RESUMEN
Hepatitis is a common and potentially fatal manifestation of severe Coxsackievirus infections, particularly in newborn children. Little is known of the immune-mediated mechanisms regulating permissiveness to liver infection. It is well established that type I interferons (IFNs) play an important role in the host innate immune response to Coxsackievirus infections. Recent studies have highlighted a role for another IFN family, the type III IFNs (also called IFN-λ), in anti-viral defence. Whether type III IFNs are produced by hepatocytes during a Coxsackievirus infection remains unknown. Moreover, whether or not type III IFNs protects hepatocytes from a Coxsackievirus infection has not been addressed. In this study, we show that primary human hepatocytes respond to a Coxsackievirus B3 (CVB3) infection by up-regulating the expression of type III IFNs. We also demonstrate that type III IFNs induce an anti-viral state in hepatocytes characterized by the up-regulated expression of IFN-stimulated genes, including IFN-stimulated gene (ISG15), 2'-5'-oligoadenylate synthetase 2 (OAS2), protein kinase regulated by dsRNA (PKR) and myxovirus resistance protein 1 (Mx1). Furthermore, our study reveals that type III IFNs attenuate CVB3 replication both in hepatocyte cell lines and primary human hepatocytes. Our studies suggest that human hepatocytes express type III IFNs in response to a Coxsackievirus infection and highlight a novel role for type III IFNs in regulating hepatocyte permissiveness to this clinically relevant type of virus.
Asunto(s)
Enterovirus/fisiología , Expresión Génica , Hepatocitos/metabolismo , Hepatocitos/virología , Interferón gamma/genética , Adulto , Anciano , Anciano de 80 o más Años , Línea Celular , Infecciones por Coxsackievirus/metabolismo , Enterovirus Humano B/fisiología , Femenino , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Humanos , Interferón gamma/biosíntesis , Interferón gamma/farmacología , Masculino , Persona de Mediana EdadRESUMEN
AIMS/HYPOTHESIS: Enterovirus (e.g. Coxsackie B virus serotypes [CVBs]) infections may be associated with development of type 1 diabetes. Studies conducted in several European countries have, however, shown an inverse correlation between the incidence of type 1 diabetes and the prevalence of enterovirus infections. These findings could in part be explained by an extension of the poliovirus hypothesis, suggesting that the absence of maternally transferred antibodies protecting offspring from early infection increases the risk for diabetes development. Experimental evidence supporting this hypothesis in type 1 diabetes is, however, lacking. As maternally transferred protection from infection is a crucial component of the extended poliovirus hypothesis, we here tested the hypothesis that previously infected females transfer protection against infection and diabetes to offspring. METHODS: The induction of CVB-specific maternal antibodies and transfer of protection from virus infection, replication and development of virus-induced diabetes to offspring was assessed using NOD and Socs1-transgenic NOD mice. RESULTS: Infected mice produced neutralising antibodies to CVB. Offspring from infected females were positive for neutralising antibodies and were strongly protected from both infection and experimental diabetes. CONCLUSIONS/INTERPRETATION: Our study shows that maternally transferred antibodies protect offspring from enterovirus infection and virus-induced diabetes. This suggests that the absence of maternally provided protection increases the risk for severe outcomes after an enterovirus infection in offspring. Moreover, our findings may have implications for the design of prospective studies aimed at investigating the possible role of enterovirus infections in the aetiology of human type 1 diabetes.
Asunto(s)
Diabetes Mellitus Experimental/prevención & control , Infecciones por Enterovirus/complicaciones , Infecciones por Enterovirus/prevención & control , Animales , Anticuerpos Antivirales/inmunología , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/inmunología , Infecciones por Enterovirus/inmunología , Femenino , Inmunoglobulina G/inmunología , Masculino , Exposición Materna , Ratones , Ratones Endogámicos NOD , Ratones Transgénicos , Embarazo , PreñezRESUMEN
Nutritional benefits of cultivated oat (Avena sativa L., 2n = 6x = 42, AACCDD) are well recognized; however, seed protein levels are modest and resources for genetic improvement are scarce. The wild tetraploid, A. magna Murphy et Terrell (syn A. maroccana Gdgr., 2n = 4x = 28, CCDD), which contains approximately 31% seed protein, was hybridized with cultivated oat to produce a domesticated A. magna. Wild and cultivated accessions were crossed to generate a recombinant inbred line (RIL) population. Although these materials could be used to develop domesticated, high-protein oat, mapping and quantitative trait loci introgression is hindered by a near absence of genetic markers. Objectives of this study were to develop high-throughput, A. magna-specific markers; generate a genetic linkage map based on the A. magna RIL population; and map genes controlling oat domestication. A Diversity Arrays Technology (DArT) array derived from 10 A. magna genotypes was used to generate 2,688 genome-specific probes. These, with 12,672 additional oat clones, produced 2,349 polymorphic markers, including 498 (21.2%) from A. magna arrays and 1,851 (78.8%) from other Avena libraries. Linkage analysis included 974 DArT markers, 26 microsatellites, 13 SNPs, and 4 phenotypic markers, and resulted in a 14-linkage-group map. Marker-to-marker correlation coefficient analysis allowed classification of shared markers as unique or redundant, and putative linkage-group-to-genome anchoring. Results of this study provide for the first time a collection of high-throughput tetraploid oat markers and a comprehensive map of the genome, providing insights to the genome ancestry of oat and affording a resource for study of oat domestication, gene transfer, and comparative genomics.