Human herpesvirus-8 infection of primary pulmonary microvascular endothelial cells.
Human herpesvirus-8 (HHV-8) is the causative agent of Kaposi's sarcoma and is associated with the angioproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. Evidence of HHV-8 infection within the pulmonary vasculature of patients with idiopathic pulmonary arterial hypertension (IPAH) has been described. We hypothesize that HHV-8 infection of pulmonary microvascular endothelial cells results in an apoptotic-resistant phenotype characteristic of severe pulmonary arterial hypertension. Our objective was to investigate the ability of HHV-8 to infect human pulmonary microvascular endothelial cells in vitro and characterize the phenotypic effect of this infection. Human pulmonary microvascular endothelial cells were exposed to HHV-8 using two methods (direct virus and co-culture technique). The presence of lytic and latent infection was confirmed. Changes in endothelial cell gene and protein expression and effects on cellular apoptosis were measured. HHV-8 can both lytically and latently infect primary human pulmonary microvascular endothelial cells in vitro. HHV-8 infection results in significant changes in gene expression, including alterations of pathways important to cellular apoptosis. HHV-8 infection also alters expression of genes integral to the bone morphogenic protein pathway, including down-regulation of bone morphogenic protein-4. Other genes previously implicated in the development of PAH are affected by HHV-8 infection, and cells infected with HHV-8 are resistant to apoptosis.
Bull
Todd M
TM
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Denver Health Sciences Center, Denver, Colorado 80207, USA. Todd.Bull@uchsc.edu
Meadows
Christina A
CA
Coldren
Christopher D
CD
Moore
Mark
M
Sotto-Santiago
Sylk M
SM
Nana-Sinkam
Serge P
SP
Campbell
Thomas B
TB
Geraci
Mark W
MW
D017209:Apoptosis / Q000187:drug effects; D001808:Blood Vessels / Q000166:cytology* / Q000201:enzymology / Q000821:virology*; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000187:drug effects; D006566:Herpesviridae Infections / Q000378:metabolism*; D019288:Herpesvirus 8, Human; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D053148:Caspase 3; D053179:Caspase 7; D017077:Culture Media, Conditioned; D015850:Interleukin-6; D000099176:Noggin Protein