Enteroviruses, type 1 diabetes and hygiene: a complex relationship

Abstract

Type 1 diabetes (T1D) is an autoimmune disease in which the immune system mounts an attack on the host's insulin-producing beta cells. Because most cases of T1D cannot be attributed only to individual genetics, it is strongly inferred that there is a significant environmental contribution, such as infection, impacting disease development. The human enteroviruses (HEV) are common picornaviruses often implicated as triggers of human T1D, although precisely which of the numerous HEV may be involved in human T1D development is unknown. Experiments using non-obese diabetic (NOD) mice, commonly used to model T1D, show that induction of T1D by HEV infection in NOD mice is a multifactorial process involving both the virus and the host. Interestingly, results demonstrate that HEV infection of NOD mice can also induce long-term protection from T1D under certain conditions, suggesting that a similar mechanism may occur in humans. Based upon both experimental animal and observational human studies, we postulate that HEV have a dual role in T1D development and can either cause or prevent autoimmune disease. Whichever outcome occurs depends upon multiple variables in the host-virus equation, many of which can be deduced from results obtained from NOD mouse studies. We propose that the background to the sharply rising T1D incidences observed in the 20th century correlates with increased levels of hygiene in human societies. Viewing T1D in this perspective suggests that potential preventative options could be developed.

Rotavirus acceleration of murine type 1 diabetes is associated with a T helper 1-dependent specific serum antibody response and virus effects in regional lymph nodes

“…Although viruses, particularly gastrointestinal pathogens, are considered to play key roles in modulating the development of diabetes in humans, a direct causal relationship is yet to be defined [7,8]. Viruses delay or accelerate the onset of diabetes in animal models, not necessarily through pancreatic infection.…”

Do viral infections protect from or enhance type 1 diabetes and how can we tell the difference?

“…The strongest evidence for an involvement of viruses in the pathogenesis if T1D derives from enteroviruses (see Ref. 19 for a recent review on that topic). For example, CVB3 and CVB4 RNA have been detected in the blood of recent onset T1D patients.…”

“…29 However, according to a recent review by Tracy et al, there is no convincing evidence indicating that the CVB4 strain is more diabetogenic than the other serotypes (CVB1-6). 19 …”

“…56 In contrast to CVB4, the strain CVB3 seems to have a dual effect on T1D. 19 Infection of young (4-6 weeks old) NOD mice with CVB3 failed to accelerate T1D, but provided a long-term (for at least 10 months of age) protection from disease. 57 Interestingly, the replication properties and the dose of administration of CVB3 substrains critically influenced the outcome of T1D in the NOD mouse.…”

“…19 This implies that antiviral vaccines should transform deleterious more severe infections into protective ones and there is indeed an initiative in Finland to develop such a vaccine and test this concept. It should also be possible to test this concept in prospective studies such as TEDDY, but to achieve this it might have been necessary to also recover samples from children precisely at the time of febrile infections, which would likely encompass the more deleterious enterovirus encounters.…”