Group B Coxsackievirus Diabetogenic Phenotype Correlates with Replication Efficiency

Abstract

Group B coxsackieviruses can initiate rapid onset type 1 diabetes (T1D) in old nonobese diabetic (NOD) mice. Inoculating high doses of poorly pathogenic CVB3/GA per mouse initiated rapid onset T1D. Viral protein was detectable in islets shortly after inoculation in association with beta cells as well as other primary islet cell types. The virulent strain CVB3/28 replicated to higher titers more rapidly than CVB3/GA in the pancreas and in established beta cell cultures. Exchange of 5-nontranslated regions between the two CVB3 strains demonstrated a variable impact on replication in beta cell cultures and suppression of in vivo replication for both strains. While any CVB strain may be able to induce T1D in prediabetic NOD mice, T1D onset is linked both to the viral replication rate and infectious dose.Insulin-dependent (type 1) diabetes mellitus (T1D) is an autoimmune, largely T-cell-mediated disease typically diagnosed before the end of the teen years (5, 6). A predisposing, multigenic component has been described but accounts for fewer than 50% of cases (7,35,45); environmental factors (e.g., viral infections) have therefore been proposed to explain the remaining cases of T1D (3,6,32,57,58) that cannot be ascribed solely to host-driven pathogenic autoimmunity. Human enterovirus (HEV) infections have long been suspected as environmental triggers of human T1D (12,22,27); infections by common HEVs, such as the group B coxsackieviruses (CVB 1 to 6) and diverse echoviruses, have been implicated as triggers of T1D onset at the time of or shortly after infection (8,9,13,19,28,37,39,40,42,52,60). Nonetheless, it remains unclear whether HEV initiates T1D in humans (18,21,24,26); evidence supporting an etiologic connection between HEV infection and T1D onset is not as well-established as the links between, for example, specific HEV infections and poliomyelitis, aseptic meningitis, or myocarditis (43).The nonobese diabetic (NOD) mouse is widely used as a model for the study of T1D. Previous work demonstrated that CVB inoculation protects young NOD mice significantly better from T1D as they age than no treatment (mock infected) (55). Unlike all other treatments that protect NOD mice from T1D (reviewed in references 4 and 46), the CVB are widely thought to be instigators of T1D onset with no protective effect. The extent of protection from T1D onset correlates directly with replication efficiency of the specific CVB strain that is employed: CVB strains that replicate to higher titers protect more mice than do CVB strains which replicate to lower titers. As NOD mice age, naturally occurring, pathogenic autoimmune insulitis develops rapidly (4) with widespread islet inflammation (insulitis) present by week 12 to 15 of age, when T1D also begins to occur. T1D rapidly ensues following inoculation of old (Ͼ12 weeks of age) NOD mice with virulent CVB (14), a model that recapitulates observations of sudden T1D onset in humans reported to occur during or shortly after an infection (37, 52). Initiation of rapid T1D onset in older mice...

Enterovirus strain and type-specific differences in growth kinetics and virus-induced cell destruction in human pancreatic duct epithelial HPDE cells

“…The experiments using primary cultures of human pancreatic islets suggest that the extent to which inflammatory mediators are produced may correlate to the severity of the infection (virus yield) (Schulte et al, 2012;Ylipaasto et al, 2012). Likewise, in mouse models it has been shown that the viral replication efficiency in pancreas contributes to the development of type 1 diabetes (Kanno et al, 2006) or chronic pancreatic inflammation (Al-Hello et al, 2005) after CVB infection. Therefore, virus strains with high productivity in pancreas are more likely to induce stronger and potentially harmful inflammatory response.…”

Induction of an Antiviral State and Attenuated Coxsackievirus Replication in Type III Interferon-Treated Primary Human Pancreatic Islets

“…This observation, coupled with in vitro studies demonstrating a gradual loss of function and viability in human pancreatic islet cells infected with enteroviruses (e.g., CVBs) (18), suggests that a direct infection of the pancreatic beta cell may be involved in the disease process. Studies in animal models have provided additional support for this hypothesis (19)(20)(21)(22). However, irrespective of these observations, surprisingly little is known about the ways in which permissiveness to enterovirus infection is regulated in pancreatic islet cells (23).…”

The microbiology of human hygiene and its impact on type 1 diabetes

“…71 But once insulitis has begun, however, HEV such as the CVB can and do infect murine islets, destroying β cells and triggering T1D onset. 72,73 Thus, the impact of HEV alone can be either protective or destructive, depending upon factors determined both by the host (state of insulitis and previous antiviral immunities) and the infecting virus (strain and dose).…”