The morbidity and mortality of viral hemorrhagic fevers are largely caused by vascular leakage and its ensuing complications. The mechanisms that lead to the vascular leakage have not been well characterized. This project will pursue the hypothesis that dengue and hantavirus-induced vascular leakage is caused by a temporal and differential responsiveness of virus-stimulated endothelium to T-cell derived inflammatory and angiogenic mediators.
The first aim will delineate the early innate immune signaling pathways activated in virus-stimulated human microvascular endothelial cells that lead to Type I IFN production. Type I IFN mediates the enhancement of endothelial barrier function and anti-angiogenic effects. Barrier function will be assessed by measuring the permeability of human microvascular endothelial monolayers to macromolecules (70 kDa dextran) and small molecule solutes (3 kDa dextran) in a transwell assay system. Early angiogenic effects on human microvascular endothelium will be measured by a cell/matrix invasion assay.
The second aim will delineate key anti-viral T-cell responses and phenotypes that interact with endothelium and lead to augmented permeability. Dengue virus and hantavirus-specific CD4+ and CD8+ T-cells will be activated under a variety of conditions and examined for their abilities to modulate vascular endothelial growth factor signaling, permeability, and cell invasion in the in vitro assays noted above.
The third aim will measure inflammatory and angiogenic markers in blood samples from patients with hantavirus infections. Multiplex protein immunoassays for selected biomarkers will be performed on serial daily plasma and urine samples collected from patients with Puumala virus (Old World hantavirus) infections. The objective is to develop a biomarker """"""""angiogenic profile"""""""" that can predict disease severity and development of vascular leakage. The effects of this """"""""angiogenic profile"""""""" on virus-infected microvascular endothelium permeability will be tested in vitro. A better understanding of vascular leakage in dengue and hantavirus hemorrhagic fever pathogenesis will lead to new diagnostic, therapeutic, and preventive approaches to these pathogens.

Public Health Relevance

Severe disease caused by hemorrhagic fever viruses, such as the dengue viruses and hantaviruses, is largely driven by a rapid leakage of plasma across blood vessels. This project will delineate the complex human immune system interactions that produce this vascular leakage. Novel diagnostic, therapeutic, and preventive approaches to these biodefense viral pathogens will arise by better understanding the mRnhanisms underlying vascular leakanp in viral hfimnrrhanir: fevers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI057319-10
Application #
8452141
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$327,892
Indirect Cost
$122,902
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Mathew, Anuja (2017) Humanized mouse models to study human cell-mediated and humoral responses to dengue virus. Curr Opin Virol 25:76-80
Ramirez, Alejandro; Co, Mary; Mathew, Anuja (2016) CpG Improves Influenza Vaccine Efficacy in Young Adult but Not Aged Mice. PLoS One 11:e0150425
Townsley, E; O'Connor, G; Cosgrove, C et al. (2016) Interaction of a dengue virus NS1-derived peptide with the inhibitory receptor KIR3DL1 on natural killer cells. Clin Exp Immunol 183:419-30
Woda, Marcia; Friberg, Heather; Currier, Jeffrey R et al. (2016) Dynamics of Dengue Virus (DENV)-Specific B Cells in the Response to DENV Serotype 1 Infections, Using Flow Cytometry With Labeled Virions. J Infect Dis 214:1001-9
Tervo, Laura; Mäkelä, Satu; Syrjänen, Jaana et al. (2015) Smoking is associated with aggravated kidney injury in Puumala hantavirus-induced haemorrhagic fever with renal syndrome. Nephrol Dial Transplant 30:1693-8
Woda, Marcia; Mathew, Anuja (2015) Fluorescently labeled dengue viruses as probes to identify antigen-specific memory B cells by multiparametric flow cytometry. J Immunol Methods 416:167-77
Becerra-Artiles, Aniuska; Dominguez-Amorocho, Omar; Stern, Lawrence J et al. (2015) A Simple Proteomics-Based Approach to Identification of Immunodominant Antigens from a Complex Pathogen: Application to the CD4 T Cell Response against Human Herpesvirus 6B. PLoS One 10:e0142871
Jaiswal, Smita; Smith, Kenneth; Ramirez, Alejandro et al. (2015) Dengue virus infection induces broadly cross-reactive human IgM antibodies that recognize intact virions in humanized BLT-NSG mice. Exp Biol Med (Maywood) 240:67-78
Co, Mary Dawn T; Terajima, Masanori; Thomas, Stephen J et al. (2014) Relationship of preexisting influenza hemagglutination inhibition, complement-dependent lytic, and antibody-dependent cellular cytotoxicity antibodies to the development of clinical illness in a prospective study of A(H1N1)pdm09 Influenza in children. Viral Immunol 27:375-82
Terajima, Masanori; Co, Mary Dawn T; Ennis, Francis A (2014) Age and different influenza viruses. Lancet Infect Dis 14:101

Showing the most recent 10 out of 109 publications