Faculty Collaboration Database

Wnt modulating agents inhibit human cytomegalovirus replication. Antimicrob Agents Chemother 2013 Jun;57(6):2761-7

Date

04/11/2013

Pubmed ID

23571549

Pubmed Central ID

PMC3716142

DOI

10.1128/AAC.00029-13

Scopus ID

2-s2.0-84877863281 (requires institutional sign-in at Scopus site)   44 Citations

Abstract

Infection with human cytomegalovirus (HCMV) continues to be a threat for pregnant women and immunocompromised hosts. Although limited anti-HCMV therapies are available, development of new agents is desired. The Wnt signaling pathway plays a critical role in embryonic and cancer stem cell development and is targeted by gammaherpesviruses, Epstein-Barr virus (EBV), and Kaposi's sarcoma-associated herpesvirus (KSHV). HCMV infects stem cells, including neural progenitor cells, during embryogenesis. To investigate the role of Wnt in HCMV replication in vitro, we tested monensin, nigericin, and salinomycin, compounds that inhibit cancer stem cell growth by modulating the Wnt pathway. These compounds inhibited the replication of HCMV Towne and a clinical isolate. Inhibition occurred prior to DNA replication but persisted throughout the full replication cycle. There was a significant decrease in expression of IE2, UL44, and pp65 proteins. HCMV infection resulted in a significant and sustained decrease in expression of phosphorylated and total lipoprotein receptor-related protein 6 (pLRP6 and LRP6, respectively), Wnt 5a/b, and β-catenin and a modest decrease in Dvl2/3, while levels of the negative regulator axin 1 were increased. Nigericin decreased the expression of pLRP6, LRP6, axin 1, and Wnt 5a/b in noninfected and HCMV-infected cells. For all three compounds, a correlation was found between expression levels of Wnt 5a/b and axin 1 and HCMV inhibition. The decrease in Wnt 5a/b and axin 1 expression was more significant in HCMV-infected cells than noninfected cells. These data illustrate the complex effects of HCMV on the Wnt pathway and the fine balance between Wnt and HCMV, resulting in abrogation of HCMV replication. Additional studies are required to elucidate how HCMV targets Wnt for its benefit.

Author List

Kapoor A, He R, Venkatadri R, Forman M, Arav-Boger R

Author

Ravit Boger MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antiviral Agents
Cell Line, Tumor
Cells, Cultured
Cytomegalovirus
Fibroblasts
Humans
Microbial Sensitivity Tests
Monensin
Nigericin
Pyrans
Vero Cells
Virus Replication
Wnt Signaling Pathway