Virus infections as potential targets of preventive treatments for type 1 diabetes

Abstract

Environmental factors play an important role in the pathogenesis of type 1 diabetes, and are attractive targets for preventive interventions. Several studies have shown that viruses can cause diabetes in animals, indicating their potential as candidates for environmental triggering agents. However, human studies have been hampered by the complex nature of the disease pathogenesis, leaving the question of viral etiology unanswered. Significant progress has recently been made in this field by searching for viruses within pancreatic tissue samples, and by carrying out prospective studies. Consequently, there is increasing evidence for a group of enteroviruses acting as possible environmental key triggers. In past studies, these viruses have been linked to type 1 diabetes. Recent studies have shown that they exert tropism to pancreatic islets, and that they are associated with the start of the beta-cell damaging process. Also, polymorphisms of the gene coding for the innate immune system sensor for enteroviruses (IFIH1) were found to modulate the risk of diabetes. Based on these findings, interest in the possible development of vaccines against these viruses has increased. However, even if enterovirus vaccines (polio vaccines) are effective and safe, we currently lack necessary information for the development of a vaccine against diabetogenic enteroviruses, e.g. regarding the identification of their specific serotypes and the causal relationship between these viruses and diabetes initiation. Ongoing research projects are currently addressing these questions, and will hopefully increase the consensus in this field. Also, new sequencing technologies will provide additional information about the whole virome, which could enable the discovery of new candidate viruses.

Figure 1. Viral and host factors regulating the risk of virus-induced beta-cell damage

The serotype of enteroviruses is a key determinant of viral tropism exerted to different organs such as pancreatic islets since it is connected to the specific binding of the virus to cell receptors. Furthermore, each serotype is represented by a variety of virus strains developed as a result of single-nucleotide mutations and genomic recombinations, resulting in different virulence characteristics. The host immune response controls the virus spread and generates inflammation in infected tissues such as the pancreas.

Figure 2. Identification of diabetogenic enterovirus types

The figure shows a hypothetical model of the probability to identify diabetogenic enterovirus types from different kinds of samples according to the level of infection. The probability is highest (i.e. it has the highest odds ratio) when samples are collected directly from the pancreas since virus types infecting the target organ have passed several anatomical and immunological barriers, being enriched with causative virus types and strains. In contrast, infections diagnosed by virus detection from stools or by antibody assays from serum mostly include non-diabetogenic enteroviruses, and the diabetogenic viruses represent only a small fraction of all virus types detected in type 1 diabetic patients.

Figure 3. Prevalence of virus antibody

The figure shows a hypothetical model of virus antibody prevalence seen in case-control studies in two-virus diseases with either low (A) or high (B) attack rate. Patients with severe enterovirus disease have only slightly higher antibody prevalence than control subjects due to the low attack rate (only <1% of poliovirus-infected individuals got paralysis) (A). A similar figure is shown for a virus disease that is characterized by a high attack rate (such as HIV-induced AIDS) (B).