Journal of IiME Volume 8 Issue 1 May 2014 Human Enteroviruses and Type 1 Diabetes onset (when older mice with insulitis are exposed to the virus). The CVB belong to one of four human enterovirus species, denoted A-D. Only human enteroviruses of the B species (or HEV-B), and this includes the CVB, have been associated with T1D onset. Poliovirus, for example, which is a species C enterovirus and to which nearly everyone in the world has been exposed (mostly now by clinical inoculations but prior to this due to wild-type infections), has had no impact on T1D incidence. Thus, we propose that the HEV-B species are the key players. Now, for an enterovirus to 'suddenly' trigger T1D (when T1D occurs shortly after or during, for example, a 'cold' or 'flu-like' illness), we believe the islets have to already be significantly experiencing extensive insulitis through one's own autoimmune disease. That is to say, insulitis has to be present. This might normally, in time, lead to T1D onset or it might not. From the NOD mouse model, we know that islets in young mice that are not inflamed cannot be normally infected by CVB. This does not have to do with the virus receptor, the protein on the cell surface which the virus uses to enter cells. The CVB receptor is well expressed in young and older mice. So, when mice are young and have no insulitis yet, the islets cannot be infected, but when the mice are older and are developing insulitis, CVB can infect remaining healthy islet tissue and if the viral damage is sufficient, T1D ensues shortly after the virus infection. However, the overwhelming majority of people do not have insulitis. Therefore, we postulate that because most enterovirus infections in humans do not induce T1D, by far most people do not have insulitis. Therefore, this is consistent with the observation that the very great majority of enterovirus infections do not trigger T1D onset. The host (humans or mice) have to "work" with the virus to cause T1D. That is to say, without hostdriven (genetically determined) insulitis, the enterovirus cannot replicate productively in beta cells and cause T1D. Viruses are opportunists and will replicate wherever they can. In the case of a normal (not inflamed) islet in the mouse pancreas, CVB can enter cells (because the receptor is present) but cannot successfully replicate. We hypothesize that this is also the case in human beings. Only when the islet is attacked by the host's autoimmune disease do islets' defenses fall, permitting the virus to replicate productively in and kill islet cells. We know this happens in mice and we postulate this is the case in human beings. But this is a contested point. Human islets, isolated from pancreas and placed in culture, can replicate enteroviruses: such infections can kill beta cells in these cultured islets. This observation suggests that human islets might be infectable in the body, whether or not they are inflamed due to the autoimmune process. Currently, this remains an open question. We also know from our work in mice, that the enterovirus infection has to be due to a strain that replicates quickly in the pancreas. Just like some humans can run faster than others, some virus strains can replicate faster than others (that is, some virus strains make more progeny virus in a shorter length of time than others). We have characterized strains (or variants) of CVB serotypes that replicate more rapidly and to higher titers, than other strains. To initiate T1D in NOD mice, we have shown that as few as 50 virus particles of a rapidly replicating strain of CVB3 can induce T1D, whereas more than 1 million virus particles of a slowly replicating strain are needed to induce T1D. Therefore, the average dose needed to successfully infect a mouse and to cause T1D with a rapidly replicating strain is far lower than for other strains. However, these rapidly replicating strains of enterovirus (which are generally termed 'virulent' strains, due to their capacity to induce disease easily in disease models) which are capable of causing severe disease, circulate relatively rarely. Most CVB strains, for example, do not cause serious disease such as myocarditis when assayed in mice. And even though all CVB strains replicate well in pancreas (thereby showing that these viruses have a predilection for replicating in pancreas tissue), this does not mean, that all are capable of replicating sufficiently well in islets to trigger T1D. The bottom line is this: the average (usual) enterovirus infection is due to a poorly virulent strain at a low dose, two factors that along with the requirement for ongoing insulitis, lower the odds dramatically for a T1D-inducing islet infection. We also know that enterovirus infections induce protective antiviral immunity in people. This is the same principle by which the poliovirus vaccines have worked so well: inoculation with the vaccine strains of poliovirus induce an immunity that Invest in ME (Charity Nr. 1114035) www.investinme.org Page 31 of 52
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