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Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens.

ABSTRACT: Gene expression patterns supply insight into complex biological networks that provide the organization in which viruses and host cells interact. Measles virus (MV) is an important human pathogen that induces transient immunosuppression followed by life-long immunity in infected individuals. Dendritic cells (DCs) are potent antigen-presenting cells that initiate the immune response to pathogens and are postulated to play a role in MV-induced immunosuppression. To better understand the interaction of MV with DCs, we examined the gene expression changes that occur over the first 24 h after infection and compared these changes to those induced by other viral, bacterial, and fungal pathogens. There were 1,553 significantly regulated genes with nearly 60% of them down-regulated. MV-infected DCs up-regulated a core of genes associated with maturation of antigen-presenting function and migration to lymph nodes but also included genes for IFN-regulatory factors 1 and 7, 2'5' oligoadenylate synthetase, Mx, and TNF superfamily proteins 2, 7, 9, and 10 (TNF-related apoptosis-inducing ligand). MV induced genes for IFNs, ILs, chemokines, antiviral proteins, histones, and metallothioneins, many of which were also induced by influenza virus, whereas genes for protein synthesis and oxidative phosphorylation were down-regulated. Unique to MV were the induction of genes for a broad array of IFN-alphas and the failure to up-regulate dsRNA-dependent protein kinase. These results provide a modular view of common and unique DC responses after infection and suggest mechanisms by which MV may modulate the immune response.

SUBMITTER: Zilliox MJ

PROVIDER: S-EPMC1413941 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens.

Zilliox Michael J MJ Parmigiani Giovanni G Griffin Diane E DE

Proceedings of the National Academy of Sciences of the United States of America 20060221 9

Gene expression patterns supply insight into complex biological networks that provide the organization in which viruses and host cells interact. Measles virus (MV) is an important human pathogen that induces transient immunosuppression followed by life-long immunity in infected individuals. Dendritic cells (DCs) are potent antigen-presenting cells that initiate the immune response to pathogens and are postulated to play a role in MV-induced immunosuppression. To better understand the interaction ...[more]

PMID: 16492729

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Project description:Characterization of human measles cases is essential in order to better assess the data generated in model systems of morbillivirus infection. To this end, we collected formalin-fixed tissue samples from 23 natural measles cases from different areas in the world and different phases of disease ranging from prodromal and acute measles to a persistent infection in an immunocompromised subject. We show that the vast majority of measles virus (MV)-infected cells in epithelia were intraepithelial immune cells that were, in most cases, positive for the CD11c myeloid cell marker. Small numbers of measles virus-infected cytokeratin-positive epithelial cells were also detected in bronchial and appendix epithelia. Dissolution and disruption of uninfected and MV-infected alveolar and bronchial epithelia were prominent features of the measles cases, especially in the established and late phases of the disease. In some instances, this was associated with the formation of MV-infected multinucleated giant cells which expressed CD11c and/or macrophage cell marker 68, a pathological feature also prominently observed in closely associated mucosa-associated lymphoid tissue. Collectively, these data show that resident and inflammatory infiltrating immune cells alter the architecture of respiratory tract epithelia and highlight the necessity for additional research into the function(s) and expression of nectin-4 in human tissues.IMPORTANCE We have brought together a unique collection of 23 human cases of measles infection and studied the types of cells that are infected. This work has not been done with modern technologies such as double labeling with antibodies and confocal microscopy in human cases primarily due to the fact that it is difficult to obtain the material because, fortunately, measles is fatal in only a very small fraction of infected patients. During the past decades, the receptors for measles virus have been elucidated and monkey models have been developed. We found that, in most cases, independently of whether the tissues were obtained early or later in the infection, the primary cell types that were infected were those of the immune system such as lymphocytes, macrophages, and dendritic cells. A very small number of epithelial cells were also found to be infected.

Project description:MicroRNAs are small non-coding RNAs approximately 22 nt long that modulate gene expression in animals and plants. It has been recently demonstrated that herpesviruses encode miRNAs to control the post-transcriptional regulation of expression from their own genomes and possibly that of their host, thus adding an additional layer of complexity to the physiological cross-talk between host and pathogen. The present study focussed on the interactions between porcine dendritic cells (DCs) and the Pseudorabies virus (PRV), an alpha-herpesvirus causing Aujeszky's disease in pigs. A catalogue of porcine and viral miRNAs, expressed eight hours post-infection, was established by deep sequencing. An average of 2 million reads per sample with a size of 21-24 nucleotides was obtained from six libraries representing three biological replicates of infected and mock-infected DCs. Almost 95% of reads mapped to the draft pig genome sequence and pig miRNAs previously annotated in dedicated databases were detected by sequence alignment. In silico prediction allowed the identification of unknown porcine as well as of five miRNAs transcribed by the Large Latency Transcript (LLT) of PRV. The gene target prediction of the viral miRNAs and the Ingenuity Pathway Analysis of differentially expressed pig miRNAs were conducted to contextualize the identified small RNA molecules and functionally characterize their involvement in the post-transcriptional regulation of gene expression. The results support a role for PRV miRNAs in the maintenance of the host cell latency state through the down-regulation of immediate-early viral genes which is similar to other herpesviruses. The differentially expressed swine miRNAs identified a unique network of target genes with highly significant functions in the development and function of the nervous system and in infectious mechanisms, suggesting that the modulation of both host and viral miRNAs is necessary for the establishment of PRV latency.

Dataset Information

Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens.

Publications

Gene expression patterns in dendritic cells infected with measles virus compared with other pathogens.

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