Modulation of lung inflammation by the Epstein-Barr virus protein Zta.
Several studies have implicated gamma-herpesviruses, particularly Epstein-Barr virus (EBV), in the progression of idiopathic pulmonary fibrosis. The data presented here examine the possible role that EBV plays in the potentiation of this disease by evaluating the pulmonary response to expression of the EBV lytic transactivator protein Zta. Expression of Zta in the lungs of mice via adenovirus-mediated delivery (Adv-Zta) produced profibrogenic inflammation that appeared most pronounced by day 7 postexposure. Relative to mice exposed to control GFP-expressing adenovirus (Adv-GFP), mice exposed to Adv-Zta displayed evidence of lung injury and a large increase in inflammatory cells, predominantly neutrophils, recovered by bronchoalveolar lavage (BAL). Cytokine and mRNA profiling of the BAL fluid and cells recovered from Adv-Zta-treated mice revealed a Th2 and Th17 bias. mRNA profiles from Adv-Zta-infected lung epithelial cells revealed consistent induction of mRNAs encoding Th2 cytokines. Coexpression in transient assays of wild-type Zta, but not a DNA-binding-defective mutant Zta, activated expression of the IL-13 promoter in lung epithelial cells, and detection of IL-13 in Adv-Zta-treated mice correlated with expression of Zta. Induction of Th2 cytokines in Zta-expressing mice corresponded with alternative activation of macrophages. In cell culture and in mice, Zta repressed lung epithelial cell markers. Despite the profibrogenic character at day 7, the inflammation resolves by 28 days postexposure to Adv-Zta without evidence of fibrosis. These observations indicate that the EBV lytic transactivator protein Zta displays activity consistent with a pathogenic role in pulmonary fibrosis associated with herpesvirus infection.
Guenther
James F
JF
Dept. of Pathology, Tulane Univ. Health Sciences Center, New Orleans, LA 70112, USA.
Cameron
Jennifer E
JE
Nguyen
Hong T
HT
Wang
Yu
Y
Sullivan
Deborah E
DE
Shan
Bin
B
Lasky
Joseph A
JA
Flemington
Erik K
EK
Morris
Gilbert F
GF
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D008262:Macrophage Activation; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000276:immunology / Q000473:pathology / Q000821:virology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
C063676:BZLF1 protein, Herpesvirus 4, Human; D015415:Biomarkers; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators
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