What Is the Relationship Between Enteroviruses and Type 1 Diabetes?
Type 1 diabetes (T1D) is a chronic condition where the body's immune system attacks and destroys insulin-producing cells, leading to a shortage of insulin and high blood sugar levels. The onset of T1D involves a complex interplay between genetic and environmental factors, which activate the immune system and cause it to mistakenly target the β cell antigens, leading to the development of autoimmunity and, ultimately, T1D. For a long time, there has been speculation about the potential involvement of viral infections in triggering T1D. Emerging evidence strongly suggests that enteroviruses, a group of viruses, are the most likely culprits.
Recent studies have further solidified the link between enterovirus infections and the development of autoimmunity in individuals with T1D. It is believed that these viruses may establish persistent infections in the body, contributing to various stages of T1D progression. The potential environmental triggers, enterovirus infections, have emerged as strong candidates, with growing evidence supporting their association with the development of autoimmunity in T1D patients. These infections may play a role in different stages of T1D progression.
Research dating back to the 1960s has suggested that viral infections, particularly those caused by human enteroviruses (HEV), which are single-stranded RNA (+) viruses belonging to the picornavirus family, may play a significant role in triggering islet autoimmunity and the onset of clinical T1D. Supporting this notion, a meta-analysis conducted in 2011, which analyzed 26 earlier studies, provided evidence that enteroviral infection was 3.7 times more common in individuals with islet autoimmunity and 9.8 times more likely at the onset of the disease compared to matched controls. Subsequent studies have further supported this hypothesis.
What Is the Role of Enteroviruses in the Onset of Type 1 Diabetes?
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Enteroviruses, specifically members of the Coxsackievirus B (CVB) family, have been found to infect human beta cells. In laboratory settings, isolated human islets have demonstrated susceptibility to infection by various EV-B family members, including CVBs and Echoviruses.
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Among the different islet cells, beta cells show a higher susceptibility to infection. Consequently, this infection leads to a significant reduction in glucose-induced insulin secretion.
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Several factors contribute to the beta cell tropism of enteroviruses. First, beta cells express receptors required for virus binding and internalization. Second, they possess specific host factors that the virus can exploit to facilitate successful infection, replication, and potential persistence. This aspect is intriguing because traditional beliefs state that enteroviruses do not establish persistent infections, but will delve into this concept further.
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One receptor of particular interest is the Coxsackie and Adenovirus receptor (CAR), which is utilized as an entry point by many viruses associated with T1D in epidemiological studies.
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Recently, it has been discovered that a specific isoform of CAR, known as CAR-SIV, with a unique C-terminal PDZ binding domain, is prominently expressed in beta cells.
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CAR-SIV exhibits an unconventional subcellular localization. Instead of primarily being present at the beta cell's plasma membrane, it is mainly found in insulin secretory granules. This unexpected localization suggests that the virus may enter the beta cell using a Trojan horse mechanism, where viral particles are internalized by the endocytic machinery during membrane recovery, as secretory granule proteins emerge onto the cell surface during exocytosis.
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Supporting this notion, electron microscopy studies conducted by Frisk et al. on human islets infected with CVBs show the presence of viral replication complexes and newly synthesized virions near or at insulin granule membranes.
How to Treat and Prevent the Risk of Enterovirus in Patients With Risk Factors of Developing Diabetes?
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There are two primary strategies being investigated to address HEV infection in T1D: the use of anti-viral agents as treatment and vaccination. Both approaches have the potential to slow down disease progression, but there are significant challenges that need to be overcome before they can be implemented in clinical practice.
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Islet autoimmunity in children at risk for T1D peaks at different ages, and the specificity of the initial autoantibody also varies at each age.
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The first peak of autoimmunity occurs during the second year of life and is associated with the development of insulin autoantibodies (IAA), while the second peak is observed between 3 and 5 years and is predominantly linked to the emergence of GADA autoantibodies.
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Considering that these early signs of islet autoimmunity occur in infancy, effective vaccination against HEV infection would likely need to be administered within the first few months of life. This necessitates the development of safe and efficient vaccines capable of targeting multiple HEVs associated with the disease.
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The success of neonatal vaccination against poliomyelitis (another enterovirus) serves as a precedent for this approach. A new formalin-inactivated CVB1 vaccine newly invented has been successfully developed and tested in animal models. Furthermore, multivalent CVB1-6 vaccines are currently being generated.
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Epidemiological data support the concept that a vaccination strategy may effectively reduce the incidence of T1D, as Finnish children infected with CVB3 or CVB6 early in life appear to have immune protection against subsequent infections with different HEVs, which could potentially trigger T1D.
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Alternative approaches under investigation involve the development of virus-like particles (VLPs) as antigens. These particles resemble the viral capsid of HEVs but do not contain the infectious genome. Vaccines or VLP-based strategies primarily rely on the host generating neutralizing antibodies against the virus. Therefore, they are most effective when administered to individuals prior to any exposure to diabetogenic viruses. The aim is to ensure that the immune response is robust enough to prevent the spread of infectious viruses to the pancreas.
Conclusion
The concept of a viral origin in T1D has been a well-established hypothesis, but it has yet to be definitively proven. Nonetheless, there is a mounting body of evidence that continues to emerge rapidly, and there is growing momentum in the development of effective strategies to mitigate the risks associated with HEV infection in individuals susceptible to T1D. It is only when the findings of these studies become available that will be able to confirm once and for all whether T1D has a significant enteroviral component.
