title: Elevated cytokines, thrombin and PAI-1 in severe HCPS patients due to Sin Nombre virus.
abstract: Sin Nombre Hantavirus (SNV, Bunyaviridae Hantavirus) is a Category A pathogen that causes Hantavirus Cardiopulmonary Syndrome (HCPS) with case fatality ratios generally ranging from 30% to 50%. HCPS is characterized by vascular leakage due to dysregulation of the endothelial barrier function. The loss of vascular integrity results in non-cardiogenic pulmonary edema, shock, multi-organ failure and death. Using Electric Cell-substrate Impedance Sensing (ECIS) measurements, we found that plasma samples drawn from University of New Mexico Hospital patients with serologically-confirmed HCPS, induce loss of cell-cell adhesion in confluent epithelial and endothelial cell monolayers grown in ECIS cultureware. We show that the loss of cell-cell adhesion is sensitive to both thrombin and plasmin inhibitors in mild cases, and to thrombin only inhibition in severe cases, suggesting an increasing prothrombotic state with disease severity. A proteomic profile (2D gel electrophoresis and mass spectrometry) of HCPS plasma samples in our cohort revealed robust antifibrinolytic activity among terminal case patients. The prothrombotic activity is highlighted by acute ≥30 to >100 fold increases in active plasminogen activator inhibitor (PAI-1) which, preceded death of the subjects within 48 h. Taken together, this suggests that PAI-1 might be a response to the severe pathology as it is expected to reduce plasmin activity and possibly thrombin activity in the terminal patients.
authors: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. vbondu@salud.unm.edu.
authors: Virginie
authors: V
authors: Bondu
authors: Clinical and Translational Science Center, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. rschrader@salud.unm.edu.
authors: Ron
authors: R
authors: Schrader
authors: Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10031, USA. mag4@columbia.edu.
authors: Mary Ann
authors: MA
authors: Gawinowicz
authors: Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. pmcguire@salud.unm.edu.
authors: Paul
authors: P
authors: McGuire
authors: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109-5644, USA. dlawrenc@med.umich.edu.
authors: Daniel A
authors: DA
authors: Lawrence
authors: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. bhjelle@salud.unm.edu.
authors: Brian
authors: B
authors: Hjelle
authors: Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA. buranda@unm.edu.
authors: Tione
authors: T
authors: Buranda
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002522:Chlorocebus aethiops; D016207:Cytokines / Q000097:blood*; D003588:Cytopathogenic Effect, Viral; D042783:Endothelial Cells / Q000378:metabolism / Q000821:virology; D018804:Hantavirus Pulmonary Syndrome / Q000097:blood* / Q000175:diagnosis / Q000276:immunology / Q000821:virology*; D006801:Humans; D008954:Models, Biological; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D020543:Proteome; D040901:Proteomics / Q000379:methods; D012189:Retrospective Studies; D012720:Severity of Illness Index; D029261:Sin Nombre virus / Q000502:physiology*; D013917:Thrombin / Q000378:metabolism*; D014709:Vero Cells
chemical_list: D001798:Blood Proteins; D016207:Cytokines; D017395:Plasminogen Activator Inhibitor 1; D020543:Proteome; D013917:Thrombin