Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses

Phillip D. Smith, Masako Shimamura, Lois C. Musgrove, Evida A. Dennis, Diane Bimczok, Lea Novak, Mary Ballestas, Anne Fenton, Satya Dandekar, William J. Britt, Lesley E. Smythies

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Circulating monocytes carrying human CMV (HCMV) migrate into tissues, where they differentiate into HCMV-infected resident macrophages that upon interaction with bacterial products may potentiate tissue inflammation. In this study, we investigated the mechanism by which HCMV promotes macrophage-orchestrated inflammation using a clinical isolate of HCMV (TR) and macrophages derived from primary human monocytes. HCMV infection of the macrophages, which was associated with viral DNA replication, significantly enhanced TNF-α, IL-6, and IL-8 gene expression and protein production in response to TLR4 ligand (LPS) stimulation compared with mock-infected LPS-stimulated macrophages during a 6-d in vitro infection. HCMV infection also potentiated TLR5 ligand-stimulated cytokine production. To elucidate the mechanism by which HCMV infection potentiated inducible macrophage responses, we show that infection by HCMV promoted the maintenance of surface CD14 and TLR4 and TLR5, which declined over time in mock-infected macrophages, and enhanced both the intracellular expression of adaptor protein MyD88 and the inducible phosphorylation of IκBα and NF-κB. These findings provide additional information toward elucidating the mechanism by which HCMV potentiates bacteria-induced NF-κB-mediated macrophage inflammatory responses, thereby enhancing organ inflammation in HCMV-infected tissues.

Original languageEnglish (US)
Pages (from-to)5604-5612
Number of pages9
JournalJournal of Immunology
Volume193
Issue number11
DOIs
StatePublished - Dec 1 2014

ASJC Scopus subject areas

  • Immunology

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    Smith, P. D., Shimamura, M., Musgrove, L. C., Dennis, E. A., Bimczok, D., Novak, L., Ballestas, M., Fenton, A., Dandekar, S., Britt, W. J., & Smythies, L. E. (2014). Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses. Journal of Immunology, 193(11), 5604-5612. https://doi.org/10.4049/jimmunol.1302608