title: Gene control of tyrosine kinase TIE2 and vascular manifestations of infections.
abstract: Ligands of the endothelial-enriched tunica interna endothelial cell kinase 2 (Tie2) are markedly imbalanced in severe infections associated with vascular leakage, yet regulation of the receptor itself has been understudied in this context. Here, we show that TIE2 gene expression may constitute a novel vascular barrier control mechanism in diverse infections. Tie2 expression declined rapidly in wide-ranging models of leak-associated infections, including anthrax, influenza, malaria, and sepsis. Forced Tie2 suppression sufficed to attenuate barrier function and sensitize endothelium to permeability mediators. Rapid reduction of pulmonary Tie2 in otherwise healthy animals attenuated downstream kinase signaling to the barrier effector vascular endothelial (VE)-cadherin and induced vascular leakage. Compared with wild-type littermates, mice possessing one allele of Tie2 suffered more severe vascular leakage and higher mortality in two different sepsis models. Common genetic variants that influence TIE2 expression were then sought in the HapMap3 cohort. Remarkably, each of the three strongest predicted cis-acting SNPs in HapMap3 was also associated with the risk of acute respiratory distress syndrome (ARDS) in an intensive care unit cohort of 1,614 subjects. The haplotype associated with the highest TIE2 expression conferred a 28% reduction in the risk of ARDS independent of other major clinical variables, including disease severity. In contrast, the most common haplotype was associated with both the lowest TIE2 expression and 31% higher ARDS risk. Together, the results implicate common genetic variation at the TIE2 locus as a determinant of vascular leak-related clinical outcomes from common infections, suggesting new tools to identify individuals at unusual risk for deleterious complications of infection.
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; cghosh@bidmc.harvard.edu sparikh1@bidmc.harvard.edu.
authors.forename: Chandra C
authors.initials: CC
authors.lastname: Ghosh
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; Division of Hypertension and Nephrology, Hannover Medical School, 30625 Hannover, Germany;
authors.forename: Sascha
authors.initials: S
authors.lastname: David
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston MA 02114; Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Ruyang
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors.forename: Anthony
authors.initials: A
authors.lastname: Berghelli
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors.forename: Katelyn
authors.initials: K
authors.lastname: Milam
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; Sandra Rotman Centre for Global Health, University Health Network and Department of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A1;
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Higgins
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors.forename: Jon
authors.initials: J
authors.lastname: Hunter
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors.forename: Aditi
authors.initials: A
authors.lastname: Mukherjee
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston MA 02114; Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Yongyue
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors.forename: Mei
authors.initials: M
authors.lastname: Tran
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Freeman
authors.initials: F
authors.lastname: Suber
authors.affiliation: Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.affiliation: Sandra Rotman Centre for Global Health, University Health Network and Department of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A1;
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Kain
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors.forename: Shulin
authors.initials: S
authors.lastname: Lu
authors.affiliation: Silence Therapeutics GmbH, 13125 Berlin, Germany;
authors.forename: Ansgar
authors.initials: A
authors.lastname: Santel
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215;
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Yano
authors.affiliation: Roger Williams Medical Center, Providence, RI 02908;
authors.forename: Prajna
authors.initials: P
authors.lastname: Guha
authors.affiliation: Sunnybrook Institute, University of Toronto, Toronto, ON, Canada M4N 3M5.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Dumont
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital and Harvard Medical School, Boston MA 02114; Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115;
authors.forename: David C
authors.initials: DC
authors.lastname: Christiani
authors.affiliation: Center for Vascular Biology Research and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215; cghosh@bidmc.harvard.edu sparikh1@bidmc.harvard.edu.
authors.forename: Samir M
authors.initials: SM
authors.lastname: Parikh
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D004730:Endothelium, Vascular / Q000503:physiopathology; D007239:Infections / Q000503:physiopathology*; D051379:Mice; D042787:Receptor, TIE-2 / Q000235:genetics*
chemical_list: D042787:Receptor, TIE-2; C079086:Tek protein, mouse
keywords: Tie2; angiopoietin; endothelium; infection; permeability