Human adenovirus modulates surfactant phospholipid trafficking.
Surfactant, highly enriched with phosphatidylcholine (PC), is secreted into the airspace by a classic apical secretory route, thereby maintaining lung stability. Herein, we show that adenoviral infection decreases surfactant PC in lungs by inhibiting its apical secretion and redirecting its export in alveolar cells by a basolateral route. These effects were not observed with replication-deficient adenovirus (Ad), specifically lacking early region 1 (E1) gene products. Adenoviral stimulation of basolateral PC export from cells was not observed after pharmacologic inhibition of ATP-binding cassette proteins, after introduction of small interfering RNA to the lipid pump ATP-binding cassette transporter A1 (ABCA1) or in ABCA1-defective human Tangier disease fibroblasts. Adenovirus and its E1A gene product increased ABCA1 levels by transcriptionally activating the ABCA1 gene. Thus, Ad lowers surfactant, in part, by triggering ABCA1-directed basolateral PC export, thereby limiting the cellular pool of surfactant PC destined for apical secretion. The results support a novel pathway, whereby a viral pathogen disrupts surfactant trafficking.
Miakotina
Olga L
OL
Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
McCoy
Diann M
DM
Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
Shi
Lei
L
Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
Look
Dwight C
DC
Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
Mallampalli
Rama K
RK
Department of Internal Medicine, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.|Department of Biochemistry, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.|Department of Veterans Affairs Medical Center, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA 52242, USA.
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry; D000256:Adenoviridae / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010743:Phospholipids / Q000737:chemistry*; D013501:Surface-Active Agents / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D010743:Phospholipids; D013501:Surface-Active Agents; D000255:Adenosine Triphosphate