Dengue fever is one of the most important emerging infections across the globe. The goal of this project is to characterize the transcriptional responses of children with dengue fever. The broad objectives are to identify critical features of the protective and pathogenic features of the host response, and to provide a basis for developing novel diagnostic and prognostic tools in humans with dengue fever and other similar illnesses. There are three Specific Aims:
Aim i. Characterization of the relationship between transcriptional response and disease evolution in dengue infection. Genome-wide transcript abundance levels will be measured in peripheral blood mononuclear cell (PBMC) samples collected from children diagnosed with dengue fever in Managua, Nicaragua. We will evaluate the clinical and laboratory features associated with inter-individual variation in gene expression, and determine the relationship between transcriptional profiles and WHO staging criteria. Analysis of sequential samples will provide important information about the relative stability of clinically relevant expression signatures, and help to identify temporal trends in associated biological processes.
Aim 2. Identification of a gene set for predicting Dengue Hemorrhagic Fever/Dengue Shock Syndrome. The ability to distinguish children destined to develop DHF/DSS from those who are destined to have a benign course of infection is a critical unmet clinical need. We will identify a set of genes whose corresponding transcript abundance pattern predicts the clinical evolution of acute dengue infection. An important feature of this work will be the use of samples collected over a separate dengue season as an independent test set for validation.
Aim 3. Classification of dengue fever and dengue-like illnesses using transcription profiles. Genome-wide transcript abundance will be measured in patients who are evaluated for dengue fever because of similarities in clinical presentation, but are found not to have dengue. Comparison of expression profiles from those with and without dengue will lead to the identification of host response features that are dengue-specific, and those that are conserved among many infections. This work will identify markers that can be used to improve the diagnosis of dengue fever and other diseases that mimic dengue.

Public Health Relevance

Dengue fever (DF) and its dreaded complications, Dengue Hemorrhagic Fever (DHF) and Dengue Shock Syndrome (DSS), have become the most important mosquito-borne viral diseases in the world. Unfortunately, we do not adequately understand the disease mechanisms, and are unable to predict during the early phase of the illness?when interventions are most effective?which patients are destined to develop DHF/DSS. The proposed work will lead to novel diagnostic and prognostic tools, and an improved understanding of this disease, with the goal of managing patients more effectively.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI065359-09
Application #
8462539
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$194,510
Indirect Cost
$18,941
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Waggoner, Jesse J; Gresh, Lionel; Mohamed-Hadley, Alisha et al. (2016) Single-Reaction Multiplex Reverse Transcription PCR for Detection of Zika, Chikungunya, and Dengue Viruses. Emerg Infect Dis 22:1295-7
Ziegler, Christopher M; Eisenhauer, Philip; Bruce, Emily A et al. (2016) The Lymphocytic Choriomeningitis Virus Matrix Protein PPXY Late Domain Drives the Production of Defective Interfering Particles. PLoS Pathog 12:e1005501
Barbour, Alan G (2016) Infection resistance and tolerance in Peromyscus spp., natural reservoirs of microbes that are virulent for humans. Semin Cell Dev Biol :
Park, Arnold; Yun, Tatyana; Hill, Terence E et al. (2016) Optimized P2A for reporter gene insertion into Nipah virus results in efficient ribosomal skipping and wild-type lethality. J Gen Virol 97:839-43
Levin, Mattias; King, Jasmine J; Glanville, Jacob et al. (2016) Persistence and evolution of allergen-specific IgE repertoires during subcutaneous specific immunotherapy. J Allergy Clin Immunol 137:1535-44
Chomel, Bruno B; Molia, Sophie; Kasten, Rickie W et al. (2016) Isolation of Bartonella henselae and Two New Bartonella Subspecies, Bartonellakoehlerae Subspecies boulouisii subsp. nov. and Bartonella koehlerae Subspecies bothieri subsp. nov. from Free-Ranging Californian Mountain Lions and Bobcats. PLoS One 11:e0148299
Kern, Aurelie; Zhou, Chensheng W; Jia, Feng et al. (2016) Live-vaccinia virus encapsulation in pH-sensitive polymer increases safety of a reservoir-targeted Lyme disease vaccine by targeting gastrointestinal release. Vaccine 34:4507-13
Zeltina, Antra; Bowden, Thomas A; Lee, Benhur (2016) Emerging Paramyxoviruses: Receptor Tropism and Zoonotic Potential. PLoS Pathog 12:e1005390
Waggoner, Jesse J; Ballesteros, Gabriela; Gresh, Lionel et al. (2016) Clinical evaluation of a single-reaction real-time RT-PCR for pan-dengue and chikungunya virus detection. J Clin Virol 78:57-61
Sanman, Laura E; Qian, Yu; Eisele, Nicholas A et al. (2016) Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. Elife 5:e13663

Showing the most recent 10 out of 434 publications