No abstract

Enterovirus 94 (EV‐94) is an enterovirus serotype described recently which, together with EV‐68 and EV‐70, forms human enterovirus D species. This study investigates the seroprevalences of these three serotypes and their abilities to infect, replicate, and damage cell types considered to be essential for enterovirus‐induced diseases. The cell types studied included human leukocyte cell lines, primary endothelial cells, and pancreatic islets. High prevalence of neutralizing antibodies against EV‐68 and EV‐94 was found in the Finnish population. The virus strains studied had wide leukocyte tropism. EV‐94 and EV‐68 were able to produce infectious progeny in leukocyte cell lines with monocytic, granulocytic, T‐cell, or B‐cell characteristics. EV‐94 and EV‐70 were capable of infecting primary human umbilical vein endothelial cells, whereas EV‐68 had only marginal progeny production and did not induce cytopathic effects in these cells. Intriguingly, EV‐94 was able to damage pancreatic islet β‐cells, to infect, replicate, and cause necrosis in human pancreatic islets, and to induce proinflammatory and chemoattractive cytokine expression in endothelial cells. These results suggest that HEV‐D viruses may be more prevalent than has been thought previously, and they provide in vitro evidence that EV‐94 may be a potent pathogen and should be considered a potentially diabetogenic enterovirus type. J. Med. Virol. 82:1940–1949, 2010. © 2010 Wiley‐Liss, Inc.

The genus Enterovirus (family Picornaviridae) contains five species with strains isolated from humans: Human enterovirus A (HEV-A), HEV-B, HEV-C, HEV-D and Poliovirus. In this study, a proposed new serotype of HEV-D was characterized. Four virus strains were isolated from sewage in Egypt and one strain from acute flaccid paralysis cases in the Democratic Republic of the Congo. The complete genome of one environmental isolate, the complete coding sequence of one clinical isolate and complete VP1 regions from the other isolates were sequenced. These isolates had 66.6-69.4 % nucleotide similarity and 74.7-76.6 % amino acid sequence similarity in the VP1 region with the closest enterovirus serotype, enterovirus 70 (EV70), suggesting that the isolates form a new enterovirus type, tentatively designated enterovirus 94 (EV94). Phylogenetic analyses including sequences of the 59 UTR, VP1 and 3D regions demonstrated that EV94 isolates formed a monophyletic group within the species HEV-D. No evidence of recombination was found between EV94 and the other HEV-D serotypes, EV68 and EV70. Further biological characterization showed that EV94 was acid stable and had a wide cell tropism in vitro. Attempts to prevent replication with protective antibodies to known enterovirus receptors (poliovirus receptor, vitronectin a v b 3 receptor and decay accelerating factor) were not successful. Seroprevalence studies in the Finnish population revealed a high prevalence of this virus over the past two decades. INTRODUCTIONThe genus Enterovirus (family Picornaviridae) contains a large group of human pathogens. Although the majority of enterovirus infections are subclinical, enterovirus infection can lead to a variety of acute and chronic diseases including mild upper respiratory illness, febrile rash, aseptic meningitis, encephalitis, acute haemorrhagic conjunctivitis, pleurodynia, acute flaccid paralysis (AFP), diabetes, myocarditis and neonatal sepsis-like disease (Pallansch & Roos, 2001). The primary site of enterovirus infection is the mucosal tissue of the respiratory or gastrointestinal tract. After spreading through the lymphatic system and circulation, the virus can infect secondary target tissues. The secondary replication sites largely define the clinical manifestations of a given enterovirus strain. In the intestinal mucosa, virus replication can continue for several weeks, during which time progeny virus is shed into faeces.The enterovirus genome is a single-stranded RNA molecule of approximately 7500 nt consisting of a single open reading frame flanked by non-coding 59 and 39 regions. The 59 UTR contains an internal ribosome-binding site, which is essential for translation initiation (Pelletier & Sonenberg, 1988;Molla et al., 1992;Chen & Sarnow, 1995). The 39 UTR forms highly conserved secondary and tertiary structures that are thought to be important in replication initiation (Pilipenko et al., 1992(Pilipenko et al., , 1996Mirmomeni et al., 1997). The open reading frame is translated into a single, large polypeptide, which is...

No correlation was found between the presence of HEV in the first year of life and the development of islet autoantibodies. There was no association between HEV infections and dietary intervention, maternal diabetes or clinical symptoms.

Aims/hypothesis Virally induced inflammatory responses, beta cell destruction and release of beta cell autoantigens may lead to autoimmune reactions culminating in type 1 diabetes. Therefore, viral capability to induce beta cell death and the nature of virus-induced immune responses are among key determinants of diabetogenic viruses. We hypothesised that enterovirus infection induces a specific gene expression pattern that results in islet destruction and that such a host response pattern is not shared among all enterovirus infections but varies between virus strains. Methods The changes in global gene expression and secreted cytokine profiles induced by lytic or benign enterovirus infections were studied in primary human pancreatic islet using DNA microarrays and viral strains either isolated at the clinical onset of type 1 diabetes or capable of causing a diabetes-like condition in mice.Results The expression of pro-inflammatory cytokine genes (IL-1-α, IL-1-β and TNF-α) that also mediate cytokineinduced beta cell dysfunction correlated with the lytic potential of a virus. Temporally increasing gene expression levels of double-stranded RNA recognition receptors, antiviral molecules, cytokines and chemokines were detected for all studied virus strains. Lytic coxsackievirus B5 (CBV-5)-DS infection also downregulated genes involved in glycolysis and insulin secretion. Conclusions/interpretation The results suggest a distinct, virusstrain-specific, gene expression pattern leading to pancreatic 3273-3283 DOI 10.10073273-3283 DOI 10. /s00125-012-2713 islet destruction and pro-inflammatory effects after enterovirus infection. However, neither viral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. More likely the combined effect of these and possibly cellular energy depletion lie behind the enterovirus-induced necrosis of islets.