It is thought that enterovirus infections initiate or facilitate the pathogenetic processes leading to type 1 diabetes. Exposure of cultured human islets to cytolytic enterovirus strains kills beta ...cells after a protracted period, suggesting a role for secondary virus-induced factors such as cytokines.
To clarify the molecular mechanisms involved in virus-induced beta cell destruction, we analysed the global pattern of gene expression in human islets. After 48 h, RNA was extracted from three independent human islet preparations infected with coxsackievirus B5 or exposed to interleukin 1beta (50 U/ml) plus interferon gamma (1,000 U/ml), and gene expression profiles were analysed using Affymetrix HG-U133A gene chips, which enable simultaneous analysis of 22,000 probe sets.
As many as 13,077 genes were detected in control human islets, and 945 and 1293 single genes were found to be modified by exposure to viral infection and the indicated cytokines, respectively. Four hundred and eighty-four genes were similarly modified by the cytokines and viral infection.
The large number of modified genes observed emphasises the complex responses of human islet cells to agents potentially involved in insulitis. Notably, both cytokines and viral infection significantly (p<0.02) increased the expression of several chemokines, the cytokine IL-15 and the intercellular adhesion molecule ICAM-1, which might contribute to the homing and activation of mononuclear cells in the islets during infection and/or an early autoimmune response. The present results provide novel insights into the molecular mechanisms involved in viral- and cytokine-induced human beta cell dysfunction and death.
We describe a cluster of norovirus outbreaks affecting about 200 people in Southern Finland in September and October 2009. All outbreaks occurred after consumption of imported raspberries from the ...same batch intended for the catering sector. Human norovirus genotype GI.4 was found in frozen raspberries. The berries were served in toppings of cakes in separate catering settings or mixed in curd cheese as a snack for children in a daycare center. The relative risk for consumption of the berry dish was 3.0 (p <or= 0.05) at the daycare centre. Human norovirus GI.4 was also detected in samples from two patients, and in berries. Both shared identical partial capsid sequences. Based on the results of epidemiological, trace-back and laboratory investigations it was concluded that one particular batch of frozen raspberries was the source of all outbreaks.
Aims/hypothesis
The purpose of this study was to investigate whether the gut mucosa is a reservoir for enterovirus persistence in patients with type 1 diabetes.
Methods
Small intestine biopsy samples ...from 25 individuals at different stages of type 1 diabetes, 21 control individuals and 27 individuals with coeliac disease were analysed for the presence of enterovirus RNA by using both radioactive in-situ hybridisation and real-time RT-PCR and for the presence of enterovirus proteins by immunostaining with antibodies against VP1 and VP4-2-3 capsid proteins and virus polymerase. Lymphocytic enteropathy and serum anti-VP1 antibodies were also evaluated at the time of biopsy. Moreover, high-throughput sequencing was performed to identify viral transcripts or genomes.
Results
Enterovirus was not detected by in-situ hybridisation or RT-PCR in any of the individuals tested. Immunohistology revealed a few stained cells in the intestinal epithelium in a low number of individuals, with no difference between diabetic and non-diabetic individuals. Levels of serum IgG against VP1 did not differ between control individuals and those with diabetes or coeliac disease and no evidence of diabetes-related lymphocytic enteropathy was detected. High-throughput sequencing did not reveal specific enterovirus sequences in the gut mucosa of individuals with type 1 diabetes.
Conclusions/interpretation
Prolonged/persistent enterovirus infections in gut mucosa are not common in patients with type 1 diabetes.
In August 2012, an outbreak of gastroenteritis occurred among 88 persons attending a wedding reception at a resort/activity centre in Ylöjärvi, Finland. Of 39 interviewed guests, 23 met the case ...definition. Two persons were hospitalized. Epidemiological, laboratory and environmental investigations were conducted to characterize the outbreak and to recommend control measures. Investigation confirmed the presence of a new strain of norovirus GII.4 Sydney variant in stool specimens obtained from two wedding guests and on several environmental surfaces in the centre. In the questionnaire study, none of the foods or beverages served during the reception were significantly associated with the illness. Additional cases of gastroenteritis that occurred at the centre before and after the wedding reception supported the hypothesis of environmental transmission of norovirus. After thorough cleansing and disinfection and 1 week's quarantine, no new cases with symptoms typical for norovirus infection were identified at the centre.
Military conscripts are susceptible to respiratory and gastrointestinal tract infections. In previous studies probiotics have shown potency to reduce upper respiratory and gastrointestinal ...infections. The aim was to study whether probiotic intervention has an impact on seasonal occurrence of upper respiratory and gastrointestinal infections in two different conscript groups. In a randomised, double-blinded, placebo controlled study (https://clinicaltrials.gov NCT01651195), a total of 983 healthy adults were enrolled from two intakes of conscripts. Conscripts were randomised to receive either a probiotic combination of Lactobacillus rhamnosus GG (LGG) and Bifidobacterium animalis ssp. lactis BB12 (BB12) or a control chewing tablet twice daily for 150 days (recruits) or for 90 days (reserve officer candidates). Clinical examinations were carried out and daily symptom diaries were collected. Outcome measures were the number of days with respiratory and gastrointestinal symptoms and symptom incidence, number and duration of infection episodes, number of antibiotic treatments received and number of days out of service because of the infection. Statistically no significant differences were found between the intervention groups either in the risk of symptom incidence or duration. However, probiotic intervention was associated with reduction of specific respiratory infection symptoms in military recruits, but not in reserve officer candidates. Probiotics did not significantly reduce overall respiratory and gastrointestinal infection morbidity.
Direct infection of beta cells could explain the diabetogenic effect of enteroviruses. Primary adult human beta cells are susceptible to coxsackievirus infections, which could result in impaired ...beta-cell function or cell death (coxsackieviruses B3, B4, B5) or both, or no apparent immediate adverse effects (coxsackievirus A9). We extended these studies to additional enterovirus serotypes including several echoviruses, some of which have been associated clinically with the development of Type I (insulin-dependent) diabetes mellitus.
The patterns and consequences of enterovirus infections were investigated in cultured adult human isolated islets. Cell type-specific infection and viability were assessed by immunocytochemical methods. Beta-cell function was studied by perifusion.
Poliovirus type 1/Mahoney, coxsackievirus A13, human parechovirus 1 and several echoviruses (serotypes 6, 7, 11) were capable of causing significant functional impairment ( p<0.05) and beta-cell death. In contrast, echovirus serotypes 9 and 30 were not destructive. However, when several different field isolates of echovirus 30 were investigated, some of them were found to be clearly more destructive than the corresponding prototype strain. This was also true for echovirus 9. A strain isolated from a 6-week-old baby suffering from acute Type I diabetes was functionally more destructive than either of the echovirus 9 prototype strains.
These observations indicate that the capacity of an enterovirus to kill human beta cells or impair their function is not entirely defined by the serotype, but in addition by as yet unidentified characteristics of the virus strain involved. Moreover, any serotype could potentially be diabetogenic.
Common enterovirus infections appear to initiate or facilitate the pathogenetic processes leading to type 1 diabetes, and sometimes also precipitate the clinical disease. It is not known in detail ...how enterovirus infections bring about the loss of insulin-producing β-cells, a phenomenon characteristic of the disease. Recent results from studies on pancreases from human autopsies and cultured human islets support the idea that during systemic enterovirus infections, the virus may reach pancreatic islets and cause direct β-cell damage. Although individual enteroviruses (EV) exhibited differences in their β-cell tropism in the cultured human islets, all serotypes studied contained highly destructive strains. The final confirmation on the role of enteroviruses in type 1 diabetes can only be obtained from intervention studies. If the association holds true then it would be possible to reduce the risk of developing type 1 diabetes by preventing enterovirus infections with a multivalent enterovirus vaccine that could be given to children soon after birth.
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