“Our hope is that by using a newly developed model of live human pancreatic slices to unravel the complex interplay between viruses, beta cells and the immune system, we will identify the best approaches for therapeutic and preventive therapies for type 1 diabetes.”
Can a virus trigger type 1 diabetes?
FUNDED: JANUARY 2021
FUNDED BY: the generosity of the donors to the Sierra Shapery Memorial
Type 1 diabetes (T1D) is a chronic disease where insulin-producing beta-cells in the pancreas are the victims of the body’s own immune cells. Beta-cells are responsible for insulin production and regulation of glucose balance. Patients with T1D require a lifelong insulin therapy and are at high risk of developing severe secondary complications. The incidence of T1D has been increasing over the years and this can only be explained by changes in the environment.
Decades of research have provided epidemiological evidence for an association between T1D and viruses particularly coxsackieviruses of the Enterovirus genus. The viruses’ implication in the crime is still not clear. They could either directly infect and kill beta-cells or indirectly by promoting an inflammatory environment attracting autoreactive T cells to the crime scene.
I will be using a newly developed model of human pancreatic slices (HPS), which can be kept alive in vitro. Pancreatic tissue is sliced 120 µm thick (slightly thicker than a human hair), which preserves endocrine, exocrine, innervation and immune tissue compartments. A coxsackievirus B3 genetically engineered to express an enhanced green fluorescent protein will be used to infect the HPS and address the following questions: Which cell types in the pancreas are susceptible to infection? What is the impact of viral infection on beta cell function? Which inflammatory responses are induced and do they correlate with beta cell function? What is the effect of viral infection on islet-resident macrophages and other immune interactions? What is the effect of viral infection on HLA class I expression and autophagy in islet pancreatic cells?
Six-Month Project Update
In people with type 1 diabetes (T1D), insulin-producing beta cells in the pancreas are destroyed—and scientists still don’t know why. Yet there are clues suggesting that both environmental factors, such as viruses, and genetic susceptibility play important roles in triggering the disease. Several viruses, mainly from the enterovirus family, have been considered potential culprits for human T1D, but there is little solid evidence of this link. For my SPARK project, I investigated the impact of viral infections on human pancreatic tissue slices. We obtained these samples from non-diabetic donors provided by the Network for Pancreatic Organ Donors with Diabetes (nPOD). We infected, human pancreatic slices using a pathogen called coxsackievirus B3, which was genetically engineered to express a green fluorescent protein (GFP). After three days of infection, we could detect the GFP by high-resolution confocal microscopy in the insulinproducing beta cells. These infected beta cells also expressed HLA-I, a molecule that cells use to alert the immune system to a potential threat. HLA-I is also a hallmark of T1D. While it is too soon to conclude that a virus could trigger T1D, this study gives us a direction for further testing that link.