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

TLDR

Type 1 diabetes involves T‑cell‑mediated destruction of pancreatic β‑cells, and although Coxsackie enterovirus seroconversion has been linked to disease onset, a direct causal connection to β‑cell infection and islet inflammation had not been proven. The study examined pancreatic tissue from six type 1 diabetic donors and 26 controls to investigate viral presence. Coxsackie B4 virus was detected in β‑cells of three diabetic donors, causing natural‑killer‑cell‑mediated, non‑destructive islet inflammation, impaired insulin secretion, and the ability to infect healthy β‑cells, while no viral infection was seen in controls.

Abstract

Type 1 diabetes is characterized by T cell-mediated autoimmune destruction of pancreatic beta cells. Several studies have suggested an association between Coxsackie enterovirus seroconversion and onset of disease. However, a direct link between beta 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, whole-genome 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 beta 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 beta 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 beta cells in patients with type 1 diabetes and that infection is associated with inflammation and functional impairment.