Interactions between enteroviruses and the host : implications for type 1 diabetes

Type 1 diabetes (T1D) is a disease that results after a selective destruction of the insulin-producing β-cells in the pancreas. The lack of β-cells renders T1D patients completely unable to synthesize and secrete insulin, which leads to a life-long need of exogenous insulin for survival. The cause for this selective destruction is still debated, but both genetic and environmental factors have been shown to regulate susceptibility and development of T1D. Together with my colleagues, I have studied different aspects of the observed link between enterovirus (EV) infections, especially those by Coxsackievirus serotype B (CVB) and the development of T1D.

CVB infections may accelerate diabetes development in diabetes-prone mice. This acceleration can however be abrogated by activated iNKT cells. By studying how stimulated or non-stimulated iNKT cells differently regulated macrophages after a CVB4 infection, we have suggested a mechanism for this suppression. We showed that iNKT cells activated in the presence of CVB4 induced suppressive functions in isletresident macrophages, which then inhibited diabetes development in diabetes-prone mice.

Recently, two multi-center studies suggested CVB1 infections to be diabetogenic, causing human β-cell autoimmunity and T1D development. The identification of a specific virus strain suggests a possibility to use a vaccine, in order to reduce diabetes development. We therefore developed a prototype CVB1 vaccine and tested the functions and safety profile in two different animal models. We showed that the vaccine was well tolerated and protected mice from CVB1 infection. Furthermore, we also observed that the vaccine was safe in an autoimmune setting where we showed no acceleration of diabetes development or triggered autoimmunity in vaccinated mice prone to develop autoimmune diabetes.

Despite the findings that CVB1 may be diabetogenic, an inverse correlation between the incidence of T1D and the number of recorded EV infections have been observed. This counterintuitive observation may be explained by the poliovirus hypothesis, stating that a low herd immunity due to a low frequency of virus infections in the population, may make children that lack maternally transferred antibodies more susceptible to diabetogenic infections. Hence, we tested if maternally transferred antibodies transferred could protect offspring from a diabetogenic CVB3 infection in a mouse model for virus-induced diabetes. Our results support a role for the poliovirus hypothesis in explaining the observed inverse correlation between T1D incidence and prevalence of EVs.

The primary site of replication for CVBs is in intestinal epithelial cells (IECs), but what regulates the viral spread to other targeted organs is not known. IFN-λs may regulate permissiveness to the infection. We therefore investigated how intestinal epithelial cells respond to IFN-λ stimulation and found that they could upregulate specific antiviral proteins. This suggested that IECs could be used in a model to study if IFN-λs can regulate IEC permissiveness to CVBs.

List of scientific papers

I. Liana Ghazarian, Julien Diana, Lucie Beaudoin, Pär G. Larsson, Raj K. Puri, Nico van Rooijen, Malin Flodström-Tullberg, and Agnès Lehuen. Protection against type 1 diabetes upon Coxsackievirus B4 infection and iNKT cell stimulation: role of suppressive macrophages. Diabetes. 2013 vol. 62 (11) pp. 3785-3796.
https://doi.org/10.2337/db12-0958

II. Pär G. Larsson, Lakshmikanth Tadepally, Olli H. Laitinen, Renata Utorova, Stella Jacobson, Minni Koivunen, Nicolas Devard, Valerie Lecouturier, Mikael Knip, Heikki Hyöty and Malin Flodström-Tullberg. Preclinical evaluation of efficacy and safety of a new vaccine against Coxsackievirus B1 – Implications for type 1 diabetes development. [Submitted]

III. Pär G. Larsson, Tadepally Lakshmikanth, Emma Svedin, Cecile King and Malin Flodström-Tullberg. Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice. Diabetologia. 2013 vol. 56 (4) pp. 867-874.
https://doi.org/10.1007/s00125-013-2834-z

IV. Pär Larsson, Virginia Stone, Erna Domsgen and Malin Flodström-Tullberg. Human intestinal epithelial cells enter an antiviral state upon stimulation with interferon lambda. [Manuscript]