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.
Highlights
Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS, called HPS) which can collectively cause over 100,000 cases per annum worldwide [1,2,3,4,5]
We found that plasma samples from patients with acute Hantavirus Cardiopulmonary Syndrome (HCPS) induce loss of cell barrier function in confluent epithelial and endothelial cell monolayers grown in Electric Cell-substrate Impedance Sensing (ECIS) cultureware
When cells are exposed to HCPS patient plasma, the accompanying changes in cell morphology such as loss of cell barrier function are measured as drops in resistance over time
Summary
Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS, called HPS) which can collectively cause over 100,000 cases per annum worldwide [1,2,3,4,5]. After entry of SNV through inhalation, infected individuals experience an asymptomatic incubation period of one to six weeks, followed by a period of prodromal illness including headache, nausea, vomiting, myalgias and fever. This is followed by profound dyspnea and shortness of breath due to noncardiogenic pulmonary edema (capillary leak) [3]. We found that plasma samples from patients with acute HCPS induce loss of cell barrier function in confluent epithelial and endothelial cell monolayers grown in ECIS cultureware. We suggest that the extremely high levels of PAI-1 might be a response to the severe pathology, where PAI-1 is expected to limit plasminogen activation and possibly thrombin activity in terminal-case patients [16,17,18]
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