infection and suggest an important role for IFNs in preserving NK cell tolerance to beta cells during viral infection. Thus, alterations in target cell defenses can critically influence susceptibility to disease.
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