Coxsackie B4 virus infection of β cells and natural killer cell insulitis in recent-onset type 1 diabetic patients

Abstract

Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic ␤ cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between ␤ cell viral infection and islet inflammation has not been established. We analyzed pancreatic tissue from six type 1 diabetic and 26 control organ donors. Immunohistochemical, electron microscopy, wholegenome ex vivo nucleotide sequencing, cell culture, and immunological studies demonstrated Coxsackie B4 enterovirus in specimens from three of the six diabetic patients. Infection was specific of ␤ cells, which showed nondestructive islet inflammation mediated mainly by natural killer cells. Islets from enterovirus-positive samples displayed reduced insulin secretion in response to glucose and other secretagogues. In addition, virus extracted from positive islets was able to infect ␤ cells from human islets of nondiabetic donors, causing viral inclusions and signs of pyknosis. None of the control organ donors showed signs of viral infection. These studies provide direct evidence that enterovirus can infect ␤ cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.Coxsackie B4 enterovirus ͉ type 1 diabetes

Complete Nucleotide Sequence of a Coxsackievirus B4 Strain that Establishes Infection in ICR Mice Pancreas and Induces Glucose Intolerance

“…The Tuscany strain was originally isolated from islets of a 19-year-old male who accidentally died 9 months after diabetes onset. The Tuscany strain has been shown to cause infection of b-cells from nondiabetic multiorgan donors and b-cell dysfunction characterized by impaired glucose-stimulated insulin release (Dotta et al, 2007). Infection of the CVB4 strain Tuscany led to insulitis in patients and partial loss of b-cell function on human islet cells in vitro, which is similar to our results with ICR mice infected with the jlu06 strain.…”

“…The virus isolates were shown to induce a diabetes-like syndrome when injected into susceptible mice strains, CD1 and/or SJL (Yoon et al, 1978). Further direct evidence has been obtained from the isolation of CVB4 (Tuscany strain), isolated from the islets of a patient who died at diabetes onset, which is capable of infecting b-cells from nondiabetic multiorgan donors, causing b-cell dysfunction (Dotta et al, 2007).…”

“…Recent studies have demonstrated the association of the virulence with the genetics of the virus strain (Yin et al, 2002b;Paananen et al, 2003;Al-Hello et al, 2005;Dotta et al, 2007). Based on the sequence comparison of the diabetogenic E2 strain of CVB4 and the nondiabetogenic JVB strains, it was revealed that some amino acid changes in the capsid and noncapsid proteins of the E2 strain might be responsible for determination of its diabetogenicity (Kang et al, 1994).…”

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

“…In addition, the presence of enteroviral RNA was revealed by in situ hybridisation in the islets of four recent-onset type 1 diabetes cases [12] and the enteroviral capsid protein vp1, was detected in the beta cells of two of five patients with type 1 diabetes, and in a sixth diabetic patient who had received a recent pancreatic transplant [13]. Electron microscopic analysis revealed the presence of virus particles within the islet beta cells of vp1-positive cases, and a strain of CVB4 was isolated from the pancreas of one patient.…”

“…Electron microscopic analysis revealed the presence of virus particles within the islet beta cells of vp1-positive cases, and a strain of CVB4 was isolated from the pancreas of one patient. This was capable of infecting normal human islets in vitro, resulting in their functional impairment [13].…”