Human cytomegalovirus (HCMV) causes severe disease in immunocompromised hosts, as well as in immunocompetent hosts. HCMV disease involves multiple organ systems, thus an essential feature of infections is the hematogenous dissemination of the virus. We recently provided evidence that monocytes and macrophages are principal cell types responsible for viral spread and life-long persistence. Our data suggest the following model for viral spread. Monocytes are infected in the blood, although not productively at the time of initial infection, and are induced by viral binding to cognate receptors to extravasate into various tissues. There they differentiate into long-lived macrophages, which support replication of the original virus, allowing for viral persistence in target organs. The ability to drive monocyte extravasation and monocyte-to-macrophage differentiation appears to be an essential function of HCMV. Our results are supported by clinical evidence, suggesting that the strategy of utilizing monocytes and macrophages for viral dissemination and persistence links HCMV infection to viral-mediated pathogenesis. How does HCMV influence monocyte function and force the infected monocyte to serve as Trojan Horses for hematogenous spread? Our new data show that viral binding is the key biological trigger for the changes in monocytes during infection. Viral binding to cognate cellular receptors on monocytes allows for the successful manipulation of the host-signaling pathways that serve as essential molecular determinants for viral dissemination. With the recent identification of HCMV receptors on fibroblasts (the epidermal growth factor receptor (EGFR) and cellular integrins), along with our new data showing that EGFR and integrins are bona fide receptors on monocytes that link viral binding to the unique functional changes in monocytes, we are now poised to decipher mechanisms by which HCMV manipulates monocyte function. We hypothesize that a unique combination of HCMV-mediated receptor/ligand interactions triggers distinct and specific changes in infected monocytes that promote viral persistence. To test our hypothesis, we will examine if HCMV glycoprotein binding to monocytes and macrophages functionally triggers biological changes;investigate the HCMV-signal-mediated transcriptome in monocytes and macrophages;and, determine the cellular mechanisms by which viral-mediated signaling promotes monocyte motility and survival. The results from this study will provide new insight into the mechanisms by which HCMV infection initiates unique molecular changes in infected monocytes and into the underlying causes of HCMV pathogenesis, as well as identify new potential targets for therapeutic intervention.

Public Health Relevance

Human cytomegalovirus causes severe disease in congenitally infected infants, in transplant and AIDS patients, and is considered a strong risk factor for the development and severity of cardiovascular diseases. By defining the mechanisms of viral spread within the host and how the virus establishes life-long persistence, we provide fundamental insight into the underlying viral pathogenesis, as well as open up new potential targets for therapeutic or pharmacological intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056077-09
Application #
8507128
Study Section
Virology - B Study Section (VIRB)
Program Officer
Beisel, Christopher E
Project Start
2003-07-01
Project End
2014-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
9
Fiscal Year
2013
Total Cost
$337,425
Indirect Cost
$107,101
Name
Louisiana State University Hsc Shreveport
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Nogalski, Maciej T; Chan, Gary; Stevenson, Emily V et al. (2011) Human cytomegalovirus-regulated paxillin in monocytes links cellular pathogenic motility to the process of viral entry. J Virol 85:1360-9
Khoretonenko, Mikhail V; Leskov, Igor L; Jennings, Stephen R et al. (2010) Cytomegalovirus infection leads to microvascular dysfunction and exacerbates hypercholesterolemia-induced responses. Am J Pathol 177:2134-44
Chan, Gary; Bivins-Smith, Elizabeth R; Smith, M Shane et al. (2009) NF-kappaB and phosphatidylinositol 3-kinase activity mediates the HCMV-induced atypical M1/M2 polarization of monocytes. Virus Res 144:329-33
Chan, Gary; Nogalski, Maciej T; Yurochko, Andrew D (2009) Activation of EGFR on monocytes is required for human cytomegalovirus entry and mediates cellular motility. Proc Natl Acad Sci U S A 106:22369-74
Chan, Gary; Bivins-Smith, Elizabeth R; Smith, M Shane et al. (2008) Transcriptome analysis reveals human cytomegalovirus reprograms monocyte differentiation toward an M1 macrophage. J Immunol 181:698-711
Bentz, Gretchen L; Yurochko, Andrew D (2008) Human CMV infection of endothelial cells induces an angiogenic response through viral binding to EGF receptor and beta1 and beta3 integrins. Proc Natl Acad Sci U S A 105:5531-6
Yurochko, A D (2008) Human cytomegalovirus modulation of signal transduction. Curr Top Microbiol Immunol 325:205-20
Chan, Gary; Bivins-Smith, Elizabeth R; Smith, M Shane et al. (2008) Transcriptome analysis of NF-kappaB- and phosphatidylinositol 3-kinase-regulated genes in human cytomegalovirus-infected monocytes. J Virol 82:1040-6
Nogalski, Maciej T; Podduturi, Jagat P; DeMeritt, Ian B et al. (2007) The human cytomegalovirus virion possesses an activated casein kinase II that allows for the rapid phosphorylation of the inhibitor of NF-kappaB, IkappaBalpha. J Virol 81:5305-14
Smith, M Shane; Bivins-Smith, Elizabeth R; Tilley, A Michael et al. (2007) Roles of phosphatidylinositol 3-kinase and NF-kappaB in human cytomegalovirus-mediated monocyte diapedesis and adhesion: strategy for viral persistence. J Virol 81:7683-94

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