Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes 2. The CVB do not invade and destroy islet cells of healthy mice. Viruses generally destroy cells by direct infection: viruses enter a cell, take it over, replicate themselves and in the process, kill the cell, releasing newly-created progeny virus to repeat this process. If enteroviruses such as the CVB are to be considered causes of T1D, then - most simply - the viruses must be able to destroy the insulin-producing beta cells in the pancreatic Islets of Langerhans. We observed that no virus was detectable within the islets of young, healthy NOD mice, even though we could detect the receptor protein that the CVB uses to gain entrance to cells. Receptors are like doors to rooms: a virus has to have a receptor in order to gain entrance to a host cell. Thus, even though we showed the receptor is present in islets, the 'door' appears somehow barred to effective CVB entry. This observation was consistent with our failure to observe that CVB cause T1D in young, healthy mice: if the virus cannot kill islet cells, then one would suspect the virus cannot induce T1D, either. In fact, this is what we observed. mechanism called the innate immune response and production of specific antiviral protein molecules called interferons. Using a CVB3 strain that we developed in the laboratory which was bioengineered to produce a mouse immune protein (cytokine) called interleukin-4 (or IL-4), we showed that this virus did gain entry to islets in young, healthy NOD mice. This experiment was important for two reasons. One, it showed that the expression of the virus receptor meant that CVB could gain access to islet cells. While this was logical, it had not been shown before in the mouse itself, only in a special condition (cell culture). Secondly, it showed that by changing the local microenvironment of the islet by the virus-induced production of IL-4, the virus could replicate successfully in the islets. We also noticed two more things of importance. One, this type of virus infection caused no insulitis: the virus which produced IL-4 did not induce the mouse to attack the islets with its anti-viral immune response. Two, mice inoculated with this strain of virus had a better chance of never developing T1D than mice which did not get the virus infection. This surprising finding meant that despite intraislet replication of this bioengineered virus, this group of mice developed fewer cases of T1D than did mice without the virus injection. This observation showed that in some cases, virus infection of islets does not lead to more T1D or rapid onset T1D and therefore, the story was not quite so simple [2]. (This is a picture of a human pancreatic islet that was stained for the expression of a protein, called CAR, the receptor which the coxsackie B viruses require in order to enter a cell to replicate. The dark brown is the islet to which an antibody against CAR is bound. Clearly, human islets, like mouse islets, express CAR and so, should be able to be infected under the right circumstances.) 3. However, if the islet microenvironment is altered in specific ways, CVB can enter the islets. Other workers have suggested that the islets defend themselves against virus entry through a Islets in older NOD mice naturally become massively inflamed with autoimmune lymphocytes. This kills beta cells and the islet then loses the ability to produce insulin. Here you can see the residual small areas in such an islet in which Invest in ME (Charity Nr. 1114035) www.investinme.org Page 29 of 52

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