Ablation of the Regulatory IE1 Protein of Murine Cytomegalovirus Alters In Vivo Pro-inflammatory TNF-alpha Production during Acute Infection

Rodríguez-Martín, Sara; Kropp, Kai Alexander; Wilhelmi, Vanessa; Lisnic, Vanda Juranic; Hsieh, Wei Yuan; Blanc, Mathieu; Livingston, Andrew; Busche, Andreas; Tekotte, Hille; Messerle, Martin; Auer, Manfred; Fraser, Iain; Jonjic, Stipan; Angulo, Ana; Reddehase, Matthias J; Ghazal, Peter; Britt, William J

Abstract

Little is known about the role of viral genes in modulating host cytokine responses. Here we report a new functional role of the viral encoded IE1 protein of the murine cytomegalovirus in sculpting the inflammatory response in an acute infection. In time course experiments of infected primary macrophages (MWs) measuring cytokine production levels, genetic ablation of the immediate-early 1 (ie1) gene results in a significant increase in TNFa production. Intracellular staining for cytokine production and viral early gene expression shows that TNFa production is highly associated with the productively infected MW population of cells. The ie1-dependent phenotype of enhanced MW TNFa production occurs at both protein and RNA levels. Noticeably, we show in a series of in vivo infection experiments that in multiple organs the presence of ie1 potently inhibits the pro-inflammatory cytokine response. From these experiments, levels of TNFa, and to a lesser extent IFNb, but not the anti-inflammatory cytokine IL10, are moderated in the presence of ie1. The ie1-mediated inhibition of TNFa production has a similar quantitative phenotype profile in infection of susceptible (BALB/c) and resistant (C57BL/6) mouse strains as well as in a severe immuno-ablative model of infection. In vitro experiments with infected macrophages reveal that deletion of ie1 results in increased sensitivity of viral replication to TNFa inhibition. However, in vivo infection studies show that genetic ablation of TNFa or TNFRp55 receptor is not sufficient to rescue the restricted replication phenotype of the ie1 mutant virus. These results provide, for the first time, evidence for a role of IE1 as a regulator of the pro-inflammatory response and demonstrate a specific pathogen gene capable of moderating the host production of TNFa in vivo. Citation: Rodríguez-Martín S, Kropp KA, Wilhelmi V, Lisnic VJ, Hsieh WY, et al. (2012) Ablation of the Regulatory IE1 Protein of Murine Cytomegalovirus Alters In Vivo Pro-inflammatory TNF-alpha Production during Acute Infection. PLoS Pathog 8(8): e1002901.

Citation

Rodríguez-Martín, S., Kropp, K. A., Wilhelmi, V., Lisnic, V. J., Hsieh, W. Y., Blanc, M., Livingston, A., Busche, A., Tekotte, H., Messerle, M., Auer, M., Fraser, I., Jonjic, S., Angulo, A., Reddehase, M. J., Ghazal, P., & Britt, W. J. (2012). Ablation of the Regulatory IE1 Protein of Murine Cytomegalovirus Alters In Vivo Pro-inflammatory TNF-alpha Production during Acute Infection. PLOS Pathogens, 8(8), Article e1002901. https://doi.org/10.1371/journal.ppat.1002901

• Journal Article Type: Article
• Acceptance Date: Jul 27, 2012
• Online Publication Date: Aug 30, 2012
• Publication Date: 2012
• Deposit Date: Feb 14, 2025
• Publicly Available Date: Feb 14, 2025
• Journal: PLoS Pathogens
• Print ISSN: 1553-7366
• Electronic ISSN: 1553-7374
• Publisher: Public Library of Science
• Peer Reviewed: Peer Reviewed
• Volume: 8
• Issue: 8
• Article Number: e1002901
• DOI: https://doi.org/10.1371/journal.ppat.1002901
• Public URL: http://researchrepository.napier.ac.uk/Output/4119463