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Transcriptomic Analysis of the Dialogue Between Pseudorabies Virus and Porcine Epithelial Cells During Infection

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Transcriptomic Analysis of the Dialogue Between Pseudorabies Virus and Porcine Epithelial Cells During Infection Transcriptomic analysis of the dialogue between Pseudorabies virus and porcine epithelial cells during infection. Laurence Flori, Claire Rogel-Gaillard, Marielle Cochet, Gaetan Lemonnier, Karine Hugot, Patrick Chardon, Stéphane Robin, François Lefèvre To cite this version: Laurence Flori, Claire Rogel-Gaillard, Marielle Cochet, Gaetan Lemonnier, Karine Hugot, et al.. Tran- scriptomic analysis of the dialogue between Pseudorabies virus and porcine epithelial cells during infec- tion.. BMC Genomics, BioMed Central, 2008, 9, pp.123. 10.1186/1471-2164-9-123. cea-00307390 HAL Id: cea-00307390 https://hal-cea.archives-ouvertes.fr/cea-00307390 Submitted on 29 Jul 2008 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. BMC Genomics BioMed Central Research article Open Access Transcriptomic analysis of the dialogue between Pseudorabies virus and porcine epithelial cells during infection Laurence Flori*1, Claire Rogel-Gaillard1, Marielle Cochet2, Gaetan Lemonnier1, Karine Hugot1, Patrick Chardon1, Stéphane Robin3 and François Lefèvre2 Address: 1INRA, DGA, UMR 314, Laboratoire de Radiobiologie et d'Etude du Génome, Jouy-en-Josas, F-78350 France; CEA, DSV, IRCM, SREIT, Laboratoire de Radiobiologie et d'Etude du Génome, Jouy-en-Josas, F-78350, France, 2INRA, DSA, UR892, Unité de Virologie et Immunologie Moléculaires, Jouy-en-Josas, F-78350, France and 3AgroParisTech-ENGREF-INRA, UMR 518, Unité de Mathématiques et Informatique Appliquées, Paris F-75005, France Email: Laurence Flori* - [email protected]; Claire Rogel-Gaillard - [email protected]; Marielle Cochet - [email protected]; Gaetan Lemonnier - [email protected]; Karine Hugot - [email protected]; Patrick Chardon - [email protected]; Stéphane Robin - [email protected]; François Lefèvre - [email protected] * Corresponding author Published: 10 March 2008 Received: 20 August 2007 Accepted: 10 March 2008 BMC Genomics 2008, 9:123 doi:10.1186/1471-2164-9-123 This article is available from: http://www.biomedcentral.com/1471-2164/9/123 © 2008 Flori et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: Transcriptomic approaches are relevant for studying virus-host cell dialogues to better understand the physiopathology of infection and the immune response at the cellular level. Pseudorabies virus (PrV), a porcine Alphaherpesvirus, is a good model for such studies in pig. Since PrV displays a strong tropism for mucous epithelial cells, we developed a kinetics study of PrV infection in the porcine PK15 epithelial cell line. To identify as completely as possible, viral and cellular genes regulated during infection, we simultaneously analyzed PrV and cellular transcriptome modifications using two microarrays i.e. a laboratory-made combined SLA/PrV microarray, consisting of probes for all PrV genes and for porcine genes contained in the Swine Leukocyte Antigen (SLA) complex, and the porcine generic Qiagen-NRSP8 oligonucleotide microarray. We confirmed the differential expression of a selected set of genes by qRT-PCR and flow cytometry. Results: An increase in the number of differentially expressed cellular genes and PrV genes especially from 4 h post-infection (pi) was observed concomitantly with the onset of viral progeny while no early global cellular shutoff was recorded. Many cellular genes were down-regulated from 4 h pi and their number increased until 12 h pi. UL41 transcripts encoding the virion host shutoff protein were first detected as differentially expressed at 8 h pi. The viral gene UL49.5 encoding a TAP inhibitor protein was differentially expressed as soon as 2 h pi, indicating that viral evasion via TAP inhibition may start earlier than the cellular gene shutoff. We found that many biological processes are altered during PrV infection. Indeed, several genes involved in the SLA class I antigenic presentation pathway (SLA-Ia, TAP1, TAP2, PSMB8 and PSMB9), were down-regulated, thus contributing to viral immune escape from this pathway and other genes involved in apoptosis, nucleic acid metabolism, cytoskeleton signaling as well as interferon-mediated antiviral response were also modulated during PrV infection. Conclusion: Our results show that the gene expression of both PrV and porcine cells can be analyzed simultaneously with microarrays, providing a chronology of PrV gene transcription, which has never been described before, and a global picture of transcription with a direct temporal link between viral and host gene expression. Page 1 of 24 (page number not for citation purposes) BMC Genomics 2008, 9:123 http://www.biomedcentral.com/1471-2164/9/123 Background A precise and more complete identification of cellular and In vitro analyses of host cell/pathogen interactions are viral genes, which are up- or down-regulated during the essential to unravel the mechanisms of infection and to time course of infection, is essential to better understand investigate the host response to infection. Pseudorabies the physiopathology of infection and to identify the mol- virus (PrV) belongs to the Alphaherpesvirinae subfamily as ecules involved in host resistance/susceptibility mecha- for example the human herpes simplex virus 1 (HSV-1) nisms. During recent years, DNA microarray technology and is a well-known pig pathogen responsible for has proven to be a very efficient high-throughput tool to Aujeszky's disease, causing considerable economical study the gene expression profiles of infected host cells or losses worldwide in this species [1]. Although some coun- pathogens [10,11]. To date, three transcriptomic analyses tries have succeeded in eradicating Aujeszky's disease focused on cellular gene expression have been carried out through vaccination and health policies, the disease prev- in non-porcine PrV infected cells [12-14]. Ray and Enquist alence still remains variable in other countries. Young pig- have compared the cellular pathways regulated by PrV lets are more severely affected by PrV infection often and HSV-1 during infection of rat embryonic fibroblast resulting in fatal encephalitis, than older infected pigs, cells using a rat microarray [12]. In a similar system, Bruk- which can remain asymptomatic or develop mild to man and Enquist have explored how PrV evades the IFN- severe respiratory disease symptoms associated with a mediated immune response [13]. Finally, Blanchard et al limited mortality. Indeed, PrV displays a strong tropism have used a human microarray to characterize the impact for epithelial cells of the oronasal respiratory tract, which of PrV infection in human embryonic kidney cells (HEK- are the first cells targeted by virions [1,2]. Abortions, still- 293) [14]. These studies have identified many biological births or weak piglets that die within 48 h of birth are also processes and host cell genes regulated during infection. observed when pregnant sows are infected [1]. Moreover, The next step in a transcriptomic approach would be the PrV can infect a broad range of vertebrates resulting in a simultaneous analysis of viral and cellular modifications uniform lethality but it is generally considered as a non- of transcription during PrV infection [10,11] using por- pathogenic agent for man [3]. Because PrV is easy to prop- cine genomic tools. Since the pig whole genome assembly agate in cells of several mammalian species including is not yet achieved, no complete pan-genomic array exists rodents and is not harmful to laboratory workers, PrV is a and only partial generic microarrays are commercially highly relevant model to study the biology of alphaher- available [15]. However, the pig MHC region referred to as pesviruses and their interactions with host cells in vitro [1]. the SLA (Swine Leukocyte Antigen) complex, located on In addition, its genome has been reconstructed from chromosome 7, is the first region of the pig genome that sequences of six different strains (Kaplan, Becker, Rice, is entirely sequenced and annotated [16]. Indiana-Funkhauser, NIA-3, and TNL) and 70 genes encoding structural and non structural proteins have been In this context, our aim was to study the dialogue between annotated [4]. PrV and the PK15 porcine epithelial cell line, which mim- ics the first porcine target cells. Using two different por- Viruses have evolved strategies to evade the host immune cine microarrays, we followed both the viral and cellular response. In particular, herpesviruses interfere with the transcriptome kinetics during infection. These microar- Major Histocompatibility Complex (MHC) class I antigen rays were the Qiagen-NRSP8 commercial array [17] and a presentation pathway to avoid the Cytotoxic T Lym- microarray we constructed, referred to as SLA/PrV, which phocyte (CTL) response [5]. MHC class I molecules are combines probe sets
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