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Principal Investigator: Sina A Gharib
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2021
Award: $758,287
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Melioidosis, a tropical infection commonly manifesting as acute pneumonia and sepsis in humans, is caused
by the Gram-negative Tier 1 select agent Burkholderia pseudomallei and represents a global public health
threat with an estimated 165,000 cases and 89,000 deaths annually worldwide (an overall mortality rate of
54%). Unfortunately numerous barriers exist to decreasing the burden of melioidosis including lack of an
effective vaccine, difficulty diagnosing and identifying high-risk patients, and challenges in treatment due to
extensive antimicrobial resistance of B. pseudomallei and lack of targeted immunotherapies. While work to
date spotlights the promise of the application of advanced technologies to melioidosis and identifies several
targets for further study, an incomplete understanding of the pathogenic mechanisms underlying host
susceptibility and outcome impedes efforts to prevent, diagnose, risk-stratify and treat this infection. The
overall hypothesis of this project is that by generating and integrating a rich compendium of multidimensional
data – transcriptomic, proteomic, and metabolomic – from circulating immune cells and blood of patients with
melioidosis and selected controls, it is possible to identify fundamental biological pathways and processes
activated during melioidosis. Such comprehensive data, complemented by targeted in vitro experiments, are
desperately needed to inform the design of vaccines, diagnostics, prognostics and therapeutics to combat this
infectious threat. This hypothesis will be tested in the following aims: 1) Identify biological pathways that
distinguish melioidosis from other causes of sepsis; 2) Define biological processes and develop prognostic
signatures that predict death in melioidosis; and 3) Validate the function of key genes and pathways in human
cells infected with B. pseudomallei in vitro. This application leverages the investigators’ scientific and clinical
expertise in melioidosis, cutting edge bioinformatics capacity in transcriptomics, proteomics, and metabolomics
both as independent domains and integrated together, and a rich clinical and biological dataset of over 5,000
septic patients due to melioidosis or to other infections. The successful completion of this project will yield an
unprecedented granular overview of mechanisms leading to melioidosis and the molecular signatures
associated with clinical outcomes, while also providing a unique resource to the scientific community to guide
further research into this important but neglected disease.
Terms: <Acute Pneumonia><Address><Antimicrobial Resistance><Antimicrobial resistant><B pseudomallei><B. pseudomallei><Bacteria><Bacterial Infections><Bio-Informatics><Bioinformatics><Biological><Biological Function><Biological Process><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood leukocyte><Blood specimen><Burkholderia pseudomallei><Candidate Disease Gene><Candidate Gene><Cell Body><Cells><Cessation of life><Clinical><Collaborations><Communities><Complement><Complement Proteins><Data><Data Set><Dataset><Death><Development><Diagnosis><Diagnostic><Disease><Disorder><Early identification><Environmental Exposure><Exposure to><Gene Transcription><Genes><Genetic Determinism><Genetic Diversity><Genetic Transcription><Genetic Variation><Host Defense Mechanism><Human><Human Genetics><Immune><Immune mediated therapy><Immune response><Immunes><Immunological response><Immunologically Directed Therapy><Immunotherapy><In Vitro><Infection><Inflammatory Response><Ingestion><Inhalation><Inhaling><Investigation><Investigators><Knowledge><Leukocytes><Leukocytes Reticuloendothelial System><Marrow leukocyte><Measures><Melioidosis><Messenger RNA><Metabolic Pathway><Micro RNA><MicroRNAs><Modern Man><Molecular><Molecular Fingerprinting><Molecular Profiling><Outcome><P pseudomallei><P. pseudomallei><Pathogenesis><Pathogenicity><Pathway interactions><Patients><Plasma><Plasma Serum><Play><Predisposition><Process><Prognosis><Proteins><Proteomics><Pseudomonas pseudomallei><Public Health><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Research><Research Personnel><Research Resources><Researchers><Resistance to antimicrobial><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Role><Sepsis><Soil><Susceptibility><Technology><Testing><Therapeutic><Transcription><Vaccine Design><Vaccines><White Blood Cells><White Cell><Work><adverse consequence><adverse outcome><anti-microbial resistance><anti-microbial resistant><aptamer><bacteria infection><bacterial disease><base><blood infection><bloodstream infection><combat><computational framework><computer framework><develop a vaccine><development of a vaccine><developmental><differential expression><differentially expressed><exome sequencing><exome-seq><experience><experiment><experimental research><experimental study><genetic determinant><high dimensional data><high risk><host response><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunoresponse><improved><in vitro Assay><in vivo Model><innovate><innovation><innovative><interest><mRNA><metabolism measurement><metabolomics><metabonomics><miRNA><miRNAs><molecular profile><molecular signature><mortality><multidimensional data><multidimensional datasets><multiomics><multiple omics><neglect><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next generation><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapy target><pathway><peripheral blood><predictive signature><prevent><preventing><prognostic><prognostic profile><prognostic signature><resistance to anti-microbial><resistant to anti-microbial><resistant to antimicrobial><risk stratification><sepsis patients><septic patients><social role><stratify risk><tool><transcriptional differences><transcriptome sequencing><transcriptomics><vaccine development><vaccine formulation><white blood cell><white blood corpuscle>